Reduce, Refine, Replace: New Opportunities in Alternatives Research

?R eduction, refinement, and replacement--the Three R's--are the basic tenets of EU research and other policies concerning the use of animals in scientific testing and experimentation.

?Research into alternative methods to animal experimentation and testing is more than ever a necessity. The new EU system for registration, evaluation, authorisation, and restriction of chemical substances foresees risk assessment for 30,000 chemical substances by 2012, at a cost of ?2.1 billion. According to independent estimates, this would imply the use of several million animals."

These words are taken from a press release issued by the European Commission on 9 July 2002, in connection with a conference held in Brussels on Research into Alternatives to Animal Experimentation. During the conference Philippe Busquin, the EU Research Commissioner, said, ?This is a challenge for the research community, but we can only get a good result if there is a joint effort between scientists, national administrators, industry, nongovernmental organisations and policy-makers." As an indication of the EU?s commitment, some of the funding for this effort will be provided through the Sixth Framework Programme of the European Commission, which covers 2003 to 2006. The question, though, is how much, and whether the funding for the development and validation of replacement alternative tests will be adequate--and what genuine support the EU Member States themselves will give to the Three R's.

Nonetheless, my message to young scientists is that this signal of a renewed commitment to the Three R's should also lead to unique career opportunities. I will explain why.

The EU chemicals legislation (see box--EU Chemicals Policy) distinguishes between ?existing substances," that is, chemicals declared to have been on the market before 18 September 1981, when the current system for registering chemical substances came into force, and ?new substances" registered since that date. According to this distinction, there are about 100,000 existing substances, and 3000 new substances.

EU Chemicals Policy

The potential danger to human health and the environment represented by the existing substances is unknown, hence the new policy. The initial focus will be primarily on the approximately 30,000 substances that are marketed in volumes greater than 1 tonne per year. The problem is the immense amount of work needed, first to evaluate the need for further testing, and then to conduct tests to provide any missing data on potential hazards. These data, coupled with estimates of likely exposure, will be required for conducting risk assessments as a basis for risk limitation and risk management.

It is not possible at this time to say how much additional testing will be required or how many laboratory animals would be needed, although authoritative estimates speak of more than 10 million animals. Additional animal testing on such a scale would be very time consuming, highly expensive, and politically very unpopular, especially given increasing doubts as to whether the data gathered could be used effectively in increasing protection of human health and the environment. This is not only because tests on laboratory animals can cause much suffering, but also because the relevance of the data they provide for predicting effects in humans or other animals is severely limited by differences among major species. Also, it is rarely possible to reproduce in the laboratory the kinds of exposure that humans are likely to encounter or that are relevant to the environment in general.

Be that as it may, one thing is certain--this is a golden opportunity for the development, validation, and application of alternative test methodologies and testing strategies, namely, procedures that do not rely on the use of laboratory animals.

Replacement alternative methods include the use of data concerning the physicochemical properties of chemicals; predictions based on structure-activity relationships, including the use of qualitative and quantitative mathematical models; the biokinetic modelling of physiological, pharmacological, and toxicological processes; experiments on lower organisms not classed as ?protected animals" (i.e., bacteria, fungi, plants, invertebrate animals); studies on vertebrates at early stages of development (before they become ?protected animals"); studies on in vitro systems (whole perfused organs, tissue slices, cell and tissue cultures, and subcellular fractions); and human studies (including estimations of occupational and environmental exposure, postmarketing surveillance, epidemiology, and the ethical and strictly controlled use of human volunteers).

The European Centre for the Validation of Alternative Methods ( ECVAM), which is part of the Institute for Health & Consumer Protection of the European Commission?s Joint Research Centre, has just produced a comprehensive review of the current status of alternative methods for chemicals testing and prospects for their further development ( 1). It is expected that this will provide the basis for the necessary research effort.

It is also important to recognise that numerous exciting technological developments are taking place, which, in due course, promise to revolutionise our understanding of the causes, prevention, and treatment of diseases, as well as the applied sciences of pharmacology and toxicology. For example, the use of computer graphics permits cellular receptors to be visualised and the design of molecules to fit them. High-throughput systems make it possible for thousands of molecules to be screened for potentially useful pharmacological activity. Cells can be transfected with selected genes with specific properties as a means of evaluating the mechanisms of interaction between cells and chemicals.

Of particular interest are the emerging techniques for genomics and proteomics, which allow profiles of gene expression and protein synthesis to be produced and comparisons to be made between normal and abnormal cells, as well as between cells before and after exposure to medicines or toxic chemicals. These new approaches will provide huge amounts of data, so their exploitation will also depend on further developments in the computer sciences and bioinformatics.

Where Will the Jobs Be?

The legislation to put the new chemicals policy into practice is currently being drawn up, and it is certain that alternatives will play a key role in its execution. There will be funding and jobs from industry, as well from the Member States, which will share the administrative burden with the Commission.

If you?re interested in moving into alternatives research from another subject area, you should do some background reading on this new field, so that, both on application forms and in interviews, you can show how your own training and experience could be useful. It also will give you some feeling for what is important and what kinds of contributions you could make to the field. Here are some good places to start:

Thus, if the challenge issued by Commissioner Busquin is to be met, and if the potential benefits spelled out in the ECVAM report and offered by the emerging new technologies are to be reaped, a very large number of young scientists from all kinds of disciplines will have to be recruited, in industry, in academia, and in government departments and research institutes. It is clear that expertise will be needed in chemistry and physics; in mathematics and statistics; in computer science and information science; in biology, biochemistry, and molecular biology; in pharmacy, pharmacology, and toxicology; in ecology and ecotoxicology; in medicine; and in law.

ECVAM advocates the integrated use of alternative methods in intelligent testing strategies, such as the combined use of computer models based on quantitative structure-activity relationships (QSARs) and cell culture systems. Such an approach can be conducted by teams of scientists from different backgrounds, but individuals who are themselves trained in different disciplines are especially valuable, for example, a biochemist who is a competent statistician, a chemist capable of developing QSAR models, or a molecular biologist with a knowledge of pharmacology.

Therefore, my advice to young scientists considering what kind of research to do for a Ph.D. or where to do a postdoctoral fellowship, would be to heed the motto of the county of Norfolk, U.K., and ?do different," learning a varied combination of skills as a means of becoming more interesting to potential employers.


1. A. P. Worth and M. Balls, "Alternative (nonanimal) methods for chemicals testing: current status and future prospects," ATLA ( Alternatives to Laboratory Animals) 30, supplement 1, 125 pp. (2002) (Available online from

Michael Balls is an emeritus professor in the University of Nottingham and has been Chair of the Trustees of FRAME ) since 1981. From April 1993 until June 2002, he was the first head of ECVAM.

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