DOSE-RESPONSE RELATIONSHIP OF TERATOGENICITY AND PRENATAL TOXIC RISK-ESTIMATION OF 6-MERCAPTOPURINE RIBOSIDE IN MICE

6-Mercaptopurine riboside (6-MPr) is used as a cytostatic chemotherape utic. The teratogenic potential in rodents has been well known for sev eral decades. In this study, the teratogenic risk of low doses of 6-MP r in NMRI mice was estimated based on a dose-response study. The effec tive doses corresponding to the incidences of 5%, 1%, and 0.1% were ca lculated using the probit and Weibull model. The evaluation was perfor med on the basis of both the fetus and the litter by evaluating the va riable all gross structural abnormalities. From these experiments, ben chmark doses were obtained which were used in low-dose risk assessment to define a reference dose. Depending on the biometrical model and th e statistical unit used, values between 1.9 and 5.2 mg/kg (benchmark E D(1)) and 3.8 and 6.7 mg/kg (benchmark ED(5)) were obtained. These val ues were compared to the no observed adverse effect level (NOAEL) whic h was determined experimentally. The NOAEL was found to be 5 mg/kg, wh ich is quite similar to the ED(5) benchmark doses. (C) 1996 Wiley-Liss , Inc.