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There is an increased need to develop novel alternative approaches to the two-year rodent bioassay for the carcinogenicity assessment of substances where the rodent bioassay is still a basic requirement, as well as for those substances where animal use is banned or limited or where information gaps are identified within legislation. The current progress in this area was addressed in a EURL ECVAM- ESTIV workshop held in October 2016, in Juan les Pins. A number of initiatives were presented and discussed, including data-driven, technology-driven and pathway-driven approaches. Despite a seemingly diverse range of strategic developments, commonalities are emerging. For example, providing insight into carcinogenicity mechanisms is becoming an increasingly appreciated aspect of hazard assessment and is suggested to be the best strategy to drive new developments. Thus, now more than ever, there is a need to combine and focus efforts towards the integration of available information between sectors. Such cross-sectorial harmonisation will aid in building confidence in new approach methods leading to increased implementation and thus a decreased necessity for the two-year rodent bioassay.

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen- specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88% correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. [ABSTRACT FROM AUTHOR]

Information on the carcinogenic potential of chemicals is primarily available for High Production Volume (HPV) products. Because of the limited knowledge gain from routine cancer bioassays and the fact that HPV chemicals are tested only, there is the need for more cost-effective and informative testing strategies. Here we report the application of advanced genomics to a cellular transformation assay to identify toxicity pathways and gene signatures predictive for carcinogenicity. Specifically, genome-wide gene expression analysis and quantitative real time polymerase chain reaction (qRT-PCR) were applied to untransformed and transformed mouse fibroblast Balb/c 3T3 cells that were exposed to either 2, 4-diaminotoluene, benzo(a)pyrene, 2-acetylaminoflourene, or 3-methycholanthrene at IC20 conditions for 24 and 120 h, respectively. Then, bioinformatics was applied to define toxicity pathways and a gene signature predictive of the carcinogenic risk of these chemicals. Although bioinformatics revealed distinct differences for individual chemicals at the gene-level pathway, analysis identified common perturbation that resulted in an identification of 14 genes whose regulation in cancer tissue had already been established. Strikingly, this gene signature was identified in short-term (24 and 120 h) untransformed and transformed cells (3 weeks), therefore demonstrating robustness for its predictive power. The developed testing strategy thus identified commonly regulated carcinogenic pathways and a gene signature that predicted the risk for carcinogenicity for three well-known carcinogens. Overall, the testing strategy warrants in-depth validation for the prediction of carcinogenic risk of industrial chemicals in in vitro carcinogenicity assay. [ABSTRACT FROM AUTHOR]

Omics methodologies are widely used in toxicological research to understand modes and mechanisms of toxicity. Increasingly, these methodologies are being applied to questions of regulatory interest such as molecular point-of-departure derivation and chemical grouping/read-across. Despite its value, widespread regulatory acceptance of omics data has not yet occurred. Barriers to the routine application of omics data in regulatory decision making have been: 1) lack of transparency for data processing methods used to convert raw data into an interpretable list of observations; and 2) lack of standardization in reporting to ensure that omics data, associated metadata and the methodologies used to generate results are available for review by stakeholders, including regulators. Thus, in 2017, the Organisation for Economic Co-operation and Development (OECD) Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST) launched a project to develop guidance for the reporting of omics data aimed at fostering further regulatory use. Here, we report on the ongoing development of the first formal reporting framework describing the processing and analysis of both transcriptomic and metabolomic data for regulatory toxicology. We introduce the modular structure, content, harmonization and strategy for trialling this reporting framework prior to its publication by the OECD. • Omics reporting framework established for regulatory toxicology. • Modular structure accommodates various technologies and analyses. • Harmonization of reporting fields for transcriptomics and metabolomics. • Tool for documenting analysis steps used to generate interpretable results from omics data. [ABSTRACT FROM AUTHOR]