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RTD info logoMagazine on European Research N° 48 - February 2006   
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ALTERNATIVES TO EXPERIMENTS USING ANIMALS
Title  Action stations for in vitro

Tuesday 13 December 2005 was an important day for the chemicals sector. It was then that the EU Competition Council gave the green light for the entry into force of the famous REACH legislation. Industrialists are now obliged to organise a vast evaluation and control exercise to ensure the safety for human health and the environment of almost 30 000 chemicals currently available on the market. While REACH is an historic advance for public health and the quality of life, its implementation raises the controversial and far from secondary issue of a massive increase in experiments inflicting suffering on animals. The desire to limit substantially the hecatomb among laboratory animals is serving to shed the spotlight on progress in in vitro tests. In many respects, the latter could even prove scientifically superior in guaranteeing that chemical molecules are without risk to man or nature.

Progress in in vitro methodologies.
Progress in vitro methodologies would make it possible to avoid tests that could otherwise involve experiments on several millions of animals over the next decade.
Nobody would deny that the need to ‘consume’ others lies at the very heart of the natural world and interaction between species. Man, a carnivore, has extended this right to use other members of the animal kingdom for his own purposes into many different fields, not least of which is progress in knowledge by carrying out experiments on laboratory animals. Without this ‘sacrifice’ of other species for scientific ends, we would quite simply be denied the constant progress brought about by medicine and pharmacology.

But, inevitably, the right to use animals for the purposes of experiments raises ethical issues – at least that is the strongly held view of a section of public opinion that wants to be fully informed about the precise aims and methods of such practices.

What is more, this is not in any way a subject that the scientific community seeks to avoid as it also recognises the legitimacy of the debate and accepts that the ‘need’ for animal testing raises real questions. It was as long ago as 1957 that the scientists W. Russell and R. Burch formulated the deontological rule known as the three Rs – Reduction, Refinement and Replacement – to be applied to the necessary recourse to tests on laboratory animals to ensure that the suffering inflicted is kept to an absolute minimum. This charter of good conduct is today a universal leitmotif recognised throughout the world of research and industry.

The last of these three Rs – Replacement  implies the need to find alternatives to in vivo experiments on animals by means of in vitro methods. The latter covers the development and use of reactive tests in the ‘test tube’ on cell cultures or tissue without the use of laboratory animals. This has become an extremely active field of research that continually draws on progress in the biosciences. 

Urgency created by REACH
Cells
Cells
Cells
The problem of using animals assumes a much more acute dimension when it occurs in a field that clearly extends beyond that of scientific research proper and is for the purposes of what is known as toxicology, i.e. the need to ensure that the constant development of technico-chemical innovations is without danger.

At European level, an initial decision of importance for strengthening the priority given to the three Rs came in 2003 when the European Cosmetics Directive outlawed the animal testing of cosmetics. This obliges industrialists in the sector to cease any use of tests on animals when making their analyses.

The huge task of the multisectoral toxicological monitoring required by virtue of the REACH legislation has now placed the subject right back on the agenda as it raises the spectre of tests involving several million laboratory animals over the next decade. It is the increasing rate at which innovations are being introduced in the field of in vitro testing that should make it possible to avoid this suffering. 

It should also be stressed that, in addition to a response to the ethical questions, the arguments in favour of progress in in vitro testing also carry considerable weight in purely functional or economic terms. For the chemical industry, tests on laboratory animals are considerably more costly than in vitro tests. At the operational level, the latter also offer many advantages in terms of the flexible scalability of tests, the automation of procedures, management of the stored results, etc. One field that is developing very rapidly at present is that of Quantitative Structure-Activity Relationships or QSARs. These innovative computer tools for mathematical modelling are making it possible to strengthen the fields of investigation.  

Last but not least, the question of the comparative validity and reliability of the two approaches is being highlighted with growing frequency. The notion that the animal does not necessarily predict human behaviour is one that more and more scientists are coming to accept. The species barrier means that zones of uncertainty remain and the potential surprises introduce risk margins that can prove very dangerous (see box).

ECVAM
Charged with drawing up common scientific standards for the Member States via the European Chemicals Bureau (ECB), the EU has long been attentive to this issue of alternatives to testing methods involving animals. As early as 1991, the European Commission set up the European Centre for the Validation of Alternative Methods (ECVAM) at the Joint Research Centre in Ispra (IT), and charged it with validating procedures for alternatives to experiments using animals. In addition to its role in analysing and validating recommendations for alternative practices, this scientific body is a central point in technological monitoring and the accumulation of knowledge, which it makes available through its Scientific Information Service (SIS) database. It fulfils its role in close co-operation with its US counterpart, the Interagency Coordination Committee on the Validation of Alternative Methods, and with the OECD’s (Organisation for Economic Co-operation and Development) Environmental Section, the two other reference bodies in this field.

As ever tighter safety regulations have been applied to European toxicology, so the ECVAM has expanded its activities to cover an increasingly wide field. Today, it has 11 departments devoted to as many types of toxicity – and thus in vitro tests that must be validated. This enables it to study an increasingly diverse range of alternative methods. It is also involved in research in this field. 

Research moves up a gear
Having supported the development of various in vitro methods during previous Framework Programmes, European research policy is also moving up a gear and currently allocates nearly €30 million to three Integrated Projects involving over 90 public and industrial laboratories.

Thirty-five partners from 12 EU countries plus Switzerland are currently working on the A-Cute-Tox (2005-2010) initiative, coordinated by the University of Oulu (FI). This project is concerned with acute systemic toxicity and is trying to develop a reliable method to replace present in vivo procedures in this field. The work involves reviewing existing technologies, identifying error factors, developing new tools and, finally, designing a global strategy amenable for robotic testing and linked to a computer forecasting model. 

For its part, the ReProTect (2004-2008) project is concerned with reproductive toxicity, a field that takes a particularly heavy toll on laboratory animals. The 27 project partners are organised into specific working groups dedicated to different aspects of the issue, such as masculine or feminine fertility, embryo implantation, pre- or post-natal development, and transverse techniques. Again, in vitro tests, computer models and sensors are being examined, developed if necessary, and then incorporated in a global strategy for the analysis of chemical products. 

Finally, the Sens-it-iv (2006-2010) Integrated Project is looking at the question of the hypersensitivity of the lungs and skin to certain products. Once again, the aim of its 31 partners is to develop a global strategy for in vitro analyses.

In these three cases, the word ‘integrated’ could not be more appropriate as the Commission is financing projects launched in response to the situation created by the REACH legislation and the Cosmetics Directive. The methods developed will pass to the ECVAM for validation before coming before the European regulators (ECB) and the OECD at world level. 

Finally, the Union is also supporting projects such as Toxdrop or NHR Devtox . The former is developing an original technology for rapid miniaturised cell culture, based on a genuine ‘cell chip’. The latter is concerned with the specific problem of nuclear hormone receptors. These molecules, which trigger the reaction of cells to hormones, can also interact with chemical products that resemble the hormones, resulting in serious development or reproduction disorders.  


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  The toxicogenomic line of inquiry

"A growing number of toxicologists are coming to recognise that all methods that are validated with reference to animal experimentation, including by in vitro means, can come up against the fundamental problem of the difference between species,” notes Thomas Hartung, Director of the ...
 
  IVTIP: the in vitro showcase for industrialists

Set up in 1993, the IVTIP (In Vitro Testing Industrial Platform) is a forum for industrialists concerned by in vitro  tests, including pharmaceutical laboratories, chemists and biotechnological SMEs. As a firm supporter of the ‘three Rs’ approach, the association advises the ...
 
  Toxicities and the target organs

There are several types of toxicity, each of which is analysed by a series of specific tests using different animal species.

Systemic toxicity concerns the body as a whole, with special focus on the liver as the organ that cleans the body of foreign substances carried in the blood. Systemic toxicity ...
 

  TO FIND OUT MORE  
 
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  • ECVAM
  • NCA (Netherlands Centre Alternatives to Animal Use )
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      The toxicogenomic line of inquiry

    "A growing number of toxicologists are coming to recognise that all methods that are validated with reference to animal experimentation, including by in vitro means, can come up against the fundamental problem of the difference between species,” notes Thomas Hartung, Director of the ECVAM (JRC). "Their results do not necessarily predict what will happen in man. But, of course, it is ethically impossible to test substance toxicity on humans. If we want to establish references using in vitro tests, we must therefore seek another way of predicting reaction to chemical products. The toxicogenomic approach is one of these innovative lines of inquiry with the potential to remove this obstacle, but it is still at the research stage.” 

    This emerging field is one of the potentially exploitable results of the decoding of the human genome and progress in understanding the role of genes. The principle involves analysing how exposure of a human cell to a chemical product can lead to a variation in gene expression, indicating a toxic effect. The measurement of the variation, detectable by means of DNA chips, would then become an instrument for measuring toxicity. Taken further, this approach could, at a subsequent stage, be used to analyse the impact on the proteins produced by cells – at which point one would speak of ‘toxicoproteomics’ – and we could then try and understand what happens to them in the body and move on to a ‘toxicometabolic’ dimension.

    As members of Antidote-Europe, a group of scientists – with the support of NGOs that are opposed to animal experimentation – are acting as spokesmen for the hopes raised by the development of this toxicogenomic approach, in particular in connection with the REACH legislation. “To date, we have tested the relevant and concordant genomic response of human liver cells when subjected to 28 toxic substances present in the environment,” says Claude Reiss, a biologist at the CNRS in France and an active member of the movement. “In addition to sparing the animals used for the toxicological tests which, in any event, do not bring sufficient guarantees of scientific safety, the toxicogenomic approach permits substantial financial savings.”  

    If nothing else, he hopes to be able to speed up awareness of the new urgency brought by the REACH legislation. “A complete ECVAM department is dedicated to this toxicogenomic approach,” stresses Sandra Coecke, Head of research in this field. “Two years ago we embarked on a major effort to standardise methods. It is a promising field, but the critical elements for operational validation are not yet sufficient.” 

      IVTIP: the in vitro showcase for industrialists

    Set up in 1993, the IVTIP (In Vitro Testing Industrial Platform) is a forum for industrialists concerned by in vitro  tests, including pharmaceutical laboratories, chemists and biotechnological SMEs. As a firm supporter of the ‘three Rs’ approach, the association advises the European Commission on industry’s needs in the field of in vitro research and encourages the development, validation and homologation of these methods. It organises public seminars and publishes recommendations, statements of principles and a newsletter.

      Toxicities and the target organs

    There are several types of toxicity, each of which is analysed by a series of specific tests using different animal species.

    Systemic toxicity concerns the body as a whole, with special focus on the liver as the organ that cleans the body of foreign substances carried in the blood. Systemic toxicity can be acute (rapid effects) or chronic.

    Local toxicity concerns precise organs that are targeted by specific products or exposure: the skin, eyes, lungs or nervous system. 

    Disproportionate immune reaction, or hypersensitivity, is a particular form of toxicity.

    In the longer term, the cancerogenicity of products is also tested, as well as their reproductive toxicity (effects on fertility and hereditary effects). 

    Ecotoxicity is concerned with a substance’s impact on the environment. In addition to these traditional cell cultures, a new generation of techniques is emerging that draws on the progress made in molecular genetics and bioinformatics.

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