The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.

Use and perceived benefits and barriers of QSAR models for REACH: findings from a questionnaire to stakeholders.

The ORCHESTRA online questionnaire on "benefits and barriers to the use of QSAR methods" addressed the academic, consultant, regulatory and industry communities potentially interested by QSAR methods in the context of REACH. Replies from more than 60 stakeholders produced some insights on the actual application of QSAR methods, and how to improve their use.Respondents state in majority that they have used QSAR methods.

Application of ERICA index to evaluation of soil ecosystem health according to sustainability threshold for chemical impact.

The aim of the improved ERICA model for risk assessment (Boriani et al., 2010) is to give an instrument able to measure the effect of xenobiotics introduced into the environment. This will be of great help for "green" processes and sustainable industries and may help to advertise their products as safe for the environment following impact assessment.

PCDD/Fs and PCBs in ambient air in a highly industrialized city in northern Italy.

Ambient air samples were collected in five locations around a polychlorobiphenyl (PCB) production plant in a highly industrialized city in the north of Italy, for the analysis of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) and PCBs. PCDD/F atmospheric concentrations were lower than those generally detected in urban areas, while PCB concentrations were higher than in urban and industrialized areas in other countries, especially in the locations closest to the plant. To identify source emissions responsible for air pollution we used principal component analysis (PCA) to compare the "fingerprint" of the air in Brescia with some source-related experimental and published data.

CORAL: binary classifications (active/inactive) for Liver-Related Adverse Effects of Drugs.

Classification data related to the Liver-Related Adverse Effects of Drugs have been studied with the CORAL software (http://www.insilico.eu/coral).

Genistein and dicarboximide fungicides in infant formulae from the EU market.

A method based on ultrasonic extraction and purification by solid phase extraction followed by LC-MS/MS and GC-MS analysis was developed for the determination of genistein, genistin, iprodione, vinclozolin and procymidone in infant powdered formulas. The method was tested for different formulations: milk, soy and hypoallergenic, and was applied to European pooled samples. Spike recoveries ranged from 53.

CORAL: QSPR model of water solubility based on local and global SMILES attributes.

Water solubility is an important characteristic of a chemical in many aspects. However experimental definition of the endpoint for all substances is impossible. In this study quantitative structure-property relationships (QSPRs) for negative logarithm of water solubility-logS (mol L(-1)) are built up for five random splits into the sub-training set (≈55%), the calibration set (≈25%), and the test set (≈20%).

Screening of endocrine-disrupting phenols, herbicides, steroid estrogens, and estrogenicity in drinking water from the waterworks of 35 Italian cities and from PET-bottled mineral water.

We investigated contamination by endocrine-disrupting chemicals in drinking water from 35 major Italian cities and five popular Italian brands of bottled mineral water. The quality of Italian drinking water was assessed by combing chemical analysis with bioassay to quantify specific estrogenic contaminants and to characterize the actual biological effect of the mixture of chemicals present in drinking water including the contribution of not targeted compounds. The selected contaminants were natural and synthetic steroid estrogens, alkylphenols and bisphenol A, linuron, triazine herbicides, and their metabolites.

Novel application of the CORAL software to model cytotoxicity of metal oxide nanoparticles to bacteria Escherichia coli.

Convenient to apply and available on the Internet software CORAL (http://www.insilico.eu/CORAL) has been used to build up quantitative structure-activity relationships (QSAR) for prediction of cytotoxicity of metal oxide nanoparticles to bacteria Escherichia coli (minus logarithm of concentration for 50% effect pEC50).

CORAL: QSPR modeling of rate constants of reactions between organic aromatic pollutants and hydroxyl radical.

The rate constants (K(OH)) of reactions between 78 organic aromatic pollutants and hydroxyl radical were examined. Simplified molecular input line entry system was used as representation of the molecular structure of the pollutants. Quantitative structure-property relationships was developed using CORAL software (http://www.

Calculation of molecular features with apparent impact on both activity of mutagens and activity of anticancer agents.

The analysis of the influence of molecular features which can be extracted from the simplified molecular input line entry system (SMILES) and involved in the process of the building up of a series of QSAR models (with different splits into training and test sets) by means of the CORAL software for mutagenicity and anticancer activity has been performed. The presence of nitrogen (sp3) is favorable for decrease of the both endpoints; the presence of only one ring is also promotor for decrease of the both endpoints; however the presence of two or three rings is favorable for increase of mutagenicity and decrease of anticancer activity. These findings provide useful criteria for further experimental and computational studies in the search for new anticancer agents.

Quantitative consensus of bioaccumulation models for integrated testing strategies.

A quantitative consensus model based on bioconcentration factor (BCF) predictions obtained from five quantitative structure-activity relationship models was developed for bioaccumulation assessment as an integrated testing approach for waiving. Three categories were considered: non-bioaccumulative, bioaccumulative and very bioaccumulative. Five in silico BCF models were selected and included into a quantitative consensus model by means of the continuous formulation of Bayes' theorem.

CORAL: QSAR models for acute toxicity in fathead minnow (Pimephales promelas).

CORrelation And Logic (CORAL) is a software that generates quantitative structure activity relationships (QSAR) for different endpoints. This study is dedicated to the QSAR analysis of acute toxicity in Fathead minnow (Pimephales promelas). Statistical quality for the external test set is a complex function of the split (into training and test subsets), the number of epochs of the Monte Carlo optimization, and the threshold that is a criterion for dividing the correlation weights into two classes rare (blocked) and not rare (active).

Evaluating the applicability domain in the case of classification predictive models for carcinogenicity based on the counter propagation artificial neural network.

The applicability domain (AD) of models developed for regulatory use has attached great attention recently. The AD of quantitative structure-activity relationship (QSAR) models is the response and chemical structure space in which the model makes predictions with a given reliability. The evaluation of AD of regressions QSAR models for congeneric sets of chemicals can be find in many papers and books while the issue about metrics for the evaluation of an AD for the non-linear models (like neural networks) for the diverse set of chemicals represents the new field of investigations in QSAR studies.

QSAR models for toxicity of organic substances to Daphnia magna built up by using the CORAL freeware.

CORAL (CORrelations And Logic, http://www.insilico.eu/coral/) is a freeware available on the Internet.

Comparison and possible use of in silico tools for carcinogenicity within REACH legislation.

Seven in silico models have been used to assess the prediction accuracy of chemical compound carcinogenicity. More than 1500 compounds with experimental values have been used to evaluate the models. Here we review the application of these models for toxicity prediction and their advantages and disadvantages, discussing the different approaches underlying the models and their main critical points.

SMILES-based QSAR approaches for carcinogenicity and anticancer activity: comparison of correlation weights for identical SMILES attributes.

CORAL software (http://www.insilico.eu/coral/) has been used for modeling of carcinogenicity (logTD50) of 401 compounds, and anticancer activity (-logIC50) of 100 compounds, on the basis of quantitative structure activity relationships (QSAR).

Concentrations of PCDD/PCDF in soil close to a secondary aluminum smelter.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs/Fs) were analyzed in samples of the emissions from a secondary aluminum smelter (ALS) and soil samples around the plant. The purpose was to estimate the impact of the emissions on the surrounding environment. PCDD/F soil concentrations were higher in the proximity of the plant, exceeding the limit adopted in Italy in soils for green areas and residential uses and the upper limit of several reference concentrations.

The acceptance of in silico models for REACH: Requirements, barriers, and perspectives.

In silico models have prompted considerable interest and debate because of their potential value in predicting the properties of chemical substances for regulatory purposes. The European REACH legislation promotes innovation and encourages the use of alternative methods, but in practice the use of in silico models is still very limited. There are many stakeholders influencing the regulatory trajectory of quantitative structure-activity relationships (QSAR) models, including regulators, industry, model developers and consultants.

Identification of toxifying and detoxifying moieties for mutagenicity prediction by priority assessment.

The search for structural subunits that affect compound toxicity cannot be manually performed on large databases. In addition, the a priori definition of important groups is impossible. Structural diversity requires the analysis of the complete data space and the selection of the details there present.

CORAL: quantitative structure-activity relationship models for estimating toxicity of organic compounds in rats.

For six random splits, one-variable models of rat toxicity (minus decimal logarithm of the 50% lethal dose [pLD50], oral exposure) have been calculated with CORAL software (http://www.insilico.eu/coral/).

Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010.

The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission's Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e.

coral Software: QSAR for Anticancer Agents.

CORrelations And Logic (coral at http://www.insilico.eu/coral) is freeware aimed at establishing a quantitative structure - property/activity relationships (QSPR/QSAR).

Simplified molecular input-line entry system and International Chemical Identifier in the QSAR analysis of styrylquinoline derivatives as HIV-1 integrase inhibitors.

The simplified molecular input-line entry system (SMILES) and IUPAC International Chemical Identifier (InChI) were examined as representations of the molecular structure for quantitative structure-activity relationships (QSAR), which can be used to predict the inhibitory activity of styrylquinoline derivatives against the human immunodeficiency virus type 1 (HIV-1). Optimal SMILES-based descriptors give a best model with n = 26, r(2) = 0.6330, q(2) = 0.