Alternative methods to safety studies in experimental animals

Abstract

During the next few years two major decisions of the European Commission will have great consequences for the use of animals to evaluate the adverse eVects of chemicals on human health and the environment. The Wrst is the implementation of REACH. It requests safety assessment of a large number of chemicals, which according to the legislation should be based preferentially on alternatives to animal testing. The second is the phasing out date for studies in animals, March 2013, of the 7th amendment of the Cosmetics Guideline 76/768/EEC for repeated dose toxicity, reproductive toxicity and carcinogenicity. In contrast to these expectations or even regulations, Lilienblum et al. (2008) recently concluded that both a signiWcant reduction of animal testing for REACH and the phasing out of in vivo testing for cosmetics in a few years appear unrealistic. Consequently, the authors recommended that established in vivo tests at least at present should be considered indispensable as basic tools for hazard and risk assessment and that development of alternative methods should be more directed towards the reWnement or reduction of animal testing. The publication of this conclusion is of utmost importance because the perception and understanding of the role of in vitro tests and other alternative methods for hazard identiWcation and risk assessment of chemical substances diVers extremely between the scientiWc community and stakeholders such as animal welfare groups, parlamentarians and the public. Whereas the non-biased scientiWc community has repeatedly stressed that there are principle obstacles to completely avoiding animal studies (e.g. Greim et al. 2006), others, including politicians, assume that suYcient availability of research funding will easily overcome these obstacles. The scientiWc community has repeatedly addressed such intrinsic pitfalls. The goal of REACH and other programs is to evaluate the risk of human or environmental exposure to chemical compounds. Risk assessment follows the generally accepted methodology comprising hazard identiWcation, exposure assessment, and the assessment of the risk at a given exposure. Hazard identiWcation requires identiWcation of all relevant endpoints of adverse eVects (e.g. organ-speciWc toxicity, carcinogenicity, genotoxicity, reproductive toxicity or teratogenicity), their dose responses, thresholds and the NOEL of the prominent eVect. Toxicokinetic data clarify the metabolic fate of the chemical under assessment and can provide a scientiWc basis for this extrapolation. Based on our current understanding of biological complexity, it is very unlikely that a few selected cell culture models could mimic the multitude of potential target cells with respect to physiology, biochemistry, pathogenesis, capacity for biotransformation of chemicals and hence the sensitivity to toxic eVects. Many chemicals show target organ-speciWc responses in animal toxicity studies arising from a combination of a number of processes. These include the accumulation of the chemical in the target organ, speciWc capacity of the target organ for biotransformation of the chemical, speciWc sensitivity of the target cells to the toxic eVects, and the complex and often poorly understood interactions of cells and their mediators in diVerent tissues and organs that are regulated by complex systems of the organism such as the neuroendocrine and immune systems. Without such understanding, an estimation of the risk of human exposure cannot be performed. The various eVects and the critical H. A. Greim (&) Institute of Toxicology and Environmental Hygiene, Technical University, Munich, Germany e-mail: helmut.greim@lrz.tum.de