Development of alternatives to animal experiments with in vitro cultures of undifferentiated embryonic cells and organ primodia

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Effects of chemicals on cultured fetal organsThe palates of day-12.5 and day-13.5 fetal mice were explanted and exposed in vitro for 72 hr to 0.1-50 mg 5-fluorouracil (5-FU) /ml or to 5-76 mg hydroxyurea (HU) /ml. 5-FU inhibited the growth and fusion of day-12.5 palatal shelves in vitro dependently on its concentrations. Day-13.5 palates were significantly less sensitive to 5-FU than day-12.5 palates, and the minimal toxic concentrations(MTCs)of 5-FU were 0.1 and 10 mg/ml for day-12.5 and day-13.5 fetal palates, respectively. HU inhibited the in vitro growth and fusion of day-12.5 fetal palatal shelves in a concentration dependent manner, but only slightly suppressed the growth of day-13.5 fetal palates. The MTCs of HU were 19 and 76 mg/ml for day-12.5 and day-13.5 fetal palates, respectively. The palates of day-12.5 ICR fetal mice may be more suitable than day-13.5 palates for in vitro teratogen screening and for the study of mechanisms of normal and abnormal palatogenesis.2.Usefulness of fetal organ cultures for teratogen screeningThe maxillary regions of day-12.5 ICR mouse fetuses were cultured in a chemicallydefined serumless medium, and the developmental toxicity of 15 chemical teratogens on cultured palates was studied. Explanted palates were exposed in vitro for 72 hr to each drug at various concentrations. A significant in vitro toxicity was shown for ll out of the 15 compunds which are teratogenic in vivo, and the in vitro predictability for developmental toxicity was 73%. The IC_<50>(50% inhibitory concentration)values calculatrd based on palatal fusion rates appeared to be a useful index of developmental toxicty of drugs. In addition, the human risk shall be assessed by comparing the minimal toxic concentrations with maximal plasma levels in human clinical conditions.