| 1. |
- Carlsson, Carina, et al.
(författare)
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Olfactory mucosal toxicity screening and multivariate QSAR modeling for chlorinated benzene derivatives
- 2004
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 78:12, s. 706-715
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Tidskriftsartikel (refereegranskat)abstract
- The olfactory mucosa (OM) is an important target for metabolism-dependent toxicity of drugs and chemicals. Several OM toxicants share a 2,6-dichlorinated benzene structure. The herbicides dichlobenil (2,6-dichlorobenzonitrile) and chlorthiamide (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide all induce toxicity in the OM following covalent binding in the Bowmans glands. In addition, we have shown that 2,6-dichlorophenyl methylsulfone targets the Bowmans glands and is probably the most potent OM toxicant so far described. These findings suggest that the 2,6-positioning of chlorines in combination with an electron-withdrawing group in the primary position of the benzene ring is an arrangement that facilitates OM toxicity. This study examined the physicochemical characteristics of the 2,6-dichlorinated OM toxicants. A number of 2,6-dichlorinated benzene derivatives with various types of substituents in primary position were tested for OM toxicity in mice. In addition, some other 2,6- and 2,5-substituted benzene derivatives were examined. Two novel OM toxicants, 2,6-dichlorobenzaldehyde oxime and 2,6-dichloronitrobenzene, were identified. By the use of partial least squares projection to latent structures with discriminant analysis (PLS-DA) a preliminary quantitative structure-activity relationship (QSAR) model was built also using reported OM toxicity data. Physicochemical properties positively correlated with olfactory mucosal toxicity were identified as molecular dipolar momentum and the electronic properties of the substituent. Inversely correlated descriptors were variables describing the hydrophobicity, electronic properties of the molecule such as electron affinity and the electronic charge on the primary carbon. In conclusion, this preliminary PLS-DA model shows that a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron-withdrawing substituent in the primary position has the potential of being a potent OM toxicant in mice.
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| 2. |
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| 3. |
- Haglund, Peter, et al.
(författare)
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Effects of temperature and flow regulated carbon dioxide cooling in longitudinally modulated cryogenic systems for comprehensive two-dimensional gas chromatography
- 2002
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Ingår i: Journal of Chromatography A. ; 962:1-2, s. 127-34
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Tidskriftsartikel (refereegranskat)abstract
- Two different modes of temperature regulation in longitudinally modulated cryogenic systems (LMCSs) for comprehensive two-dimensional gas chromatography (GC×GC) were compared. Carbon dioxide was used as coolant. In the first mode of operation, the temperature of the trap was regulated to a pre-set temperature using a digital temperature controller (“the constant temperature mode”). In the second, the temperature was regulated to a fixed negative offset to the oven temperature by using a constant flow of CO2 (“the constant flow mode”). A number of problems were occasionally observed using the constant temperature mode: (1) severe band broadening of high boiling analytes in the second dimension; (2) non-Gaussian reconstructed first-dimension peak profiles; (3) high background due to modulation of first-dimension column bleed. It was concluded that these problems were associated with inefficient solute remobilization at low LMCS trap temperatures (1 and 2) or large trap temperature fluctuations (3). These problems could be avoided or significantly reduced by using the constant flow mode. Best results were obtained as the trap temperature was kept about 70 °C below the oven temperature.
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| 4. |
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| 5. |
- Haglund, Peter, et al.
(författare)
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Shape selectivity : A key factor in comprehensive two-dimensional gas chromatographic analysis of toxic PCBs
- 2001
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Ingår i: Journal of Microcolumn Separations. - : Wiley. - 1040-7685 .- 1520-667X. ; 13:7, s. 306-311
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Tidskriftsartikel (refereegranskat)abstract
- A number of toxic planar PCBs, that is, PCB 77, 105, 118, 126, 156, and 169, were successfully separated from other PCB congeners present in technical PCB formulations using comprehensive GC×GC. The planar PCBs were selectively retained using a liquid crystal column, which was used as the first-dimension column. A short and narrow bore (0.25 m×0.1 mm) nonpolar 5%-phenyl-methylpoly-siloxane column was used as the second-dimension column. A longitudinally modulating cryogenic system (LMCS) was used to modulate the first-dimension signal. Since the planar PCBs elute from the first column at relatively high oven temperatures they were rapidly eluted from the second column. Altogether, this resulted in a significant peak sharpening, and a 20-fold increase in the signal-to-noise ratio, as compared to standard one-dimensional GC. This column set also seems to separate seven frequently measured congeners, that is, PCBs 28, 52, 101, 118, 138, 153, and 180, from other major PCB congeners.
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| 6. |
- Harju, Mikael, 1968-
(författare)
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Analysis of PCBs with special emphasis on comprehensive two-dimensional gas chromatography of atropisomers
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are 209 PCB congeners, 136 of which have been found in technical PCB mixtures and hence may be found in the environment as a result of either intentional or unintentional release. The identification and quantification of the congeners are difficult due to analytical bias from coeluting PCBs and other persistent organic pollutants. Among the 209 possible PCB congeners, 19 tri- and tetra-ortho chlorinated congeners exist in stable atropisomeric conformations. The racemization barrier were determined for twelve of the nineteen atropisomers and was found to be between 176-185 kJ × mol-1 and ca. 250 kJ × mol-1 for tri- and tetra-ortho PCB, respectively. Further, a buttressing effect of 6.4 kJ × mol-1 was observed for congeners with vicinal ortho-meta chlorines. Comprehensive two-dimensional gas chromatography (GC×GC) was used to analyze the atropisomers and other PCBs. A Longitudinally Modulated Cryogenic System (LMCS) was used with liquid CO2 as cryogen. The LMCS was optimized for semi-volatile organic substances, primarily PCBs. The trap temperature was shown to be an important factor for the trapping and desorption efficiency, as was the thermal mass of the column used in the modulator region. A number of column sets were tested and the separation efficiency, congener resolution and analysis time was evaluated. Good separation of non- and mono-ortho PCBs and “bulk” PCBs (in a technical PCB) was obtained within 8 min using a smectic liquid crystal column (LC50) as the first and a nonpolar column as the second dimension column. Using a second column, an efficient nonpolar (DB-XLB) column, which separates many PCB congeners, were combined with a polar (cyanopropyl) or shape selective (LC50) second dimension column. As a maximum, 181 of the 209 congeners and 126 of the 136 Aroclor PCBs were resolved. The seven frequently measured PCBs (PCBs 28, 52, 101, 118, 138, 153 and 180) and all WHO-PCBs were separated from all other Aroclor PCBs. Chiral PCBs are released into the environment as racemic mixtures. However, organisms have been shown to enantiomerically enrich many of the atropisomers, suggesting that enantioselective biotransformations occur. Non-racemic PCB enrichment has also been seen in mammalians including humans, which is of particular concern because of the potential health risk. An analytical procedure were therefore developed and used to determine the levels of atropisomeric PCBs, planar-PCBs (WHO-PCBs) and total PCBs in seals with different health status. GC×GC was used to separate the target PCBs from other PCBs and potential interferences. A chiral column (permethylated â-cyclodextrin) was used in combination with a polar or shape selective column and enantiomeric fractions (EFs) were determined for five atropisomeric PCBs, i.e. CBs 91, 95, 132, 149 and 174. Some atropisomers had EF that deviated largely from racemic. The deviation was larger in liver than blubber, indicating enantioselective metabolism. However, there was no selective passage of the studied atropisomeric PCBs across placenta and no selective blood-brain barrier. Similarly, no correlation between EFs and health status was observed, although there was a correlation between total PCBs and health status.
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| 7. |
- Harju, Mikael, et al.
(författare)
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Comprehensive two-dimensional gas chromatography (GC x GC) of atropisomeric PCBs, combining a narrow bore beta-cyclodextrin column and a liquid crystal column
- 2001
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Ingår i: Journal of Microcolumn Separations. - : Wiley. - 1040-7685 .- 1520-667X. ; 13:7, s. 300-305
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Tidskriftsartikel (refereegranskat)abstract
- Peak assignment and quantification of PCBs in environmental samples is a time-consuming and costly process, and the analysis of atropisomeric PCBs is even more laborious and costly due to the elaborate analytical work involved. GC X GC can solve some of the problems entailed by increasing congener resolution and instrument sensitivity. In this study. a comprehensive two-dimensional gas chromatography (GC X GC) system was utilized with a combination of a permethylated beta -cyclodextrin column in the first dimension and a liquid crystal column in the second dimension. Using this system, in a single GC X GC run six out of nine studied atropisomeric PCBs (PCBs 91, 132, 135. 136, 149, and 176) can be resolved, and two (PCBs 84 and 174) can be partially separated from coeluting congeners in a mixture of 144 congeners (the most abundant congeners in technical PCBs). The chiral resolution (Rs) of the enantiomeric pairs ranged between 0.6 and 2.0, with PCB 132 having the highest resolution. Furthermore, the congers that (partially) coelute with enantiomers of PCBs 84, 95, and 174 have low abundance in technical PCB as well as in environmental samples. Thus, all of the nine target PCBs could be separated from significant interfering compounds in a single GC X GC run.
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| 8. |
- Harju, Mikael, et al.
(författare)
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Comprehensive two-dimensional gas chromatography of the 209 polychlorinated biphenyls
- 2003
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Ingår i: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1019:1-2, s. 111-126
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Tidskriftsartikel (refereegranskat)abstract
- Comprehensive two-dimensional gas chromatography (GC×GC) of the 209 polychlorinated biphenyls (CBs) was carried out using a longitudinally modulated cryogenic system (LMCS) and liquid carbon dioxide as cryogen. The effluent from a non-polar column was modulated and further separated on either a polar or a shape-selective second-dimension column. Five GC×GC column combinations were evaluated, with DB-XLB as the first column in each case. DB-XLB separates more congeners than any other GC column currently available. When combined with a biscyanopropyl siloxane (SP-2340 or BPX70) or smectic liquid crystal (LC-50) second-dimension column in a GC×GC system many additional CBs can be separated. In total, 176 and 181 of the 209 congeners were separated (Rs=0.5) on the column combinations DB-XLB/SP-2340 and DB-XLB/LC-50, respectively. Of the 136 CBs present in any Aroclor mixture at concentrations greater than 0.05% (w/w), 126 were resolved using either of these two column combinations. The seven frequently measured CBs 28, 52, 101, 118, 138, 153, 180, and the WHO-PCBs 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169 and 189 were all separated from Aroclor CBs on the DB-XLB/LC-50 column set, whereas CBs 118 and 131 coeluted on the DB-XLB/SP-2340 column set. In addition, three technical CB formulations (Aroclors 1232, 1248 and 1260) and a seal blubber sample (Halichoerus grypus) from the Baltic Sea were analyzed. Similar peak patterns were found for Aroclor 1260 and the CBs in the seal blubber, facilitating use of this technical CB formulation to identify the CBs in the blubber by GC×GC. Individual CBs in environmental samples, such as seal blubber, may be identified semi-automatically by matching the samples GC×GC profiles to a template generated using a standard containing all 209 CBs. Using such a template, 64 CBs were identified in the grey seal blubber sample.
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| 9. |
- Harju, Mikael, et al.
(författare)
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Determination of atropisomeric and planar polychlorinated biphenyls, their enantiomeric fractions and tissue distribution in grey seals using comprehensive 2D gas chromatography
- 2003
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Ingår i: Journal of Chromatography A. - Amsterdam : Elsevier. - 0021-9673 .- 1873-3778. ; 1019:1-2, s. 127-142
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Tidskriftsartikel (refereegranskat)abstract
- High prevalence of uterine occlusions and sterility is found among Baltic ringed and grey seal. Polychlorinated biphenyls (CBs) are suspected to be the main cause. The CB concentrations are higher in affected than in healthy animals, but the natural variation is considerable. Thus, it might be possible to assess the health status of seals by CB analysis. The ratios of chiral compounds (enantiomeric fractions (EFs)) such as atropisomeric CBs are of particular interest, since these may reflect differences in metabolic rates. An analytical procedure was developed and used to determine the levels of atropisomeric CBs, planar-CBs (WHO-PCBs) and total CBs in seals of different health status. Comprehensive 2D gas chromatography (GC×GC) was used to separate the target analytes from other CBs and interferences and a micro electron-capture detector (μECD) was used for detection. EFs of the atropisomeric CBs were difficult to determine as the levels were low and the interferences many. Two column combinations had to be used to avoid biased results—both had a chiral column as first-dimension column. The second-dimension column was coated with either a high-polarity cyanopropyl or a liquid crystal phase. EFs were determined for five atropisomeric CBs, i.e. CBs 91, 95, 132, 149 and 174. The results were verified by GC×GC–time-of-flight mass spectrometry (TOF-MS). Some atropisomeric CBs had EFs that deviated strongly from the racemic-mixture value. The deviations were larger in liver than blubber, which indicates enantioselective metabolism. However, there was no selective passage of the studied atropisomeric CBs across placenta and no selective blood–brain barrier. Similarly, no correlation between EFs and health status was observed, although there was a correlation between the total CB levels and health status.
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| 10. |
- Harju, Mikael, et al.
(författare)
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Multivariate physicochemical characterisation and quantitative structure–property relationship modelling of polybrominated diphenyl ethers
- 2002
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Ingår i: Chemosphere. ; 47:4, s. 375-84
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Tidskriftsartikel (refereegranskat)abstract
- Levels of polybrominated diphenyl ethers (PBDEs) are increasing in the environment and may cause long-term environmental problems. Developing a model describing the chemical variation among the 209 possible congeners would be a useful step in any systematic approach for assessing the fate and risk posed by the PBDEs. Therefore, 40 physicochemical descriptors were derived for all PBDEs using a semi-empirical method (AM1), molecular mechanics, and empirically estimated parameters. Descriptors included heats of formation, frontier molecular orbital energies, atomic charges, dipole moments, logP values, and molecular surface areas. Principal component analysis (PCA) was used to evaluate the descriptors. The first four PCs, explaining 76% of the variation in the data, described the size, charge distribution and symmetric elements of the congeners. A quantitative structure–activity relationship model was constructed based on data for dioxin-like activity (using the luciferase bioassay) for 17 PBDEs with the partial least squares method. In addition, quantitative structure–property relationship models for gas chromatographic relative retention times on four capillary columns were developed. These models proved suitable to assist in the identification of untested PBDEs. Based on the results of the PCA, a factorial design was applied for selecting 21 representative congeners, PBDEs 11, 13, 17, 32, 35, 47, 53, 77, 85, 99, 119, 135, 153, 155, 156, 169, 176, 181, 190, 192, and 209. The spacing of these congeners in the physicochemical domain maximises the coverage of key factors such as molecular size and substitution pattern. Consideration of the selected congeners should be useful for guiding the synthesis of new compounds for use in future studies of the fate and biological effects of PBDEs.
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