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- Andersson, Patrik, et al.
(författare)
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Multivariate modeling of polychlorinated biphenyl-induced CYP1A activity in hepatocytes from three different species : ranking scales and species differences
- 2000
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Ingår i: Environmental Toxicology and Chemistry. - : Wiley. - 0730-7268 .- 1552-8618. ; 19:5, s. 1454-1463
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Andersson, Patrik, et al.
(författare)
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General and Class Specific Models for Prediction of Soil Sorption Using Various Physicochemical Descriptors
- 2002
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 0095-2338. ; 42:6, s. 1450-9
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Tidskriftsartikel (refereegranskat)abstract
- Diverse chemical descriptors were explored for use in QSAR models aimed to screen the soil sorption potential of organic compounds. The descriptors included logP, HyperChem QSARProperties descriptors, a combination of connectivity indices, geometrical, and quantum chemical measures, and two sets from the DRAGON and CODESSA program packages, respectively. Generally, the univariate logP models were capable of capturing most of the variation and give an indication of the sorption potential. The multivariate models required refined variable selection procedures but were shown to include crucial descriptors for modeling compound classes with specific chemical characteristics.
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- Andersson, Patrik, 1967-
(författare)
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Physico-chemical characteristics and quantitative structure-activity relationships of PCBs
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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- Eriksson, Lennart, et al.
(författare)
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Multivariate biological profiling and principal toxicity regions of compounds: the PCB case study
- 2002
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Ingår i: Journal of Chemometrics. - : Wiley. - 0886-9383 .- 1099-128X. ; 16:8-10, s. 497-509
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Tidskriftsartikel (refereegranskat)abstract
- The chemometric QSAR strategy, as applied in environmental sciences and drug design, is based on (1) multivariate characterization of chemical structure, (2) multivariate design in the principal properties of a set of compounds to select a representative training set, and (3) multivariate modelling of the structure-activity relationships. A multivariate QSAR investigation is often commenced by applying a screening design, and the selected compounds are tested biologically in a broad battery of test systems (multivariate biological profiling). In many cases the result is such that for certain biological end-points only some of the tested compounds are active, while for another set of biological end-points other tested chemicals are active. In other words, when looking at the chemical property space, there may be both responding and non-responding toxicity regions, or even regions of very specific toxicity mechanisms. This may lead to loss of resolution and balance in the resulting QSAR models. Therefore it might sometimes be worthwhile to focus the QSAR modelling on parts of the chemical space where high toxicity is expected or known to be the case. In this paper we describe a multi-stage modification of the chemometric QSAR strategy, aimed at identifying focused sets of compounds that provide a good mapping of such principal toxicity regions. This strategy is based on PCA, PLS and multivariate design in several stages. The strategy is illustrated using a data set of polychlorinated biphenyls, a set of compounds for which seven biological end-points were determined. Copyright © 2002 John Wiley & Sons, Ltd.
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- Fick, Jerker, et al.
(författare)
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Selection of antibiotics : A chemometric approach
- 2004
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Ingår i: 4th International Conference on Pharmaceuticals and Endocrine Disrupting Chemicals in Water, Minneapolis, USA. ; , s. 143-50
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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