Validated alternative test methods are urgently required for safety toxicology of drugs, chemicals and cosmetics. Both REACH and 7th amendment of Cosmetics Directive call for the broad replacement of animal experiments on a short-term. While some animal tests for topical toxicity have been successfully replaced one by one by alternative methods, systemic toxicities require new test strategies in order to achive an adequate safety level. The aim of A-Cute-Tox is to develop a simple and robust in vitro testing strategy for prediction of human acute systemic toxicity, which could replace the animal acute toxicity tests used today. The involvement of ECVAM in the project management and that of regulators (such as ECB) guarantees of the follow-up. The Scientific objectives of the project are: 1. Compilation, critical evaluation and generation of high quality in vitro and in vivo data for comparative analysis. 2. Identifying factors (ADE, metabolism and organ specificity) that influence the correlation between in vitro toxicity (concentration) and in vivo toxicity (dosage), and to define an algorithm that accounts for this. 3. Explore innovative tools and cellular systems to identify new end-points and strategies to better anticipate animal and human toxicity. 4. To design a simple, robost and reliable in vitro test strategy amenable for robotic testing, associated with the prediction model for acute toxicity. The project will develop the concepts required to compose testing strategies via the continuous implementation of novel in vitro and in silico alternatives. The approach requires the dimensions of a transnational Integrated Project, involving prominent toxicity research groups in the EU, close monitoring by and input from the regulatory community and professional managerial steering. In return, it offers the realistic opportunity to achive a substantial reduction of animal experiments in acute systemic toxicity assessments.
Keywords:
Acute toxicity testing, biokinetic modelling, biotransformation, BBB models, in vitro models, in silico models, gut absorption, distribution, human, neurotoxicity, nephrotoxicity, hepatotoxicity, QSAR
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