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

The interaction of the DNA-alkylating model compounds, ethylmethanesulfonat e (EMS) and methylnitrosourea (MNU), was studied in pregnant NMRI mice by m easuring DNA adduction in vivo. Previously, large-scale dose-response studi es on teratogenicity as well as on DNA modification were performed using th ese substances. In addition, the risk of low doses in mice was estimated by comparative use of several approaches including molecular dosimetry. The r isk was further analysed by combination experiments on teratogenesis with E MS and MNU. This paper describes a further approach with regard to an inter action of these compounds: the formation of DNA adducts was determined usin g a combined treatment regimen of [C-14]-labelled MNU and EMS. The mutual i nfluence of EMS and MNU on the DNA alkylation rates was found to be moderat e. The dramatic increase in the teratogenic outcome following combined trea tment found in previous studies was obviously not due to a massive interact ion regarding the initial DNA alkylation rates. It may be explained, howeve r, by the concept of toxic equivalency. (C) 2000 Wiley-Liss, Inc.