An 8-month-old, female infant with partial DiGeorge syndrome was found to be associated with cardiovascular malformation. She had a characteristic face of the syndrome, manifesting hypocalcemic tetany and congenital heart disease. The autopsy revealed tetralogy of Fallot and abnormal branches of the pulmonary artery, which have never been observed among patients with DiGeorge syndrome ever reported, and led to death in the present case. Microscopic study disclosed thymic aplasia with partial absence of the parathyroid gland, and a decrease in number of small lymphocytes of the thymus-dependent areas in lymphoid tissue.

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Acetaldehyde (AcH) was administered intraperitoneally (50, 75, 100 and 150 mg/kg) to CF rats from day 8 to 15 of gestation (sperm positive day = day 1) and the fetuses were collected on day 21 of gestation. Besides dose dependent embryolethality, the fetuses were significantly stunted as evidenced by somatometric measurements and skeletal preparations. The malformations observed included microcephaly, micrognathia, micromelia, digital anomalies, edema, hemorrhages in the face, paws and brain and hydronephrosis. Mean placental weight and umbilical cord length were also significantly reduced. Amniotic fluid weight showed consistent increase. It is suggested that ACH affects both the fetus and fetal milieu in this species.

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Combination (1 : 20) of pyrimethamine (PY) and sulfamonomethoxine (SMX) was mixed with mashed feed and given to the Goettingen miniature pig during gestational days 11 - 35. Major malformations such as cleft palate and micrognathia were observed in 7 out of 1 8 newborns from 3 pregnant sows which received 3.6 mg/kg/day of PY with 72 mg/kg of SMX. Two sows of a higher dose group (7.2 mg/kg PY + 144 mg/kg SMX) showed severe anemia during the experiment and did not give a birth. No major malformation was found in 23 newborns of lower dose groups. In comparison with the previous results by PY alone, it is concluded that sulfa drug might not potentiate the teratogenic action of PY in pig .

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There are five objectives inherent in this review. First: To summarize selected aspects of the differential effect of environmental lead upon children, versus adult humans with emphasis upon the increased sensitivity of the developing brain to lead toxicity. We have reviewed experimental studies which indicate that at relatively low concentrations, lead is toxic and may be lethal to gametocytes, preimplantation embryos and is teratogenic in fetuses. Second: To provide teratologists and interested others, with diverse medical and biological backgrounds with a fundamental concept of the postnatal maturation of the cortical cells of the human brain with emphasis on animal species differentials which must be considered when trying to extrapolate such data to humans. Third: To review experimental animal studies which indicate that exposure of newborn and sucking animals to lead, hypoxia, mercury, phenobarbital, alcohol and severe inanition inhibits postnatal maturation of neurocortical cells, induces neurochemical changes which are reflected as behavioral aberrations and learning defects. Fourth: The experimental studies previously mentioned support recent clinical studies which indicate that in young children, low levels of lead exposure, do result in behavioral aberrations and learning disorders which are commonly referred to as minimal brain dysfunction. Fifth: Lead in the atmosphere is not a local problem but represents a universal problem of the biosphere which we occupy. Sustained efforts of all nations of the world to reduce the levels of human exposure to lead are essential to the health of all people and particularly children.

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The problems on performing the monitoring and surveillance of con-genital malformations, are as follows; 1. Establishment of standard of surveillance. 2. Selection of objects for monitoring. 3. Selection of markers. 4. Set up the time of making diagnosis and diagnostic standard. 5. Establishment of system how to collect reports and to analyse these data.

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Using Medline File, 295 articles which deals with both multiple births and congenital anomalies were obtained out of total 1,680,029 ones, during 1976. 01-1982. 05. These articles constitute the combinations of form and content. The form consists of three major categories : 1) original case(s) report, 2) population study (incidence study) concerning multiple births with particular anomalies and 3) general remarks. The content was classified into research study regarding the etiology of congenital anomalies and/or multiple births and practical aspects such as prenatal diagnosis, genetic counselling, care or treatment of the patients and monitoring or surveillance. The sets among original case(s) report include 231 twins, 16 triplets and one quintuplet. In 231 twins were seen 141 MZ, 56 DZ and 34 unknown zygosity. As for concordance or discordance, rates of concordance were 68.1% for MZ and 61.1% for DZ, respectively. Rates of discordance were 31.9% for MZ and 38.9% for DZ, respectively. A few incidence studies indicated that the frequencies of congenital anomalies were higher in twins than in singletons, and also higher in the same-sexed twins or MZ than in the opposite-sexed twins or DZ. The etiology of congenital anomalies oftenly seen in twins was considered to be classified into three categories : 1) common cause to MZ twinning as well as congenital anomalies, 2) vascular interchange between each member of MZ twins and 3) intrauterine crowding usually seen in both MZ and DZ. These three categories were in good agreement with the causes in 141 MZ above mentioned.

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Mayer called "embryopathia diabetica" as the abnormalities of fetuses of diabetic mothers. These abnormalities including congenital malformations (CM) are seen under inadequate control of maternal diabetes. CM and respiratory distress syndrome are still main causes of death among IDM. I analysed the frequency, type of malformation, and relationship of maternal diabetes treatment with regards to 117 babies born to 93 cases of pregnant diabetics treated by us. CM in the IDM in Japan over a ten year period during 1971-1980 was also surveyed by questionnaire. To elusidate the mechanism of CM, the influence of maternal hyperglycemia and hypoglycemia on the fetuses was observed using streptozotocine induced diabetic rats and insulin induced hypoglycemic rats. The frequency of CM was 16.2%, 19 out of 117 newborns in our hospital compared with 1.5% of controls. Although most of the IDM had minor anomalies, four newborns died due to major anomalies. The 78% of mothers who had infants with CM showed poor control in the first trimester. Specially, fasting blood glucose of pregnant diabetics who had neonates with major anomaly was over 200 mg/dl in the early stages of their gestation in all cases. In a survey in Japan. CM was 6.2%, 44 out of 1042 IDM. The types of CM seen in IDM are distributed through all organ systems. Including the results of animal experiments, it is suggested that CM is not related to maternal hypoglycemia but hyperglycemia in very early stages of gestation.

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Among radiation effects on developing embryos and fetuses, occurrence of germinal mutation due to exposure of the gonads and postnatal manifestation of neoplasms are considered to be stochastic effects from the aspect of radiation protection. On the other hand, somatic effects such as teratogenic and embryo-toxic effects can be regarded as nonstochastic ones with threshold doses. In experimental teratological studies with mice and rats, the lowest radiation doses for manifestation of the non-stochastic somatic effects which have been recognized so far are:5 rad for resorption of preimplantation embryos; 5-10 rad for acute cytological changes such as pyknosis, cytoplasmic degeneration and mitotic delay; 5 rad for increasing frequency of spontaneous minor anomalies of the skeleton; 15-20 rad for malformations of the eye, brain and spinal cord; 20-25 rad for histogenetic and functional disorders of the central nervous system; and 20-25 rad for impaired fertility. Pregnant women who are subject to X-ray examinations are much concerned about potential hazard of radiation to their offspring in utero. The above experimental findings suggest that the possibility of non-stochastic somatic effects of diagnostic radiation on human embryos and fetuses is extremely low, and probably negligible, given the proper dose control measures. Possible effects which should be considered for risk evaluation of diagndstic exposure are two stochastic effects, carcinogenic and mutagenic.

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Many explorations have been done by our antecessors to find out about the congenital anomalies which might be caused by X-ray or γ-ray and experimental teratological researches have also been done, with some results. However, there have been less systematic studies on corpuscular radiation. Neutron ray is a radioactive ray no electrically-charged equally as photon (X-ray, γ-ray). With an equal dosage of it as photon's, its localized energy is high so that it is different in RBE. OER, etc. In heavy charged particle (proton ray. He ion, Ne ion, π-meson ray), there is the characteristic that the energy increases at around the deepest spot within the range rather than at the point of injection into a system, which is called Bragg peak. The type and energy of this radiation reflected in the uniqueness in energy distribution, in ionization density and in LET makes it the most important radioactive biological parameter. At this paper, we shall review the types of radioactive rays and discuss the congenital anomalies (teratogenecity) including the experimental results obtained by application of our proton ray.

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It is estimated that only a small portion (less than 2 %) of the congenital anomalies is attributed to chemicals including drugs. However, developmental toxicity of pharmaceutical drugs has the following characteristics. 1. A considerable number of new compounds are introduced into market every year after reproduction tests in animals. 2. Drugs are intentionally administered, often subchronically with a relatively high dose. They are given after consideration that potential benefits to a pregnant mother outweigh possible hazards to both mother and her unborn child. 3. Congenital anomalies induced by drugs can be prevented if they are withdrawn from the market. Therefore, a more strong administrative judgement is requested in evaluating the hazards to human development as compared to not only environmental chemicals but also physical and biological develop-mental toxicity agents. In this short review, first, methods for detection of developmental toxicity of drugs are commented. Significance of animal studies and basic principles for evaluation of human survey (case reports and epidemiological studies) are discussed. Secondly, critical reviews are presented on some drugs which have recently become the subjects of controversial discussion. These include Bendectin, vaginal spermicides, diethylstilbestrol, progestogens and anticonvulsants. Bendectin episode may be a typical example how difficult to treat the tetatogenicity of drugs as the social problem. Other topics of special concern are adverse effects of drugs therapeutically used for the fetus itself and of preconceptional chemical exposure to not only mothers but also fathers. Finally, various problems on the balance between benefits and risk of drug usage in pregnancy are commented and the author's opinion is expressed how doctors and patients should consider the use of drugs in reproductive age in order to clarify the etiology of congenital anomalies by drugs and their prevention.

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Of the preventable causes of congenital abnormalities, maternal drinking of alcohol and caffeine during pregnancy was investigated. Japanese cases of fetal alcohol syndrome (FAS) tended to show mild effects of maternal ethanol consumption, especially on growth retardation, suggesting some timing discrepancy between growth and mental retardation. To study the cause of the FAS, an experimental rat model was employed. An increase in perinatal mortality, a decrease in fetal body and cerebral weights and decreases in DNA, RNA and protein contents or syntheses in cerebrum were observed. Hypoplasia, as one of the characteristic features of FAS, was related to maternal serum and fetal body ethanol levels. It occurred prior to the development of ethanol-induced hypoglycemia in late pregnancy, so hypoglycemia is not the main cause of FAS. Low levels of maternal serum insulin and cerebral carbonic anhydrase and zinc were observed. Zinc ad-ministration to rats on alcohol diet resulted in better effect on fetal body weight and preventing resorption than administration of ethanol alone but no better than control. To determine whether maternal caffeine ingestion was a risk factor in brain development, an experimental rat model was employed. A decrease in cerebral weight and DNA synthesis was observed when dams were ingested throughout pregnancy, but with no reduction of fetal body weight, litter size or maternal weight. The fetal surviving rate was related to maternal serum caffeine levels. In conclusion, it would be prudent for women planing to have a baby to limit their alcohol and caffeine intake.

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Results of a survey and our study on fetal and neonatal abnormalities associated with maternal metabolic disorders and endocrine diseases are reported. DQs in two histidinemic cases of maternal histidinemia were within the normal range. It has been reported that 3 cases of maternal histidinemia with normal histidine metabolism and 10 histidinemic patients of maternal histidinemia including the above 2 cases showed normal DQs. DQs of 4 phenylketonuria (PKU) patients of maternal PKU and 5 cases of maternal PKU with normal phenylalanine metabolism have been reported in Japan. Two of the maternal PKUs had normal phenylalanine metabolism and DQs. One patient died from multiple congenital anomalies accompanied by hypoplastic left heart syndrome while the mother was on a low phenylalanine diet beginning at 6 weeks of gestation. It has been shown that the most common maternal endocrine diseases were maternal thyroid disorders. Nine to 14 per cent of maternal thyroid disorders showed neonatal abnormalities. Uncontrolled Cushing syndrome, pheochromocytoma, pituitary gigantism and acromegaly in the mother were responsible for occasional spontaneous abortions, premature labor, fetal death and neonatal anomalies. The high frequency of neonatal abnormalities were associated with uncontrolled hypoparathyroidism in the mother. Therefore, early treatment of metabolic disorders and endocrine diseases in pregnant women is important for the prevention of severe fetal and neonatal abnormalities.

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The historical background of activities in behavioral teratology studies in Japan and the Japanese Teratology Society is briefly summarized and the Behavioral Teratology Meeting, a satellite group discussion meeting to the Annual Meeting of the Japanese Teratology Society, is introduced. International collaboration between domestic members of the Japanese Teratology Society and scientists outside Japan in the study of behavioral teratogenesis is eagerly anticipated.

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Evidence of several different types was reviewed to assess the validity and reliability of open-field test. Some measures were found to possess acceptable reliability. However, findings reviewed did not show an adequate evidence that open-field test is a valid index of "emotionality". An alternative approach which attempts to obtain a set of criterion-related validity was suggested.

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The open-field test has been one of the most widely used methods in behavioral teratological studies. Although the test has been suggested to be sensitive to teratological manipulations, it should be noted that there is some methodological ambiguity in the open-field test to evaluate the effects of teratogens on the motivational states or "emotionality." The confusions of the studies were partially derived from the innumerable variations of the experimental apparatus and procedure of the open-field test. The more serious problems are that some of the open-field measures have been used without examining the validity and the reliability. For example, in mice, the defecation score increases by sessions, whereas the data of rats constantly showed the decreasing function and it has been assumed that the defecation score is the primary index of emotional responses according to the latter findings. Therefore, it is suggested that the adequate standardization of the methods is needed to apply the open-field test in behavioral teratology, and that another behavioral tests to evaluate the motivational states should be used together with the open-field test, especially with mice.

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Open field test is a test for observing behavioral movement in detail and it is also a test for detecting chronological change of behavior, when an animal is put in a strange environment. The author and his colleague have established a standardized method including the determination of operating conditions, the analysis of data, and evaluation of the results based on the basal data that we have accumulated. In the present report, we have mentioned a process which we have established as valid up to the present. Namely, it involves one 3-minute trial at age 35 days. As the result of a large number of subjects which received the test under these operating condition, the physiological normal range in the ambulation values was 27.1 to 97.7 (times/trial) for the male and 42.0 to 105.5 (times/trial) for the female, and that in the rearing values was 2.6 to 30.6 for the male and 5.6 to 33.6 for the female. Thus there are sexual differences. Besides, variation due to estrous cycle is confirmed in the female. However, the coefficient of variance in females' group is always lower than males' in the ambulation and the rearing scores. It is interesting to note that variation in the females is lower than that in the males even if estrous variance was included. Consequently, when we compare the difference of mean score, it could be possible to neglect an effect caused by estrous differences. We are now utilizing this information to find abnormal animals or to evaluate the results in the nonclinical fertility study.

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The purpose of behavioral teratology screening is to pick up agents in animal studies, which may cause behavioral dysfunction of human offspring whose mothers were insulted during the prenatal period. Recently, a behavioral test battery has been employed for estimating effects of environmental compounds or drugs on functional and neurobehavioral developments of offspring born from insulted mothers. Open field behaviors have been used frequently for investigating the effects on emotionality or activity of rodents in a novel situation. Although an open field test is the most traditional and the most popular method of measuring emotionality or activity of rodents, experimental conditions concerning apparatus, noise level, lighting, handling, number of trials and so on have varied among researchers depending on the different purposes. Before employing this test as one of the behavioral teratology screening tests, sensitivity of this test should be examined with known behavioral teratogens and the adequacy of this test should be determined by examining reproducibility of the results obtained from a positive control. However, if the tests are not carried out under the optimum experimental situations and standardized techniques, the results might be confused with variations. Standardization of experimental condition and accumulation of background data on animals are exceedingly required on this test. For this purpose, we discussed problems associated with experimental condition in the open field test based on our own experiments and review of literature.

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Total number of 248 cases of multiple births with congenital anomalies shown in the Table was obtained from 212 literatures in the study "A study of multiple births with congenital anomalies by use of Medline system", which appeared in this issue (Cong. Anom., 23: 69-77, 1983).

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