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Predicting long-term toxic effects using computer models based on systems characterization of organotypic cultures (NOTOX)

Based on the forthcoming ban of animal testing in Europe for cosmetic products and the lack of assessment methods for long-term toxicity testing, we propose an integrated multifaceted experimental and computational platform especially using a systems biology approach. We think that experimental work should focus on the application of cellular systems that come most close to the human in vivo situation while at the same time allowing their transfer into applicable test systems. In these systems viability and physiological toxicity response parameters (-omics) will be monitored together with genetic, epigenetic and structural characteristics in parallel. Large-scale models of pathways and cellular systems will, together with bioinformatic integration of human and across species literature data, lead to reliable toxicity prediction.

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

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.

Profiling the toxicity of new drugs: a non animal-based approach integrating toxicodynamics and biokinetics (PREDICT-IV)

The overall aim of Predict-IV is to develop strategies to improve the assessment of drug safety in the early stage of development and late discovery phase, by an intelligent combination of non animal-based test systems, cell biology, mechanistic toxicology and in-silico modelling, in a rapid and cost effective manner. A better prediction of the safety of an investigational compound in early development will be delivered. Margins-of-safety will be deduced and the data generated by the proposed approach may also identify early biomarkers of human toxicity for pharmaceuticals. The results obtained in Predict-IV will enable pharmaceutical companies to create a tailored testing strategy for early drug safety. The project will integrate new developments to improve and optimize cell culture models for toxicity testing and to characterize the dynamics and kinetics of cellular responses to toxic effects in vitro. The target organs most frequently affected by drug toxicity will be taken into account, namely liver and kidney. Moreover, predictive models for neurotoxicty are scarce and will be developed. For each target organ the most appropriate cell model will be used. The approach will be evaluated using a panel of drugs with well described toxicities and kinetics in animals and partly also in humans.

Development of methodology for alternative testing strategies for the assessment of the toxicological profile of nanoparticles used in medical diagnostics (NANOTEST)

Objective: Nanoparticles (NP) have unique, potentially beneficial properties, but their possible impact on human health has not been adequately assessed. The main goal of this proposal is to develop alternative high-throughput testing strategies using in vitro and in silico methods to assess the toxicological profile of NP used in medical diagnostics. Our specific aims are to: 1. Define NP properties and fully characterize NP to be used 2. Study NP interactions with molecules, cells and organs and develop in vitro methods to study the toxicological potential of NP 3. Validate in vitro findings in short-term in vivo models and study particle effects in animals and (ex vivo) in humans to assess individual susceptibility to NP 4. Develop in silico models of NP interactions Experimental work is structured in 4 WPs to address NP characterisation and key elements in evaluation of NP uptake, exposure and toxicology. NANOTEST integrates the investigation of toxicological properties and effects of NP in several target systems by developing a battery of in vitro assays using cell cultures, organotypic cell culture and small organ fragments (ex vivo) derived from different biological systems; blood, vascular system, liver, lung, placenta, digestive and central nervous systems.

Dosimetry and Health Effects of Diagnostic Applications of Radiopharmaceuticals with particular emphasis on the use in children and adolescents (PEDDOSE.NET)

'The aim of this proposal is to provide data on dosimetry and corresponding dose related risks when administering radiopharmaceuticals for diagnostic purposes in children and adults. The composition of the consortium ensures that contacts to other bodies such as the International Commission on Radiological Protection (ICRP), the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine or member state radiation protection agencies are provided in order to obtain up-to-date information on the developments in this field. In addition, data on imaging device-specific parameters and corresponding phantoms will be gathered in order to get information on potential dose reductions with emphasis on paediatric nuclear medicine procedures, and on computed tomography absorbed doses in hybrid scanners. If, as a result of the reviews, the need for additional clinical trials is identified, details for the set-up of such trials will be given. Finally, recommendations for weight-dependent minimum and maximum activities with particular emphasis on paediatric nuclear medicine will be developed. The dissemination of results will be coordinated by the European Institute for Biomedical Imaging Research (EIBIR) and undertaken with the help of the radiation protection authorities in individual member states and the European Association of Nuclear Medicine (EANM).'

Monoclonal antibody-targeted carbon nanobues against cancer (ANTICARB)

Objective: ANTICARB attempts to exploit the advantages offered by a novel nanotechnology platform carbon nanotubes and apply them to a clinically established therapeutic modality targeted antibody therapy for the creation of hybrid nanotechnology-based monoclonal antibody targeted cancer therapeutics. ANTICARB combines two emerging technologies, antibody and nanotube technology, in a way that will allow safe development of antibody-nanotube conjugates and explore their swift translation into a clinical oncology setting. By combining proven, clinically used, anti-cancer agents' antibodies with a novel nanotechnology-based platform made of advanced nanomaterials, ANTICARB aims at enhancing the therapeutic potency of the antibody and establish a new paradigm for oncology therapeutics. The ability of carbon nanotube technology to transport antibodies into the tumour cell cytoplasm may lead to validation of specific intracellular targets for oncology. This objective will be reached by adopting a multidisciplinary approach and by bringing together expertise from the fields of drug delivery, molecular biology, chemistry, engineering, pharmacology and toxicology.

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