Mutagenesis, Vol. 15, No. 3, 235-238,
May 2000
© 2000 UK Environmental Mutagen Society/Oxford University Press
Supra-additive genotoxicity of a combination of 
-irradiation and ethyl methanesulfonate in mouse lymphoma L5178Y cells
Department of Toxicology, University of Würzburg, Versbacher Straße 9, D-97078 Würzburg, Germany
While testing for genotoxicity is usually performed on single chemicals, exposure of humans always comprises a number of genotoxic agents. The investigation of potentially synergistic effects of combinations therefore is an important issue in toxicology. Combinations of 511 keV 
-radiation with the chemical alkylating agent ethyl methane-sulfonate were investigated in the in vitro micronucleus test in mouse lymphoma L5178Y cells. With combinations in the low dose linear effect range for the individual agents (0.25–2 Gy and 0.8–3.2 mM, respectively), supra-additivity by 34–86% was seen. The synergism was more pronounced at the higher dose levels. Supra-additivity was confirmed in experiments using cytochalasin B and analyzing binucleate cells only, to control for putative effects on the cell cycle. Statistical significance was shown by a 2-factor analysis of variance with interaction. The results indicate that damage to DNA by -radiation and alkylation could affect different rate limiting steps in the formation of micronuclei. Further investigations will have to show whether the observations are of general validity, in particular, whether other end-points of genotoxicity produce the same results and whether the degree of supra-additivity is always dose dependent. The latter would have a strong impact on risk assessment for mixtures at low doses.
1 To whom correspondence should be addressed. Tel: +49 0931 201 3427; Fax: +49 0931 201 3446; Email: stopper{at}toxi.uni-wuerzburg.de
2 Present address: NIEHS/NIH, Research Triangle Park, NC, USA
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  H. Stopper and W. K. Lutz Induction of micronuclei in human cell lines and primary cells by combination treatment with {gamma}-radiation and ethyl methanesulfonate Mutagenesis, March 1, 2002; 17(2): 177 - 181. [Abstract] [Full Text] [PDF]
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