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Physico-chemical characteristics and quantitative structure-activity relationships of PCBs
Umeå University, Faculty of Science and Technology, Chemistry.
2000 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The polychlorinated biphenyls (PCBs) comprise a group of 209 congeners varying in the number of chlorine atoms and substitution patterns. These compounds tend to be biomagnified in foodwebs and have been shown to induce an array of effects in exposed organisms. The structural characteristics of the PCBs influence their potency as well as mechanism of action. In order to assess the biological potency of these compounds a multi-step quantitative structure-activity relationship (QSAR) procedure was used in the project described in this thesis.

The ultraviolet absorption (UV) spectra were measured for all 209 PCBs, and digitised for use as physico-chemical descriptors. Interpretations of the spectra using principal component analysis (PCA) showed the number of ortho chlorine atoms and para-para substitution patterns to be significant. Additional physico-chemical descriptors were derived from semi-empirical calculations. These included various molecular energies, the ionisation potential, electron affinity, dipole moments, and the internal barrier of rotation. The internal barrier of rotation was especially useful for describing the conformation of the PCBs on a continuous scale.

In total 52 physico-chemical descriptors were compiled and analysed by PCA for the tetra- to hepta-chlorinated congeners. The structural variation within these compounds was condensed into four principal properties derived from a PCA for use as design variables in a statistical design to select congeners representative for these homologue-groups. The 20 selected PCBs have been applied to study structure-specific biochemical responses in a number of bioassays, and to study the biomagnification of the PCBs in various fish species.

QSARs were established using partial least squares projections to latent structures (PLS) for the PCBs potency to inhibit intercellular communication, activate respiratory burst, inhibit dopamine uptake in synaptic vesicles, compete with estradiol for binding to estrogen receptors, and induce cytochrome P4501A (CYP1A) related activities. By the systematic use of the designed set of PCBs the biological potency was screened over the chemical domain of the class of compounds. Further, sub-regions of highly potent PCBs were identified for each response measured. For risk assessment of the PCBs potency to induce dioxin-like activities the predicted induction potencies (PIPs) were calculated. In addition, two sets of PCBs were presented that specifically represent congeners of environmental relevance in combination with predicted potency to induce estrogenic and CYP1A related activities.

Place, publisher, year, edition, pages
Umeå: Kemi , 2000. , 70 p.
Keyword [en]
polychlorinated biphenyls, PCBs, physico-chemical properties, statistical design, multivariate, PCA, PLS, biomagnification, BMF, bioassay, CYP1A, SAR, QSAR, REPs, risk assessment, Chemistry
Keyword [sv]
Kemi
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-17ISBN: 91-7191-838-8 (print)OAI: oai:DiVA.org:umu-17DiVA: diva2:141854
Public defence
2000-05-26
Opponent
Available from: 2000-05-26 Created: 2000-05-26Bibliographically approved
List of papers
1. Ultraviolet absorption characteristics and calculated semi-empirical parameters as chemical descriptors in multivariate modelling of polychlorinated biphenyls
Open this publication in new window or tab >>Ultraviolet absorption characteristics and calculated semi-empirical parameters as chemical descriptors in multivariate modelling of polychlorinated biphenyls
1996 (English)In: Journal of Chemometrics, ISSN 0886-9383, E-ISSN 1099-128X, Vol. 10, no 2, 171-185 p.Article in journal (Refereed) Published
Abstract [en]

The structural variation within the polychlorinated biphenyls (PCBs) was characterized by using principal component analysis (PCA). A multivariate model was evolved from 52 physicochemical descriptors including measured ultraviolet (UV) absorption spectra, calculated semiempirical parameters (AM1) and properties captured from the literature. Parameters calculated by using the AM1-Hamiltonian were e.g. heat of formation, dipole moments, ionization potential and the barrier of internal rotation. The UV spectra were measured and digitized in the range 200-300 nm. The multivariate model revealed that most of the information within the set of physicochemical parameters was related to molecular size. Descriptors depending on size were e.g. GC retention times, partition coefficients and a subset of semiempirically derived energy terms. Important also were parameters reflecting differences in substitution patterns and related to electronic and steric properties, such as UV absorption in the wavelength region 245-300 nm, the barrier of internal rotation and the ionization potential. The developed model describes the large variation in physicochemical characteristics within the PCBs. The importance of a broad chemical characterization is illustrated by a quantitative structure-activity relationship (QSAR) for the potency of inhibition of intercellular communication for 27 structurally diverse tetra- to heptachlorinated PCBs.

Keyword
PCBs, UV, AM1 calculations, muitivariate modelling, PCA, QSARs
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-3296 (URN)10.1002/(SICI)1099-128X(199603)10:2<171::AID-CEM416>3.0.CO;2-U (DOI)A1996TZ90300009 ()
Available from: 2000-05-26 Created: 2000-05-26 Last updated: 2014-08-29Bibliographically approved
2. The internal barriers of rotation for the 209 polychlorinated biphenyls
Open this publication in new window or tab >>The internal barriers of rotation for the 209 polychlorinated biphenyls
1997 (English)In: Environmental science and pollution research international, ISSN 0944-1344, E-ISSN 1614-7499, Vol. 4, no 2, 75-81 p.Article in journal (Refereed) Published
Abstract [en]

The internal barrier of rotation (Erot) was calculated for all 209 polychlorinated biphenyls (PCBs) by using a semi-empirical method, viz. the Austin Model 1 (AM1) Hamiltonian. The difference in total energy between a forced planar state and an optimised twisted structure was defined as Erot. The Erot values were in the range of 8.33 to 483 kJ/mol, and were significantly influenced by the number of chlorine atoms in ortho position. An additional structural characteristic of the PCBs influencing Erot of ortho substituted congeners was substitution by chlorine atoms in vicinal meta positions, which is assumed to prevent outward bending of ortho substituents. This so-called buttressing effect contributed with 4 to 31 kJ/mol per added chlorine atom. In conclusion, the internal barrier of rotation, calculated for all 209 PCBs, provides an important structure dependent physico-chemical parameter for multivariate modelling of future quantitative structure-activity and structure-property relationships (QSARs/QSPRs).

Keyword
PCBs, physico-chemical properties, semi-empirical calculations, AM1, substitution pattern, ortho-chlorines, dihedral angle, rotational barrier, buttressing effect, QSAR, QSPR
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-3297 (URN)10.1007/BF02986283 (DOI)A1997XJ06700005 ()
Available from: 2000-05-26 Created: 2000-05-26 Last updated: 2014-08-29Bibliographically approved
3. Ultraviolet absorption spectra of all 209 polychlorinated biphenyls evaluated by principal component analysis
Open this publication in new window or tab >>Ultraviolet absorption spectra of all 209 polychlorinated biphenyls evaluated by principal component analysis
1997 (English)In: Fresenius' Journal of Analytical Chemistry, ISSN 0937-0633, E-ISSN 1432-1130, Vol. 357, no 8, 1088-1092 p.Article in journal (Refereed) Published
Abstract [en]

The ultraviolet absorption spectra of all 209 polychlorinated biphenyls (PCBs) were recorded in the range 200-300 nm and displayed two important absorption maxima, viz., the main-band, lambda(max) 200-225 nm, and the kappa-band, lambda(max) 245-265 nm. By utilising principal component analysis, substitution related spectral characteristics of the PCBs, underlying the main patterns of the spectra, were examined. Captured in the multivariate evaluation were e.g., the importance of chlorine atoms in ortho positions, determining the intensity and existence of the kappa-band, chlorine substitution in para-para position, and the total number of chlorine atoms. The measured UV-spectra of all 209 polychlorinated biphenyls provide important physico-chemical descriptors for use in future quantitative structure-activity and structure-property relationship (QSAR/QSPR) studies.

National Category
Analytical Chemistry
Identifiers
urn:nbn:se:umu:diva-3298 (URN)10.1007/s002160050310 (DOI)A1997WZ13400016 ()
Available from: 2000-05-26 Created: 2000-05-26 Last updated: 2014-08-29Bibliographically approved
4. Selection of polychlorinated biphenyls for use in quantitative structure-activity modelling
Open this publication in new window or tab >>Selection of polychlorinated biphenyls for use in quantitative structure-activity modelling
Show others...
1995 (English)In: SAR and QSAR in environmental research (Print), ISSN 1062-936X, E-ISSN 1029-046X, Vol. 4, no 1, 11-19 p.Article in journal (Refereed) Published
Abstract [en]

By characterizing the 154 tetra- through heptachlorinated biphenyl (PCB) congeners with a multitude of physico-chemical descriptors, a model representing chemical similarities and differences is achieved. The multivariate characterization of the PCBs was based on 47 physico-chemical descriptor variables, which were summarised by using principal component analysis (PCA). By applying statistical design to the orthogonal scores from the PCA, a 24-factorial design was used to select a set of 16 congeners. In addition, four congeners were added to provide information about the interior region of the chemical domain of PCBs. This set of 20 structurally different congeners is suggested to be used in future quantitative structure-activity relationships (QSARs) for screening of the toxicological and biochemical effects of the PCBs.

Keyword
polychlorinated biphenyls, multivariate chemical characterisation, PCA, statistical design, QSARs
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:umu:diva-3299 (URN)10.1080/10629369508234010 (DOI)
Available from: 2000-05-26 Created: 2000-05-26 Last updated: 2014-08-29Bibliographically approved
5. Uptake and elimination of selected PCBs in zebra fish, three-spined stickleback and arctic char after three different routes of exposure
Open this publication in new window or tab >>Uptake and elimination of selected PCBs in zebra fish, three-spined stickleback and arctic char after three different routes of exposure
Show others...
2001 (English)In: Archives of Environmental Contamination and Toxicology, ISSN 0090-4341, E-ISSN 1432-0703, Vol. 40, no 4, 519-530 p.Article in journal (Refereed) Published
Abstract [en]

The uptake and elimination of 20 structurally diverse tetra- to heptachlorinated biphenyls were studied in zebrafish (Danio rerio), three-spined stickleback (Gasterosteus aculeatus), and Arctic char (Salvelinus alpinus). The polychlorinated biphenyls (PCBs) were administered to the fish through food, intraperitoneal injection of peanut oil, or intraperitoneal implantation of silicone capsules. The retention of the PCBs in fish exposed through their diet was related with the substitution patterns of the compounds. Ortho-substituted congeners with no unsubstituted meta-para positions had high biomagnification potential. PCBs with low biomagnification all had adjacent vicinal hydrogens, indicating that congeners with this feature may have been metabolically eliminated. The retention characteristics of the PCBs in the diet-exposed and the injected zebrafish were similar. The pattern of congeners in Arctic char indicates that they have a lower capacity to metabolize PCBs compared to three-spined sticklebacks and zebrafish. The levels in the fish exposed to the PCBs through a silastic implant were negatively correlated with the hydrophobicity of the congeners. Most probably congener-specific release rates of the PCBs from the implants mask their retention characteristics. It is suggested that food, mimicking the natural intake route, should be used in PCB exposure studies to validate extrapolations to natural situations.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-3300 (URN)10.1007/s002440010205 (DOI)
Available from: 2000-05-26 Created: 2000-05-26 Last updated: 2012-04-25Bibliographically approved
6. Multivariate modeling of polychlorinated biphenyl-induced CYP1A activity in hepatocytes from three different species: ranking scales and species differences
Open this publication in new window or tab >>Multivariate modeling of polychlorinated biphenyl-induced CYP1A activity in hepatocytes from three different species: ranking scales and species differences
2000 (English)In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 19, no 5, 1454-1463 p.Article in journal (Refereed) Published
Abstract [en]

Cytochrome P4501A–induced activity of 20 selected polychlorinated biphenyls (PCBs) was evaluated by measuring ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase activities induced in the hepatocytes of cynomolgus monkeys, male castrated pigs, and chicken embryos. Quantitative structure-activity relationships have been established, including 52 physi-cochemical parameters and different measures of the dose-response curves. Relative effect potencies are predicted for the 154 tetra-to hepta-PCBs and reported for the most potent congeners according to both EC50 and maximal response values. Important physicochemical parameters of the PCBs as related to the modeled activity are parts of their ultraviolet absorption spectra, the Henry's law constant, the ionization potential, and the octanol-water partition coefficient. Interspecies differences were found in terms of varied sensitivity to different structural subgroups of the compounds. The chicken hepatocyte assay showed the most specific structure-activity relationship, with high activity for the non-ortho PCBs, whereas the pig hepatocytes responded even for some di- to tetra-ortho PCBs. An interspecies response, the principal induction potency, is presented for the 41 most potent PCBs. These responses showed strong correlation with the toxic equivalency factors and are likely to be useful in risk assessment of the compounds.

Keyword
polychlorinated biphenyls, cytochrome P4501A, quantitative structure-activity relationships, species differences, risk assessment
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:umu:diva-3301 (URN)10.1002/etc.5620190530 (DOI)000086637300030 ()
Available from: 2000-05-26 Created: 2000-05-26 Last updated: 2014-08-29Bibliographically approved

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