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A multivariate chemical map of industrial chemicals: Assessment of various protocols for identification of chemicals of potential concern
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2009 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 76, no 7, 878-884 p.Article in journal (Refereed) Published
Abstract [en]

In present study the Industrial chemical map was created, and investigated. Molecular descriptors were calculated for 56 072 organic substances from the European inventory of existing commercial chemical substances (EINECS). The resulting multivariate dataset was subjected to principal component analysis (PCA), giving five principal components, mainly reflecting size, hydrophobicity, flexibility, halogenation and electronical properties. It is these five PCs that form the basis of the map of organic, industrial chemicals, the Industrial chemical map. The similarities and diversity in chemical characteristics of the substances in relation to their persistence (P), bioaccumulation (B) and long-range transport potential were then examined, by superimposing five sets of entries obtained from other relevant databases onto the Industrial chemical map. These sets displayed very similar diversity patterns in the map, although with a spread in all five PC vectors. Substances listed by the United Nations Environment Program as persistent organic pollutants (UNEP POPs) were on the other hand clearly grouped with respect to each of the five PCs. Illustrating similarities and differences in chemical properties are one of the strengths of the multivariate data analysis method, and to be able to make predictions of, and investigate new chemicals. Further, the results demonstrate that non-testing methods as read-across, based on molecular similarities, can reduce the requirements to test industrial chemicals, provided that they are applied carefully, in combination with sound chemical knowledge.

Place, publisher, year, edition, pages
Elsevier, 2009. Vol. 76, no 7, 878-884 p.
Keyword [en]
Hazard identification, Persistent organic pollutants, Risk assessment, Molecular similarities, Non-testing methods, Read-across
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-23516DOI: 10.1016/j.chemosphere.2009.05.011OAI: oai:DiVA.org:umu-23516DiVA: diva2:224883
Note
Accepted 13 May 2009. Available online 9 June 2009. Available from: 2009-06-23 Created: 2009-06-23 Last updated: 2011-12-15Bibliographically approved
In thesis
1. In silico tools in risk assessment: of industrial chemicals in general and non-dioxin-like PCBs in particular
Open this publication in new window or tab >>In silico tools in risk assessment: of industrial chemicals in general and non-dioxin-like PCBs in particular
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Industrial chemicals in European Union produced or imported in volumes above 1 tonne annually, necessitate a registration within REACH. A common problem, concerning these chemicals, is deficient information and lack of data for assessing the hazards posed to human health and the environment. Animal studies for the type of toxicological information needed are both expensive and time consuming, and to that an ethical aspect is added. Alternative methods to animal testing are thereby requested. REACH have called for an increased use of

in silico tools for non-testing data as structure-activity relationships (SARs), quantitative structure-activity relationships (QSARs), and read-across. The main objective of the studies underlying this thesis is related to explore and refine the use of in silico tools in a risk assessment context of industrial chemicals. In particular, try to relate properties of the molecular structure to the toxic effect of the chemical substance, by using principles and methods of computational chemistry. The initial study was a survey of all industrial chemicals; the Industrial chemical map was created. A part of this map was identified including chemicals of potential concern. Secondly, the environmental pollutants, polychlorinated biphenyls (PCBs) were examined and in particular the non-dioxin-like PCBs (NDL-PCBs). A set of 20 NDL-PCBs was selected to represent the 178 PCB congeners with three to seven chlorine substituents. The selection procedure was a combined process including statistical molecular design for a representative selection and expert judgements to be able to include congeners of specific interest. The 20 selected congeners were tested in vitro in as much as 17 different assays. The data from the screening process was turned into interpretable toxicity profiles with multivariate methods, used for investigation of potential classes of NDL-PCBs. It was shown that NDL-PCBs cannot be treated as one group of substances with similar mechanisms of action. Two groups of congeners were identified. A group including in general lower chlorinated congeners with a higher degree of ortho substitution showed a higher potency in more assays (including all neurotoxic assays). A second group included abundant congeners with a similar toxic profile that might contribute to a common toxic burden. To investigate the structure-activity pattern of PCBs effect on DAT in rat striatal synaptosomes, ten additional congeners were selected and tested in vitro. NDL-PCBs were shown to be potent inhibitors of DAT binding. The congeners with highest DAT inhibiting potency were tetra- and penta-chlorinated with 2-3 chlorine atoms in ortho-position. The model was not able to distinguish the congeners with activities in the lower μM range, which could be explained by a relatively unspecific response for the lower ortho chlorinated PCBs.

Abstract [sv]

Den europeiska kemikalielagstiftningen REACH har fastställt att kemikalier som produceras eller importeras i en mängd över 1 ton per år, måste registreras och riskbedömmas. En uppskattad siffra är att detta gäller för 30 000 kemikalier. Problemet är dock att data och information ofta är otillräcklig för en riskbedömning. Till stor del har djurförsök använts för effektdata, men djurförsök är både kostsamt och tidskrävande, dessutom kommer den etiska aspekten in. REACH har därför efterfrågat en undersökning av möjligheten att använda in silico verktyg för att bidra med efterfrågad data och information. In silico har en ungefärlig betydelse av i datorn, och innebär beräkningsmodeller och metoder som används för att få information om kemikaliers egenskaper och toxicitet. Avhandlingens syfte är att utforska möjligheten och förfina användningen av in silico verktyg för att skapa information för riskbedömning av industrikemikalier. Avhandlingen beskriver kvantitativa modeller framtagna med kemometriska metoder för att prediktera, dvs förutsäga specifika kemikaliers toxiska effekt.

I den första studien (I) undersöktes 56 072 organiska industrikemikalier. Med multivariata metoder skapades en karta över industrikemikalierna som beskrev dess kemiska och fysikaliska egenskaper. Kartan användes för jämförelser med kända och potentiella miljöfarliga kemikalier. De mest kända miljöföroreningarna visade sig ha liknande principal egenskaper och grupperade i kartan. Genom att specialstudera den delen av kartan skulle man kunna identifiera fler potentiellt farliga kemiska substanser. I studie två till fyra (II-IV) specialstuderades miljögiftet PCB. Tjugo PCBs valdes ut så att de strukturellt och fysiokemiskt representerade de 178 PCB kongenerna med tre till sju klorsubstituenter. Den toxikologiska effekten hos dessa 20 PCBs undersöktes i 17 olika in vitro assays. De toxikologiska profilerna för de 20 testade kongenerna fastställdes, dvs vilka som har liknande skadliga effekter och vilka som skiljer sig åt. De toxicologiska profilerna användes för klassificering av PCBs. Kvantitativa modeller utvecklades för prediktioner, dvs att förutbestämma effekter hos ännu icke testade PCBs, och för att få ytterligare kunskap om strukturella egenskaper som ger icke önskvärda effekter i människa och natur. Information som kan användas vid en framtida riskbedömning av icke-dioxinlika PCBs. Den sista studien (IV) är en struktur-aktivitets studie som undersöker de icke-dioxinlika PCBernas hämmande effekt av signalsubstansen dopamin i hjärnan.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 62 p.
Keyword
Chemometrics, industrial chemicals, in silico tools, molecular descriptors, non-dioxin-like PCBs, partial least-squares (PLS), principal component analysis (PCA), quantitative structure-activity relationship (QSAR), REACH, risk assessment (RA), statistical molecular design, structure-activity relationship (SAR)
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:umu:diva-50609 (URN)978-91-7459-342-6 (ISBN)
Public defence
2012-01-16, KBC-huset, KB3B1, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2011-12-23 Created: 2011-12-15 Last updated: 2011-12-15Bibliographically approved

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Stenberg, MiaLinusson, AnnaTysklind, MatsAndersson, Patrik

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