The carcinoGENOMICS project: Critical selection of model compounds for the development of omics-based in vitro carcinogenicity screening assays

Vinken, Mathieu; Doktorova, Tatyana Y.; Ellinger‐Ziegelbauer, Heidrun; Ahr, Hans-Juergen; Lock, Edward A.; Carmichael, Paul L.; Roggen, Erwin L.; Delft, Joost H. van; Kleinjans, Jos; Castell, José V.; Bort, Roque; Donato, M. Teresa; Ryan, Michael P.; Corvi, Raffaella; Keun, Hector C.; Ebbels, Timothy M. D.; Athersuch, Toby J.; Sansone, Susanna-Assunta; Rocca-Serra, Philippe; Stierum, Rob; Jennings, Paul; Pfaller, Walter; Gmuender, Hans; Vanhaecke, Tamara; Rogiers, Vera

doi:10.1016/j.mrrev.2008.04.006

Cited by 55 publications

(27 citation statements)

References 64 publications

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“…Alternative methods (e.g. carcinogenomics, in vitro methods) are currently being evaluated (Vinken et al , 2008) and are promising to show a better correlation to the human situation than the rodent carcinogenicity testing, but until the validations are finished, it remains unclear which tests give better predictions for the human situation. Data from alternative methods may add valuable information to the available database, especially for the challenging human health risk assessment for inhalation exposure to poorly soluble particles.…”

Section: Toxicitymentioning

confidence: 99%

Beryllium Metal II. A Review of the Available Toxicity Data

Strupp¹

2010

The Annals of Occupational Hygiene

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Beryllium metal was classified in Europe collectively with beryllium compounds, e.g. soluble salts. Toxicological equivalence was assumed despite greatly differing physicochemical properties. Following introduction of the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulation, beryllium metal was classified as individual substance and more investigational efforts to appropriately characterize beryllium metal as a specific substance apart from soluble beryllium compounds was required. A literature search on toxicity of beryllium metal was conducted, and the resulting literature compiled together with the results of a recently performed study package into a comprehensive data set. Testing performed under Organisation for Economic Co-Operation and Development guidelines and Good Laboratory Practice concluded that beryllium metal was neither a skin irritant, an eye irritant, a skin sensitizer nor evoked any clinical signs of acute oral toxicity; discrepancies between the current legal classification of beryllium metal in the European Union (EU) and the experimental results were identified. Furthermore, genotoxicity and carcinogenicity were discussed in the context of the literature data and the new experimental data. It was concluded that beryllium metal is unlikely to be a classical nonthreshold mutagen. Effects on DNA repair and morphological cell transformation were observed but need further investigation to evaluate their relevance in vivo. Animal carcinogenicity studies deliver evidence of carcinogenicity in the rat; however, lung overload may be a species-specific confounding factor in the existing studies, and studies in other species do not give convincing evidence of carcinogenicity. Epidemiology has been intensively discussed over the last years and has the problem that the studies base on the same US beryllium production population and do not distinguish between metal and soluble compounds. It is noted that the correlation between beryllium exposure and carcinogenicity, even including the soluble compounds, remains under discussion in the scientific community and active research is continuing.

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Section: Toxicitymentioning

confidence: 99%

Beryllium Metal II. A Review of the Available Toxicity Data

Strupp¹

2010

The Annals of Occupational Hygiene

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“…Samples were generated by incubating hES-Hep with 15 compounds of three different toxicity classes that were chosen from a previously defined body of model compounds causing genotoxicity and carcinogenicity (Vinken et al , 2008). Genotoxic carcinogens (GTX) were 2-nitrofluorene (2NF), benzo[a]pyrene (BAP), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), aflatoxin B1 (AFL), and cyclophosphamide monohydrate (CYC); nongenotoxic carcinogens (NGTX) were methapyrilene hydrochloride (MPH), piperonylbutoxide (PPX), sodium phenobarbital (SPB), WY-14,643/pirinixic acid (WYE), and tetradecanoyl phorbol acetate (TPA); NC were sodium diclofenac (DIC), D -mannitol (DMA), nifedipine (NFE), clonidine hydrochloride (CLO), and tolbutamide (TOL).…”

Section: Methodsmentioning

confidence: 99%

“…For example, cholesterol-lowering drugs, such as atorvastatin, fluvastatin, and simvastatin among many other pharmaceutical agents approved as safe drugs for human use by the FDA, were classified as rodent carcinogens (Ward, 2008). Thus, it has been understood that human in vitro assays must be developed for predicting carcinogenic effects of chemicals in human more reliably (Vinken et al , 2008). …”

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confidence: 99%

Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for In Vitro Hazard Assessment of Chemical Carcinogenicity

Yildirimman

Brolén²,

Vilardell

et al. 2011

Toxicological Sciences

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Hepatocyte-like cells derived from the differentiation of human embryonic stem cells (hES-Hep) have potential to provide a human relevant in vitro test system in which to evaluate the carcinogenic hazard of chemicals. In this study, we have investigated this potential using a panel of 15 chemicals classified as noncarcinogens, genotoxic carcinogens, and nongenotoxic carcinogens and measured whole-genome transcriptome responses with gene expression microarrays. We applied an ANOVA model that identified 592 genes highly discriminative for the panel of chemicals. Supervised classification with these genes achieved a cross-validation accuracy of > 95%. Moreover, the expression of the response genes in hES-Hep was strongly correlated with that in human primary hepatocytes cultured in vitro. In order to infer mechanistic information on the consequences of chemical exposure in hES-Hep, we developed a computational method that measures the responses of biochemical pathways to the panel of treatments and showed that these responses were discriminative for the three toxicity classes and linked to carcinogenesis through p53, mitogen-activated protein kinases, and apoptosis pathway modules. It could further be shown that the discrimination of toxicity classes was improved when analyzing the microarray data at the pathway level. In summary, our results demonstrate, for the first time, the potential of human embryonic stem cell--derived hepatic cells as an in vitro model for hazard assessment of chemical carcinogenesis, although it should be noted that more compounds are needed to test the robustness of the assay.

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“…Developed for the European multi-site ‘CarcinoGENOMICS’ project (Vinken et al , 2008), the ISA software suite version one was released in early 2009. The core ISA developers are engaged with an ever-growing number of collaborators: case studies from early implementers already provide evidence of the diverse life science scenarios in which the suite's various components have been successfully tested and are being used with large datasets (details on the ISA web site).…”

Section: Collaborations and Case Studiesmentioning

confidence: 99%

ISA software suite: supporting standards-compliant experimental annotation and enabling curation at the community level

et al. 2010

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Summary: The first open source software suite for experimentalists and curators that (i) assists in the annotation and local management of experimental metadata from high-throughput studies employing one or a combination of omics and other technologies; (ii) empowers users to uptake community-defined checklists and ontologies; and (iii) facilitates submission to international public repositories.Availability and Implementation: Software, documentation, case studies and implementations at http://www.isa-tools.orgContact: isatools@googlegroups.com

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The carcinoGENOMICS project: Critical selection of model compounds for the development of omics-based in vitro carcinogenicity screening assays

Cited by 55 publications

References 64 publications

Beryllium Metal II. A Review of the Available Toxicity Data

Beryllium Metal II. A Review of the Available Toxicity Data

Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for In Vitro Hazard Assessment of Chemical Carcinogenicity

ISA software suite: supporting standards-compliant experimental annotation and enabling curation at the community level

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