DETECTIVE

Detection of endpoints and biomarkers of repeated dose toxicity using in vitro systems

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 Obiettivo del progetto (Objective)

'Assessment of repeated dose toxicity is a standard requirement in human safety evaluation and relies on animal testing as no alternatives are currently accepted for regulatory purposes. An integrated research strategy for the replacement of animal tests needs to comprise the development of biomarkers of long-term toxicity in human target cells. To this aim, the DETECTIVE project will set up a screening pipeline of high content, high throughput as well as classical functional and “-omics” technologies to identify and investigate human biomarkers in cellular models for repeated dose in vitro testing. In view of industrial use in automated high throughput systems, essential questions of repeated dose toxicity such as stability and robustness of readouts will be investigated in a first phase. This will be the foundation for innovative biomarker development based on integration of multiple data streams derived from “-omics” readouts with traditional toxicological and histopathological endpoint evaluation. Toxicity pathways identified in “-omics” readouts can thus be further investigated by the functional readouts. DETECTIVE will initially use human hepatic, cardiac and renal models as common target organs of repeated dose toxicity. Ultimately, the strategy for establishing biomarkers will also be applicable to other organs or organ systems affected by systemic toxicants. It is also expected that DETECTIVE will be able to define human toxicity pathways relevant for all organs. Based on integrative statistical analysis, systematic verification and correlation with in vivo data, the most relevant, highly specific, sensitive and predictive biomarkers will be selected. Within DETECTIVE, partners from academia, industry and research will hence generate pathway- and evidence-based understanding of toxic effects, moving toxicology beyond descriptive science towards mechanism-based prediction.'

Introduzione (Teaser)

Identification of surrogate markers for toxicity assessment, coupled to in vitro assays could speed up the toxicity screening process and replace the current use of animal testing.

Descrizione progetto (Article)

Many industries rely on safety assessments of chronically acting toxicants relevant for humans to promote their products to the market. Current methods mainly entail the use of animals, but are time consuming, expensive and ethically questionable.

The EU-funded 'Detection of endpoints and biomarkers of repeated dose toxicity using in vitro systems' (Detective) project is part of an integrated research strategy towards the replacement of animal testing set up by the European Commission. To this end, partners are concentrating their efforts on the development of robust, reliable, sensitive and specific in vitro biomarkers and surrogate endpoints.

In vitro toxicity models are initially being developed for three target organs, namely the liver, heart and kidney. In addition, a repeated toxicity model has been developed based on human embryonic stem cells (hESCs).

Upon evaluation of the most appropriate human cellular model system for each organ, researchers are testing a list of compounds generated after comprehensive review of the literature and the Repdose database. Subsequent analysis of gene expression patterns will reveal the pathways affected upon exposure to specific chemicals.

Preliminary data indicate alterations in gene transcription following exposure to these compounds. This information will form the basis for investigation of repeated dose toxicity and determine the long-term effects of application of chemicals.

Further epigenetic and proteomic evaluation of the toxicity effects impacted by various compounds is expected to identify biomarkers of different organs associated with toxicity. This would lead to pathway- and evidence-based understanding of toxic effects, thereby moving toxicology beyond descriptive science towards mechanism-based prediction.

The project deliverables have significant exploitation potential and could be commercially adopted by the pharmaceutical and cosmetics industries.