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 methy lnitrosourea (MNU) and ethylmethanesulfonate (EMS) were investigated w ith regard to dose-response of teratogenicity as well as DNA adduct fo rmation in mice. In this study the teratogenic effects induced by comb ined treatment with these substances were analyzed using doses which, following single treatment with either substance, were around the thre shold level, i.e., no adverse effect level (NOAEL) and lowest observed adverse effect level (LAOEL). Combined treatment of LAOELs resulted i n a threshold-like response, while the combination of the NOAEL of one substance with the LAOEL of the other increased the response rate dra matically 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 addit ion, a dose-response model was fitted to the data. In conclusion, the initially surprising high combination effect revealed to be not so ext raordinary when considering the steepness of the dose-response relatio nships of the single substances. (C) 1995 Wiley-Liss, Inc.