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Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH)

  • REGULATORY TOXICOLOGY
  • Published:
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Abstract

During the last two decades, substantial efforts have been made towards the development and international acceptance of alternative methods to safety studies using laboratory animals. In the EU, challenging timelines for phasing out of many standard tests using laboratory animals were established in the seventh Amending Directive 2003/15/EC to Cosmetics Directive 76/768/EEC. In continuation of this policy, the new European Chemicals Legislation (REACH) favours alternative methods to conventional in vivo testing, if validated and appropriate. Even alternative methods in the status of prevalidation or validation, but without scientific or regulatory acceptance may be used under certain conditions. Considerable progress in the establishment of alternative methods has been made in some fields, in particular with respect to methods predicting local toxic effects and genotoxicity. In more complex important fields of safety and risk assessment such as systemic single and repeated dose toxicity, toxicokinetics, sensitisation, reproductive toxicity and carcinogenicity, it is expected that the development and validation of in silico methods, testing batteries (in vitro and in silico) and tiered testing systems will have to overcome many scientific and regulatory obstacles which makes it extremely difficult to predict the outcome and the time needed. The main reasons are the complexity and limited knowledge of the biological processes involved on one hand and the long time frame until validation and regulatory acceptance of an alternative method on the other. New approaches in safety testing and evaluation using “Integrated Testing Strategies” (ITS) (including combinations of existing data, the use of chemical categories/grouping, in vitro tests and QSAR) that have not been validated or not gained wide acceptance in the scientific community and by regulatory authorities will need a thorough justification of their appropriateness for a given purpose. This requires the availability of knowledge and experience of experts in toxicology. The challenging deadlines for phasing out of in vivo tests in the Cosmetics Amending Directive 2003/15/EC appear unrealistic. Likewise, we expect that the application of validated alternative methods will only have a small or moderate impact on the reduction of in vivo tests under the regimen of REACH, provided that at least the same level of protection of human health as in the past is envisaged. As a consequence, under safety aspects, it appears wise to consider established in vivo tests to be indispensable as basic tools for hazard and risk assessment with respect to systemic single and repeated dose toxicity, sensitisation, carcinogenicity and reproductive toxicity, especially regarding quantitative aspects of risk assessment such as NOAELs, LOAELs and health-related limit values derived from them. Based on the overall evaluation in this review, the authors are of the opinion that in the short- and mid-term, the strategy of the development of alternative methods should be more directed towards the refinement or reduction of in vivo tests. The lessons learnt during these efforts will provide a substantial contribution towards the replacement initiatives in the long-term.

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Notes

  1. European Chemical Industry Council

  2. Another term for chemical category approach is grouping which is the favoured term in the frame of REACH (Art. 13, Annex XI; see also ECB 2005, 2007.

  3. With regard to the definitions and use of various data gap filling techniques the reader is referred to the Draft TGD (ECB 2007).

  4. A prevalidation study is a small-scale interlaboratory study that is designed to obtain a preliminary assessment of the reliability and relevance of the study.

  5. A formal validation study is an interlaboratory study that is designed to obtain a more definite assessment of reliability and relevance.

  6. In the EU, the ECVAM Scientific Advisory Committee (ESAC) is responsible for scientific acceptance. It consists of experts from all Member States, relevant industrial associations, academic toxicology institutions, the animal welfare movement, as well as certain Commission services.

  7. Zentrale Erfassungs- und Bewertungsstelle für den Ersatz von Tierversuchen (Centre for Documentation and Evaluation of Alternatives to Animal Experiments, Berlin)

  8. Phototoxicity is of minor importance for chemicals under REACH and is therefore not considered in the following.

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Acknowledgements

We thank Dr. Rüdiger Bartsch, Technical University of Munich, Dr. Charlotte Esser, University of Düsseldorf, Dr. Klaus Becker, Dr Simone Müller, Bayer Schering Pharma AG, Berlin, Prof. Dr. Hans-Werner Vohr, Bayer AG, Wuppertal for valuable contributions and helpful discussions.

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Authors and Affiliations

  1. Dr. Lilienblum Consulting Toxicology LiCoTox, 30966, Hemmingen/Han, Germany

    W. Lilienblum

  2. Institute of Toxicology, University of Würzburg, Versbacher Straße 9, 97078, Würzburg, Germany

    W. Dekant

  3. Institute of Environmental Toxicology, University of Halle, 06097, Halle/Saale, Germany

    H. Foth

  4. Federal Institute for Occupational Safety and Health, Friedrich-Henkel-Weg 1-25, 44149, Dortmund, Germany

    T. Gebel

  5. Leibniz Research Centre for Working Environment and Human Factors (IfADo), University of Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany

    J. G. Hengstler

  6. Institute of Toxicology, Heinrich-Heine-University, PO Box 101007, 40001, Düsseldorf, Germany

    R. Kahl

  7. Institute of Toxicology, Merck KGaA, 64271, Darmstadt, Germany

    P.-J. Kramer

  8. Nonclinical Drug Safety, Bayer Schering Pharma AG, 13342, Berlin, Germany

    H. Schweinfurth

  9. Lower Saxony Governmental Institute of Public Health, Roesebeckstraße 4-6, 30449, Hannover, Germany

    K.-M. Wollin

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Lilienblum, W., Dekant, W., Foth, H. et al. Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH). Arch Toxicol 82, 211–236 (2008). https://doi.org/10.1007/s00204-008-0279-9

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