DNA alkylation studies of combined treatment with methylnitrosourea and ethylmethanesulfonate in mice

The interaction of the DNA-alkylating model compounds, ethylmethanesulfonate (EMS) and methylnitrosourea (MNU), was studied in pregnant NMRI mice by measuring DNA adduction in vivo. Previously, large-scale dose-response studies on teratogenicity as well as on DNA modification were performed using these substances. In addition, the risk of low doses in mice was estimated by comparative use of several approaches including molecular dosimetry. The risk was further analysed by combination experiments on teratogenesis with EMS and MNU. This paper describes a further approach with regard to an interaction of these compounds: the formation of DNA adducts was determined using a combined treatment regimen of [(14)C]-labelled MNU and EMS. The mutual influence of EMS and MNU on the DNA alkylation rates was found to be moderate. The dramatic increase in the teratogenic outcome following combined treatment found in previous studies was obviously not due to a massive interaction regarding the initial DNA alkylation rates. It may be explained, however, by the concept of toxic equivalency. Teratogenesis Carcinog. Mutagen. 20:27-34, 2000.