Embryotoxicity induced by alkylating agents: 10. Analysis of the combined teratogenic effects of methylnitrosourea and ethylmethanesulfonate in mice.

In previous studies the direct-acting alkylating model compounds methylnitrosourea (MNU) and ethylmethanesulfonate (EMS) were investigated with regard to dose-response of teratogenicity as well as DNA adduct formation in mice. In this study the teratogenic effects induced by combined treatment with these substances were analyzed using doses which, following single treatment with either substance, were around the threshold level, i.e., no adverse effect level (NOAEL) and lowest observed adverse effect level (LAOEL). Combined treatment of LAOELs resulted in a threshold-like response, while the combination of the NOAEL of one substance with the LAOEL of the other increased the response rate dramatically to nearly 100%. This phenomenon was further evaluated using biometrical methods. The dose-response surface as well as isobolograms were calculated in order to describe the combination effect. In addition, a dose-response model was fitted to the data. In conclusion, the initially surprising high combination effect revealed to be not so extraordinary when considering the steepness of the dose-response relationships of the single substances.