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April 15, 2010

EU Initiative to ‘AXLR8’ Move to High-Tech, Animal-Free Methods For Chemical and Drug Testing

AXLR8, an ambitious European Commission-funded initiative [1] has launched today as part of growing international efforts to revolutionise chemical and drug safety testing with sophisticated "21st century" cell- and computer-based methods. A successful transition to 21st century toxicology could mean the end of animal testing as it exists today, sparing at least a million animals from suffering and death each year in the European Union alone [2].

AXLR8 (=accelerate) is a unique collaboration between Humane Society International [3] and academic scientists and technical experts from Germany and Belgium [4]. The initiative, which has been awarded a half-million-Euro grant from the European Commission under the 7th Framework Programme for Research and Technology Development, will help to monitor and support European research to modernise the science of safety testing, and strengthen international co-ordination in this area. The vision is of a not-so-distant future in which most toxicity testing is carried out using a combination of computer modelling and human cell tests, which can already be performed with unparalleled efficiency using "high throughput" testing robots capable of working nearly 1,500-times faster than a human technician [5].

Says Troy Seidle, director of research & toxicology for Humane Society International:

"Exposing relatively short-lived animals to unrealistic doses of chemicals in sterile laboratory conditions is a primitive approach to assessing chemical effects on humans in real-life conditions. The scientists and global corporations HSI is working with are only too aware of the urgent need to bring the science of safety testing into the 21st century. If utilised to their full potential, cutting-edge cell- and computer-based methods could transform toxicity testing, making it quicker, cheaper and more applicable to real-life human exposure scenarios. As well as having enormous benefits for human health and environmental protection, this transition towards 21st century toxicity could significantly reduce and ultimately replace testing on animals." 

There is considerable momentum behind the aim of a global transition to more modern and humane approaches in toxicity testing. In 2007 the United States National Research Council published the influential report "Toxicity Testing in the 21st Century: a Vision and a Strategy" [6] calling for just such an overhaul of safety testing. As a result, U.S. regulatory and research agencies joined forces under the banner of the "Tox21" initiative [7] to advance the scientific understanding of cellular mechanisms by which chemical toxicity occurs, and to develop more predictive methods for safety testing. In 2009, experts from six continents representing industry, academia, in vitro sciences and animal welfare endorsed a global resolution endorsing the NRC vision [8]. 

Toxicity data are needed to evaluate chemicals used in everything from cosmetics and household cleaners to pharmaceuticals, food additives and pesticides. However, scientists and legislators across the EU and United States are coming to recognise that conventional tests, in which animals such as rodents, rabbits and dogs are given unrealistically large doses of chemicals, are too costly, time-consuming and of uncertain relevance to human health effects to meet the demands for better and faster data as part of new chemicals regulation such as REACH [9]. A recent report by the U.S. Food & Drug Administration estimates that new drug candidates have only an 8 percent chance of reaching the market, in large part because animal studies so often "fail to predict the specific safety problem that ultimately halts development" [10].

For example, to evaluate the cancer-causing potential of a single chemical in a conventional rodent test takes up to 5 years, 800 animals and 3 million Euros [11]. For the same price and without any use of animals, as many as 350 chemicals could be tested in less than one week in 200 different cell or gene tests using a robot-automated high throughput approach [12]. This mechanistic approach involves a virtual "dissection" of the human body into its various cell types (brain, skin, lung, liver, etc.) and then tests each of these cell types individually for different types of toxic response. Computerised systems biology and pharmacokinetic models are then used to recreate the whole body scenario and relate conditions at the cellular level to expected real-world conditions for a living, breathing human being.

Humane Society International and its affiliates are spearheading initiatives in the EU and U.S. to achieve this transition away from observing gross pathological effects in chemically overdosed animals to one based on studying how chemicals interact with "cellular pathways" in the human body at environmentally relevant exposure levels. Some of the globe's largest consumer product, chemical and pharmaceutical companies – Dow, DuPont, Johnson & Johnson, Procter & Gamble, Unilever – have joined forces with HSI and its affiliates to add corporate support to help bring about the evolution in toxicology [13]. And in the EU, the HSI-envisioned AXLR8 initiative will bring together leading scientists to advise the European Commission regarding future research needs and priorities to transition towards 21st century toxicology.

Mapping the toxic pathways of the human body is an ambitious project that could take between 10 and 20 years – toxicology's equivalent of mapping the human genome. Such a "big biology" project will require international collaboration and substantial investment, which is why HSI is working on both sides of the Atlantic to bring together international experts comprising academia, industry, government and regulators.  

The European Union has long been a world-leader in the development and regulatory uptake of animal replacement, reduction and refinement (3Rs) approaches in toxicity testing. Over the past 20 years, the European Commission has invested upwards of 200 million Euros in the 3Rs, and already some EU-pioneered tests have been internationally accepted, including tests for skin irritation, phototoxicity and pyrogenicity [14]. Funding from the Commission's 6th and 7th Research Framework Programmes is currently supporting 18 large-scale integrated projects to develop non-animal methods and strategies for reproductive toxicity and carcinogenicity, skin allergy and other health and environmental concerns [15].

Recent advancements in molecular and cellular biology have made possible the realisation of the vision of 21st century toxicology. A range of new tools exist – such as functional genomics, proteomics, metabonomics, high data content screening and systems biology – that can be used for studying the effects of chemical stressors in the human body at a molecular and cellular level in a time- and cost-efficient manner. Rapid screening using high-throughput robotic automation means that thousands of substances can be processed in a single day. In this way data can be available to regulators in hours instead of days, weeks or even years, making future chemicals regulation more intelligent and responsive.

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Notes:

1.     AXLR8 (website: axlr8.eu) is an EU-funded coordination project developed on the initiative of Humane Society International, the Free University of Berlin, and the Flemish Institute for Technological Research.  

2.     Fifth Report on the Statistics on the Number of Animals used for Experimental and other Scientific Purposes in the Member States of the European Union (website: http://bit.ly/cg4z9y)

3.     Humane Society International and its partner organisations together constitute one of the world's largest animal protection organisations—backed by 11 million people. For nearly 20 years, HSI has been working for the protection of all animals through the use of science, advocacy, education and hands-on programs. Celebrating animals and confronting cruelty worldwide (website hsieurope.org).

4.     The Free University of Berlin (website: fu-berlin.de) and the Flemish Institute of Technological Research (website: cardam.eu)

5.     NIH/EPA Safety Testing of Chemicals: Sound Bites and Videos – sound bite #4 (website: http://bit.ly/9XJwQ3)

6.     Toxicity Testing in the 21st Century: A Vision and a Strategy (website: http://bit.ly/c7WMed)

7.     Tox21: Putting a Lens on the Vision of Toxicity Testing in the 21st Century (website: http://bit.ly/cT1mlm)

8.     Call for a new approach to toxicity testing & risk assessment to move away from animal use and better protect health, safety and the environment: signed by delegates at the 7th World Congress on Alternatives and Animal Use in the Life Sciences, Rome, August 2009 (website: http://bit.ly/l7Y18).

9.     Regulation No. 1907/2006 on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). (website: http://bit.ly/9mYso2)

10.   US Food and Drug Administration, "Challenges and Opportunities Along the Critical Path to New Medicinal Products" (website: http://bit.ly/b9Wg6z)

11.   Billington et al. Critical Reviews in Toxicology 2010; 40:35-49 (website: http://bit.ly/9LX4Ds)

12.  Personal communication from Dr. Chris Austin, director of the US National Institutes of Health Chemical Genomics Center.

13.   Human Toxicology Project Consortium flyer (website: http://bit.ly/90eZwQ)

14.   European Centre for the Validation of Alternative Methods (website: http://bit.ly/9zKC1G)

15.   "Alternative Testing Strategies: Progress Report 2009" (website: http://bit.ly/d3yA9e

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