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Third-party-funded project

Effects of combinations of genotoxic agents: comparison of human tumor cell lines to human primary cells

Project management at the University of Würzburg:

Participating scientists:

While testing for genotoxicity is usually performed on single chemicals, exposure of humans often involves combinations of agents. Previous results from this laboratory showed supra-additivity for the induction of micronuclei in p53-mutated mouse lymphoma L5178Y cells after combined treatment with gamma-radiation from a 137Cs source and ethyl methanesulfonate (EMS) (Stopper et al., 2000). The question now was whether supra-additivity was a general phenomenon for the genotoxicity of this combination of a physical and a chemical DNA-damaging agent or whether the result was species- and cell type-specific. The same combination of agents was investigated in two human lymphoblastoid cell lines, TK6 (wild-type p53) and WTK1 (mutated p53), and primary fibroblasts froma fetal human lung. Doses were in a linear dose-effect range, resulting in a 1.5- to 3-fold increase above control. Radiation doses were between 125 and 350 mGy, the EMS concentration was 20-50 myg/ml EMS for the cell lines, 250-350 myg/ml for the primary cells. In none of the human test systems was supra-additivity observed. With the WTK1 cells, which are most similar to the mouse cells regarding the p53 status, there was even a tendency for a sub-additive combination effect. Possible explanations for the difference to the mouse cells related to species-specific aspects, different consequences of the p53 mutations, or the presence of additional mutations. It is concluded that caution is advised for the interpretation and extrapolation of experimental results of mixture toxicity data because the outcome could be highly specific for the given selection of agents, doses, and assays.

Key words:
    DNA damage
    Dose-response relatiionship
    Ethyl methanesulfonate
    Leukemia L5178
    Micronucleus test
    Tumor cells
    Protein p53

Projekt period: from 05.2000 to 07.2001

Funding institution:
Sonstige öffentliche Mittel ( Bundesamt für Gesundheit, Bern )