AXLR8 is a coordination action funded by the European Commission Directorate General for Research & Innovation (Health Directorate; Advanced Therapies and Systems Medicine Unit) under the 7th European RTD Framework Programme Health Theme. AXLR8 will provide tools and opportunities for increased networking, information exchange, problem solving, strategic planning and collaboration among a variety of scientific disciplines and stakeholder groups with the goal to accelerate the transition to a toxicity pathway-based paradigm for chemical safety assessment. AXLR8 will act as a focal point for coordination among 3Rs research projects in Europe as well as internationally.
The European Commission is currently funding a number of research consortia to develop new 3Rs [replacement, reduction and refinement] test methods and strategies as potential alternatives to the use of animals in safety testing. Monitoring of these 3Rs activities at pan-European, national, and international levels is vital to facilitate swift progress. AXLR8 aims to fulfill this growing need by providing a focal point for dialogue and collaboration. Specifically, AXLR8 will:
Advances in molecular biology, biotechnology, and other fields are paving the way for major improvements in how scientists evaluate the health risks posed by potentially toxic chemicals found at low levels in the environment. These advances would make toxicity testing quicker, less expensive, and more directly relevant to human exposures. They could also reduce the need for animal testing by substituting more laboratory tests based on human cells.
Current reliance on high-dose animal toxicity studies and the application of extrapolation procedures is a source of uncertainty in human health risk assessment. Additionally, conventional animal tests are in general quite time consuming, low throughput, costly in both economic and animal welfare terms, and offer little mechanistic understanding of how chemicals act in the body. However, advancements in molecular and cellular biology in recent years have made available a wide range of new tools – including functional genomics, proteomics, metabonomics, high data content screening, and systems biology – for studying the effects of chemicals on cells, tissues and organisms in a rapid and cost-efficient manner. This convergence of factors, coupled with the need to evaluate the safety of an increasingly large number of chemicals and their mixtures, has prompted calls for a fundamental paradigm shift in toxicology.
Instead of focusing on signs of gross toxicity at high doses in living animals, an alternative, '21st century' approach advocated by leading scientific and regulatory authorities is to work towards a mechanistic understanding of how chemicals interact with cellular response pathways in the human body at environmentally relevant exposure levels. As critical pathways are identified, human cell-based tests can be developed to study chemical interactions at key cellular and molecular targets within a pathway. Through robotic automation, cell-based in vitro methods can enable the high throughput testing of thousands of substances in a single day. Data from toxicity pathway assays could then be integrated and interpreted with the aid of systems biology tools controlling pathway function and be combined with pharmacokinetic modeling to relate in vitro conditions to real-world human exposure levels.
The ultimate goals are to assess safety: