Mutagenesis, Vol. 14, No. 3, 255,
May 1999
© 1999 UK Environmental Mutagen Society/Oxford University Press
Editorial |
Applications and interpretation of data obtained in the mouse lymphoma tk assay
The work of the `Expert Working Group on Genotoxicity' of the `International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use' (ICH 1994
, 1996) to harmonise the methods used to determine the genotoxicity of pharmaceuticals has resulted in considerable discussion in various forums of our scientific discipline. A major point of discussion emerging from the ICH recommendations has been that of the application of the mouse lymphoma tk assay (ML). These discussions have focused upon both the suitability of the ML as a `catch-all' assay capable of detecting a wide range of agent induced genetic changes and the critical factors necessary for the performance of an optimal ML assay. In the UK, the Department of Health's Advisory Committee on the Mutagenicity of Chemicals in Food, Consumer Products and the Environment has had considerable problems in evaluating ML assay data and has needed expert advice on the assay to aid in Committee evaluations of genotoxic chemicals.
As part of the evaluation of the ML assay, Mutagenesis and other Journals have published a number of papers describing the considerable efforts made, mainly in Japan, to investigate critical aspects of the ML assay, for example see Sofuni et al. (1996, 1997).
In Mutagenesis 14, Issue 1, we published the results of a major Japanese study evaluating the microwell modification of the ML assay (Honma et al., 1999). During the refereeing of this paper and other manuscripts it became increasingly clear to me that the referees were raising important points about the ML assay which were critical for both its performance and interpretation. It was my view that these points deserved a wider audience to allow our readers to benefit from the expertise of individuals with extensive experience in the use of the ML assay. Thus, I invited Drs Martha Moore, Karen Harrington-Brook and Jane Cole to take advantage of the Japanese study and provide our readers with their analysis of the critical points of the ML assay (Moore et al., 1999b). During their evaluation of the Honma et al. (1999) study and a number of other publications, the three reviewers, together with Dr Deborah Collard, developed a series of important points and critical criteria necessary for the use of the ML assay and developed papers outlining their views on the current status of the ML assay as a tool in the evaluation of the potential genotoxicity of chemicals.
In this issue of Mutagenesis we publish three papers which represent the results of the evaluations of the ML assay performed by Moore, Harrington-Brock, Cole and Collard (Cole et al., 1999, Moore et al., 1999a, Moore et al., 1999b). I wish to thank the four authors for the major efforts they have made in identifying critical factors in the application and their interpretation of the ML assay, particularly for the benefit of those (like myself) who have limited practical experience in the performance of the ML assay, yet are faced with problems in interpreting the results of the assay on a regular basis.
Having read all the various manuscripts on the ML assay one might conclude that the ICH were probably premature in their recommendations on the use of the ML assay in a `catch-all' role for pharmaceutical screening at this stage in its validation.
References
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Cole,J., Harrington-Brock,K and Moore,M.M. (1999) The mouse lymphoma assay in the wake of ICH 4—Where are we now? Mutagenesis, 14, 265–270.
Honma,M., Hayashi,M., Shimada,H., Tanaka,N., Wakuri,S., Awogi,T., Yamamoto,K.I., Kodani,N.-U., Nishi,Y., Nakadate,M and Sofuni,T. (1999) Evaluation of the mouse lymphoma tk assay (microwell method) as an alternative to the in vitro chromosomal aberration test. Mutagenesis, 14, 5–22.
ICH (1994) Technical symposium: Safety, Session 1: Harmonization of genotoxicity testing requirements. In D'Arcy,P.F. and Harron,D.W.G. (eds), Proceedings of the Second International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Orlando 1993. The Queen's University, Belfast, UK, pp. 221–257.
ICH (1996) Technical symposium: Safety, Session 4: Genotoxicity testing. In D'Arcy, P.F. and Harron,D.W.G. (eds), Proceedings of the Third International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Yokohama, 1995. The Queen's University, Belfast, UK, pp. 303–329.
Moore,M.M., Collard,D.D and Harrington-Brock,K. (1999a) Failure to adequately use positive control data leads to poor quality mouse lymphoma data assessments. Mutagenesis, 14, 261–263.
Moore,M.M., Harrington-Brock,K and Cole,J. (1999b) Issues for conducting the microtitre version of the mouse lymphoma thymidine kinase (Tk) assay and a critical review of data generated in a collaborative trial using the microtitre method. Mutagenesis, 14, 271–281.
Sofuni,T., Honma,M., Hayashi,M., Shimada,H., Tanaka,N., Wakuri,S., Awogi,T., Yamamoto,K.I., Nishi,Y. and Nakadate,M. (1996) Detection of in vitro clastogens and spindle poisons by the mouse lymphoma assay using the microwell method: interim report of an international collaborative study. Mutagenesis, 11, 349–355.
Sofuni,T., Honma,M., Hayashi,M., Shimada,H., Tanaka,N., Wakuri,S., Awogi,T., Yamamoto,K.I., Nishi,Y. and Nakadate,M. (1997) Report of an international collaborative study of the mouse lymphoma assay using the microwell method. Mutat. Res., 379, S191.
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