This experiment was undertaken to elucidate the pathogenesis of abnormal architecture of the cerebral neocortex and hippocampal formation. The pregnant ICR-JCL mice were treated with 30mg/kg of cytosine arabinosicle(Ara-C) on days 13.5 and 14.5 of pregnancy. The offspring were put to death in pre- and postnatal stages in sequence, and their brains were cut coronally and stained with hematoxylin-eosin or luxol fast blue. Some brains were studied by Golgi-Cox method and ^<3>H-thymidine autoradiography. The matrix layer of the embryos were extensively destructed after 12hr of Ara-C injection, but regenerated partially on day 17 of gestation. In the cerebral neocortex of 1-, 3- and 5-day-old treated mice, abnormal clusters of young neurons were found at the surface of the developing cerebral neocortex. After 20 days of age, the clusters at the surface of the cerebral neocortex became gradually indistinct, although some vestigial groups of neurons were observed even after 120 days of age. Neurons which could not migrate to the destinated area formed cell cluster in the deep region of the neocortex. The hippocampal formation of young mice showed severe architectural abnormalities. Pyramidal cells were decreased in number and disarranged. Heterotopic pyramidal cell masses were found in the stratum radiatum. Apical dendrites of pyramidal cells exhibited abnormal arbolization. It was demonstrated by <3>H-thymidine autoradiography that young neurons in the abnormal cluster at the surface of the cerebral neocortex and heterotopic neurons at the stratum radiatum were those produced in the matrix layer regenerated from the destructive change by Ara-C.

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Palm oil contains carotene (precursor of vitamin A) in high concentration (32 to 48 mg/100ml). Excessive dose of vitamin A during pregnancy has been reported to cause congenital anomalies. In Nigeria and neighbouring countries palm oil is consumed with food in large quantities. For the present investigation albino rats were administered palm oil (1 ml to 3 ml/dam) orally in addition to the standard rat diet on day 5 through day 15 of pregnancy counting the day of sperm positive vaginal smear as day 0. Of the 191 implants collected on day 20 from treated rats by uterotomy, 20% were resorbed/dead and of the 152 live fetuses 30% were abnormal showing only growth retardation in 23%, exencephaly 7%, eye defects 2% and cleft palate in 1% of them along with growth retardation. The defects observed, although less frequent, resembled to those caused by hypervitaminosis A and may be attributed to high carotene content of palm oil.

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Although the cervical vertebrae have been documented to be a stable element for the prenatal application of potent teratogens such as x-irradiation, we observed the increased number of cervical vertebrae of rat fetuses in teratogenicity testing of a 5-fluorouracil derlvative and an aspirin derivative. The purpose of this study was to determine the morphological feature of this type of abnormality and to evaluate the significance in teratogenicity testing. Structural changes of the vertebrae at the cervico-thoracic border consisted of opening of foramen transversarium of the 7th vertebra, absence of the fovea costalis transversalis of the 8th vertebra (8th cervical vertebra) and incomplete formation or absence of rib articulated to the 8th vertebra (1st thoracic rib). The increased number of cervical vertebrae may be regarded as a cervicalization of the 1st thoracic vertebra resulted from caudal shift of cervico-thoracic border of the vertebrae. Both two drugs were highly teratogenic and opening of foramen transver-sarium of the 7th (cervical) vertebra was significantly increased at dose levels under the teratogenic threshold in these studies. By further investigation for three teratogenicity tests of oncostatic drugs, 5-fluorouracil, cyclophosphamide (endoxan) and cyclophosphamide derivative, all of which had marked teratogenicity, it was confirmed that the incidence of opening of foramen transversarium of the 7th (cervical) vertebra was also increased at dose levels under the teratogenic threshold of each drugs. It may be suggested that the skeletal abnormality in the fetuses with increased number of cervical vertebrae, particularly opening of foramen transversarium of the 7th (cervical) vertebra may serve as an indicator of teratogenicity.

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Maternal and fetal toxicity of endotoxin were studied at various doses and times of i.v. administration in pregnant rats using purified E. coli endotoxin. Endotoxin at dose levels of 1,000, 100, 10 and 1 μg/kg was injected into pregnant rats once on day 7, 12 or 17. The effects on dams and fetuses were observed on day 20 of pregnancy. The results indicated marked maternal and fetal toxicity when injected on day 12 and 17; the number of resorptoins and dead fetuses was markedly increased with the 1,000 or 100 μg/kg. However, at every dose body weight of surviving fetuses was almost unchanged in comparison to controls. Gross examinations of the fetuses at term showed no significant difference of fetal abnormalities between the treated and control groups. It was noticed that every dose of endotoxin injected on day 12 of pregnancy presented more toxic effect on fetuses than injection during the other two gestational stages.

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In safety evaluation studies, there must be some assurance that the possibility of committing a type II error is low. By using some conventional value of effect size, we can give information as to the risk of type II error.

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