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A QSAR for baseline toxicity: validation, domain of application, and prediction.
University of Kalmar, School of Pure and Applied Natural Sciences.ORCID iD: 0000-0001-9382-9296
2004 (English)In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 17, no 12, p. 1630-1637Article in journal (Refereed) Published
Abstract [en]

The interest in modeling and application of structure-activity relationships has steadily increased in recent decades. It is generally acknowledged that these empirical relationships are valid only within the same domain for which they were developed. However, model validation is sometimes neglected, and the application domain is not always well-defined. The purpose of this paper is to outline how validation and domain definition can facilitate the modeling and prediction of baseline toxicity for a large database. A large number of theoretical descriptors (867) were generated from two-dimensional molecular structures for compounds present in the U.S. EPA's Fathead Minnow Database (611) and the Syracuse Research Corporation's PhysProp Database (25,000+). A quantitative structure-activity relationship model was developed for baseline toxicity (narcosis) toward the fathead minnow (Pimephales promelas) using a projection-based regression technique, PLSR (partial least squares regression). The PLSR model was subsequently validated with an external test set. The main factors of variation were related to size/shape and polar interactions. The prediction error was comparable to, or slightly better than, the ECOSAR procedures. A set of 16,805 compounds, drawn from the PhysProp Database, was projected onto the PLSR model. More than 90% (15,597) of the compounds fall within the valid model domain, defined by the residual standard deviation and the leverage. The predicted baseline toxicity indicates an acute hazard for two-thirds of these compounds, classes I-III in the OECD Globally Harmonized Classification System (LC50 < or = 100 mg L(-1)). Finally, the mode of action assigned in the U.S. EPA Fathead Minnow Database was investigated. Reclassification to narcosis as the mode of action is suggested for 92 compounds, mostly from the groups "unsure" and "mixed". The present classification into specific modes of action seems to be further strengthened by the findings in this investigation.

Place, publisher, year, edition, pages
Washington DC: American Chemical Society , 2004. Vol. 17, no 12, p. 1630-1637
National Category
Environmental Sciences
Research subject
Environmental Science, Environmental Chemistry
Identifiers
URN: urn:nbn:se:hik:diva-1489DOI: 10.1021/tx0498253PubMedID: 15606139OAI: oai:DiVA.org:hik-1489DiVA, id: diva2:213758
Available from: 2009-04-28 Created: 2009-04-28 Last updated: 2017-12-13Bibliographically approved

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Öberg, Tomas

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