In Silico Tools for Sharing Data and Knowledge on Toxicity and Metabolism: Derek for Windows, Meteor, and Vitic

Marchant, Carol A.; Briggs, Katharine; Long, Anthony D.

doi:10.1080/15376510701857320

Cited by 285 publications

(207 citation statements)

References 37 publications

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“…Thus, Derek for Windows includes separate structural alerts for the prediction of endpoints such as carcinogenicity, peroxisome proliferation, phospholipidosis and uncoupling of oxidative phosphorylation, which may additionally impact on observations in the liver. Finally, the involvement of metabolism in many pathways of hepatotoxicity should encourage the continuing coordination of model development between Derek for Windows and the knowledgebased metabolism prediction system Meteor [14]. The latter covers a comprehensive range of metabolic and spontaneous biotransformations (Table) and may identify both metabolites and intermediates which are relevant to hepatotoxicity (Fig.…”

Section: Future Directions Andmentioning

confidence: 98%

“…Thus, for example, it predicts the formation of acyl glucuronide metabolites that may form protein adducts which have been implicated in the hepatotoxicity of non-steroidal antiinflammatory drugs such as benoxaprofen [26]. Alternatively, it offers the possibility of mechanistic insight where available evidence is limited, identifying, for example, an isocyanate intermediate, labelled as potentially adduct-forming [14], which may contribute to the hepatotoxicity described for some arylsulfonylureas such as chlorpropamide [20].…”

Section: Future Directions Andmentioning

confidence: 99%

“…Derek for Windows is a knowledge-based expert system for the prediction of toxicity [14]. The rules it uses may be based on many types of evidence including the presence of structural alerts, known toxicity data, species effects, physicochemical properties, relationships between toxicological endpoints and other parameter types defined by the user [15].…”

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confidence: 99%

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An Expert System Approach to the Assessment of Hepatotoxic Potential

Marchant

Fisk

Note

et al. 2009

Chemistry & Biodiversity

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Hepatotoxicity is a major cause of pharmaceutical drug attrition and is also a concern within other chemical industries. In silico approaches to the prediction of hepatotoxicity are an important tool in the early identification of adverse effects in the liver associated with exposure to a chemical. Here, we describe work in progress to develop an expert system approach to the prediction of hepatotoxicity, focussing particularly on the identification of structural alerts associated with its occurrence. The development of 74 such structural alerts based on public-domain literature and proprietary data sets is described. Evaluation results indicate that, whilst these structural alerts are effective in identifying the hepatotoxicity of many chemicals, further research is needed to develop additional structural alerts to account for the hepatotoxicity of a number of chemicals which is not currently predicted. Preliminary results also suggest that the specificity of the structural alerts may be improved by the combined use of applicability domains based on physicochemical properties such as log P and molecular weight. In the longer term, the performance of predictive models is likely to benefit from the further integration of diverse data and prediction model types.

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Section: Future Directions Andmentioning

confidence: 98%

Section: Future Directions Andmentioning

confidence: 99%

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An Expert System Approach to the Assessment of Hepatotoxic Potential

Marchant

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Note

et al. 2009

Chemistry & Biodiversity

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“…While in silico methods (QSAR Toolbox, Derek, 11 TIMES-SS, 12 and ToxTree 13 ) are based on structure−activity relationships, in vitro assays model the early events of the skin sensitization process. Nrf-2-based assays 14,15 (KeratinoSens, LuSens) analyze the induction of the cellular antioxidant pathway, and dendritic cell-based assays (MUSST, 16 hCLAT 17 ) measure DC maturation markers (CD86, CD54).…”

Section: ■ Introductionmentioning

confidence: 99%

Alternative Testing Methods for Skin Sensitization: NMR Spectroscopy for Probing the Reactivity and Classification of Potential Skin Sensitizers

Chittiboyina¹,

Avonto²,

Rua

et al. 2015

Chem. Res. Toxicol.

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Evaluating consumer products for potentially harmful side effects of chemical ingredients is important for the protection of both the consumer and those involved in the manufacturing process. In order to assess the risk potential of chemicals, regulatory agencies have encouraged the development of several in silico, in vitro, and in chemico methods as alternatives to eliminate or minimize the use of animals. To add structural information to the existing in chemico methods, an NMR-based method is proposed for probing the reactivity and classification of the potential electrophiles (E) using a model thiol, DCYA, as a nucleophile. The major advantage of the NMR method is the quantitation of the actual adduct, DCYA-E. The degree of reaction is here provided as a direct measurement of adduct formation and/or electrophile depletion, in contrast to other in chemico assays, e.g., ADRA and DPRA, where the reactivity is inferred from the quantification of the test nucleophile depletion. Moreover, the developed NMR method should serve as a qualitative and quantitative tool in understanding the site of reaction and other structural information associated with test sensitizer. This is particularly valuable and advantageous over methods encouraged by regulatory agencies, which merely provide quantification of the reaction but lack any structural information. Several compounds with multiple reaction sites were successfully tested with the proposed NMR method. Otherwise, these compounds have proven to be a challenge to identify and classify using existing alternative methods.

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“…A number of software systems are available for making these in silico predictions of toxicity, either employing knowledge-based data sets or QSAR-based models. An example of the former is DEREK, which identifies structural alerts for a variety of toxicological endpoints (Marchant et al, 2008). examples of QSAR-based approaches are TOPKAT and the OECD Toolbox.…”

Section: Fig 2: Responses Of An In Vitro Test System Over Timementioning

confidence: 99%

The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans

Blaauboer

Boekelheide

Clewell

et al. 2012

ALTEX

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SummaryThe role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (BoT) and determining the place these data can have in human risk assessment. As a result, a conceptual framework is presented for the incorporation of in vitro-derived toxicity data into the risk assessment process. The selection of BoT takes into account that they need to distinguish adverse and adaptive changes in cells. The framework defines the place of in vitro systems in the context of data on exposure, structural and physico-chemical properties, and toxicodynamic and biokinetic modeling. It outlines the determination of a proper point-of-departure (PoD) for in vitro-in vivo extrapolation, allowing implementation in risk assessment procedures. A BoT will need to take into account both the dynamics and the kinetics of the compound in the in vitro systems. For the implementation of the proposed framework it will be necessary to collect and collate data from existing literature and new in vitro test systems, as well as to categorize biomarkers of toxicity and their relation to pathways-of-toxicity. Moreover, data selection and integration need to be driven by their usefulness in a quantitative in vitro-in vivo extrapolation (QIVIVE). Keywords: biomarker of toxicity, integrated testing strategies, quantitative in vitro-in vivo extrapolations

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In Silico Tools for Sharing Data and Knowledge on Toxicity and Metabolism: Derek for Windows, Meteor, and Vitic

Cited by 285 publications

References 37 publications

An Expert System Approach to the Assessment of Hepatotoxic Potential

An Expert System Approach to the Assessment of Hepatotoxic Potential

Alternative Testing Methods for Skin Sensitization: NMR Spectroscopy for Probing the Reactivity and Classification of Potential Skin Sensitizers

The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans

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