regulatory toxicology

/Tag:regulatory toxicology

Validation Successes: Chemicals

Horst Spielmann and Manfred Liebsch

The ECVAM validation concept, which was defined at two validation workshops held in Amden (Switzerland) in 1990 and 1994, and which takes into account the essential elements of prevalidation and biostatistically defined prediction models, has been officially accepted by European Union (EU) Member States, by the Federal regulatory agencies of the USA, and by the OECD. The ECVAM validation concept was introduced into the ongoing ECVAM/COLIPA validation study of in vitro phototoxicity tests, which ended successfully in 1998. The 3T3 neutral red uptake in vitro phototoxicity test was the first experimentally validated in vitro toxicity test recommended for regulatory purposes by the ECVAM Scientific Advisory Committee (ESAC). It was accepted by the EU into the legislation for chemicals in the year 2000. From 1996 to 1998, two in vitro skin corrosivity tests were successfully validated by ECVAM, and they were also officially accepted into the EU regulations for chemicals in the year 2000. Meanwhile, in 2002, the OECD Test Guidelines Programme is considering the worldwide acceptance of the validated in vitro phototoxicity and corrosivity tests. Finally, from 1997 to 2000, an ECVAM validation study on three in vitro embryotoxicity tests was successfully completed. Therefore, the three in vitro embryotoxicity tests, the whole embryo culture (WEC) test on rat embryos, the micromass (MM) test on limb bud cells of mouse embryos, and the embryonic stem cell test (EST) including a permanent embryonic mouse stem cell line, are considered to be scientifically valid and appropriate for routine use in laboratories of the European pharmaceutical and chemicals industries.
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Dialogue and Collaboration: A Personal View on Laboratory Animal Welfare Developments in General, and on ECVAM’s First Decade in Particular

Herman B.W.M. Koëter

A personal view is presented on progress made during the last 25 years in applying the Three Rs (reduction, refinement, replacement) to animal testing in regulatory toxicology, with an emphasis on "good moments" (for example, international workshops on the principles and practical application of the validation process and on regulatory acceptance) and "not-so-good moments" (for example, the time taken to accept alternatives to the LD50 test and to accept in vitro tests for skin absorption as OECD Test Guidelines). The importance of dialogue and cooperation between international coordinating centres and scientific activities at the national level is stressed, as exemplified by the work of ECVAM during its first decade.
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The Use of a Chemistry-based Profiler for Covalent DNA Binding in the Development of Chemical Categories for Read-across for Genotoxicity

Steven J. Enoch, Mark T.D. Cronin and Claire M. Ellison

An important molecular initiating event for genotoxicity is the ability of a compound to bind covalently with DNA. However, not all compounds that can undergo covalent binding mechanisms will result in genotoxicity. One approach to solving this problem, when in silico prediction techniques are being used, is to develop tools that allow chemicals to be grouped into categories based on their ability to bind covalently to DNA. For this analysis to take place, compounds need to be placed within categories where the trend in toxicity can be explained by simple descriptors, such as hydrophobicity. However, this can occur only when the compounds within a category are structurally and mechanistically similar. Chemistrybased profilers have the ability to screen compounds and highlight those with similar structures to a target compound, and are thus likely to act via a similar mechanism of action. Here, examples are reported to highlight how structure-based profilers can be used to form categories and hence fill data gaps. The importance of developing a well-defined and robust category is discussed in terms of both mechanisms of action and structural similarity.
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