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 chemotherapeutic. The teratogenic potential in rodents has been well known for several decades. In this study, the teratogenic risk of low doses of 6-MPr in NMRI mice was estimated based on a dose-response study. The effective doses corresponding to the incidences of 5%, 1%, and 0.1% were calculated using the probit and Weibull model. The evaluation was performed on the basis of both the fetus and the litter by evaluating the variable all gross structural abnormalities. From these experiments, benchmark doses were obtained which were used in low-dose risk assessment to define a reference dose. Depending on the biometrical model and the statistical unit used, values between 1.9 and 5.2 mg/kg (benchmark ED1) and 3.8 and 6.7 mg/kg (benchmark ED5) were obtained. These values were compared to the no observed adverse effect level (NOAEL) which was determined experimentally. The NOAEL was found to be 5 mg/kg, which is quite similar to the ED5 benchmark doses.
Platzek
T
T
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Bochert
G
G
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D002972:Cleft Palate / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects; D005532:Foot Deformities, Congenital / Q000139:chemically induced / Q000473:pathology; D008431:Maternal-Fetal Exchange; D051379:Mice; D011247:Pregnancy; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*; D013868:Thioinosine / Q000633:toxicity*
D000964:Antimetabolites, Antineoplastic; D013723:Teratogens; D013868:Thioinosine