The RAx approach is one of the most promising new risk assessment strategies. Although frequently chosen in regulatory submission dossiers, this method often fails to be accepted by regulatory agencies, as the associated uncertainties are perceived as being too large. In its first three years, the EU-ToxRisk project has addressed this issue by developing an RAx approach that reduces uncertainties by adding NAM-generated (in silico and in vitro) data to the available in vivo data.
The EU-ToxRisk workshop on "NAM-supported read-across: from case studies to regulatory guidance in safety assessment" took place on May 21-22, 2019 and was organized by EU-ToxRisk, in close collaboration with representatives from several European regulatory agencies (ECHA, EFSA, SCCS), US agencies (NTP, EPA), and other organizations (OECD, Health Canada, NIHS Japan).
On this occasion, a group of more than 60 international experts from industry, academia, and regulatory authorities came to Helsinki/Espoo (Finland) to discuss different case studies developed within EU-ToxRisk, but also at the OECD/IATA, and NIHS Japan programs.
This unique occasion allowed the collection of the scientific and regulatory expert feedback on various RAx scenarios, serving as input to an EU-ToxRisk advisory report for NAM-supported RAx. This advisory document will target the broader toxicology community. It will contain practical instructions on RAx applications in different regulatory contexts to improve the quality of submissions by registrants and to increase the acceptance/success rate of non-animal approaches (1).
Another dimension of new approaches is the application of microphysiological systems (MPS). This comprises the use of 3D organoids and the co-culture of relevant cell types, such as neuronal and glial cells. Moreover, it is directed towards a multi-organ-on-a-chip technology (e.g., developed by the EU-ToxRisk partners TissUse, together with InSphero, Biotalentum, and the Katholieke Universiteit Leuven). The project plans to use four different organs on one chip, all integrated with microfluidics.
This topic was discussed at the t (4) think tank meeting on "Biology-Inspired Microphysiological System Approaches to Solve the Drug Testing Dilemma" which took place on June 18-20 2019, in Berlin (Germany). Almost 40 international experts, including MPS developers, test centers, industry, and regulatory end-users sat together to discuss the application of MPS in the drug safety assessment process. The prime focus was on the issues of industrial adoption and regulatory acceptance, including the validation of MPS-based approaches. An important focus was given to the definition of strategies and the development of recommendations to overcome the identified roadblocks.
In June, an overview of the EU-ToxRisk approach was published in Current Opinion in Toxicology by Grapel et al. (2019). This publication shows how the EU-ToxRisk in vitro/in silico toolbox has been applied to different toxicological scenarios. Some interesting applications of these tools have been recently published as a result of the integrative use of novel in vitro and in silico methods. Schimming et al. (2019) described the application of quantitative image analysis for prediction of cholestasis-inducing toxicants. The authors described the use of high-throughput live-cell visualization of GFP-tagged key proteins of the oxidative stress response/Nrf2 pathway and inflammatory cytokine signaling to follow the temporal responses of individual cells. In another milestone publication, Albrecht et al. (2019) established a novel in vitro/in silico method to predict the risk of human drug-induced liver injury (DILI) in relation to oral doses and patient blood concentrations. The performance of the in vitro system was optimized by the application of two novel test performance metrics: the toxicity separation index, which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds; and the toxicity estimation index, which measures how well in vivo hepatotoxic blood concentrations can be estimated.
The kick-off meeting for the new round of EU-ToxRisk case studies has taken place. The new set of case studies will address different, and relatively challenging, regulatory and scientific questions: testing of chemicals with little or no observed adverse effects or with multi-target organ toxicity. These will utilize the EU-ToxRisk battery of NAMs and assess its applicability in these contexts. In collaboration with the EC-Joint Research Center (JRC), a strong focus will also be on the assessment of chemicals without any prior knowledge of their in vivo effects and in the absence of any similar structures with in vivo data (so-called ab initio case studies).
The chosen focus is in line with the main aim of the project to further advance the field of NAM based hazard assessment. EU-ToxRisk partners will report on the achievements and challenges of the project at the 55th Congress of the European Societies of Toxicology (EUROTOX 2019) in two dedicated sessions.
Albrecht, W., Kappenberg, F., Brecklinghaus, T. et al. (2019). Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations. Arch Toxicol, Epub ahead of print. doi:10.1007/s00204-019-02492-9
Graepel, R., ter Braak, B., Escher, S. E. et al. (2019). Paradigm shift in safety assessment using new approach methods: The EU-ToxRisk strategy. Curr Opin Toxicol 15, 33-39. doi:10.1016/j. cotox.2019.03.005
Schimming, J. P., Ter Braak, B., Niemeijer, M. et al. (2019). System microscopy of stress response pathways in cholestasis research. Methods Mol Biol 1981, 187-202. doi:10.1007/978-1-4939-9420-5 13
This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 681002.
|Printer friendly Cite/link Email Feedback|
|Author:||Pallocca, Giorgia; Leist, Marcel|
|Publication:||ALTEX: Alternatives to Animal Experimentation|
|Date:||Jun 22, 2019|
|Previous Article:||Awards, Keynote Lectures and Sessions.|
|Next Article:||R2N welcomes over 3000 visitors to the stand at the IdeenExpo.|