• Biomolecules & Therapeutics
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• v.7 no.3
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• pp.292-299
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• 1999

SKI 2053 R, cis-Malonato [(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane] platinum(II), is a newly developed antitumor platinum complex derived from cisplatin. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than cisplatin. Effects of test agent on general toxicity of does and embryonic development of Fl fetuses were investigated in rabbits. Sixty eight New Zealand white rabbits were distributed among three treated groups and a control group. SKI 2053R was administered intravenously to pregnant rabbits from days 6 to 18 of gestation at dose levels of 0, 0.67, 2.0, or 6.0 mg/kg/day. The pregnant does were subjected to the caesarean section on day 28 of gestation. No treatment-related changes in clinical signs, body weight, food consumption, and necropsy findings were observed in all groups. Fl fetuses showed no changes related to the treatment of SKI 2053R, except that an increase in the incidence of skeletal variations were observed at 6.0 mg/kg. There were no signs of material toxicity or embryotoxicity at 0.67 and 2.0 mg/kg. The results show that the administration of 6.0 mg/kg SKI 2053R induces skeletal variations in fetuses and that the no observed adverse effect levels(NOAELS) of SKI 2053R are considered to be over 6.0 mg/kg for does and 2.0 mg/kg for Fl fetuses in rabbits.

• Herbal Formula Science
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• v.31 no.1
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• pp.21-28
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• 2023

Objective : Scolopendra, a dried body of Scolopendra subspinipes mutilans, is one of Korean medicine. Several reports revealed that Scolopendra has therapeutic effects for arthritis, neuroinflammatory diseases and neuropathic pain. However, the fetal adaptive response or teratogenicity associated with administration of Scolopendra is unclear. Therefore, this study aimed to investigate the fetal toxicity effects that were induced following oral administration of Scolopendra water extract (SWE) in pregnant mice. Methods : The pregnant mice were administrated SWE at dosed of 0, 100, 500 and 1000 mg/kg/day during gestation day 0-18. The mortality, body weight and clinical signs of pregnant mice were observed throughout experimental period. Also, the mortality and malformations in foetus were examined. Results : No meaningful changes were observed in the mortality and clinical signs of pregnant mice between the normal control group and SWE administrated groups. Additionally, there are no significant changes in fetal mortalities, and malformations by SWE administration. conclusion : These results suggest that oral exposure to SWE during pregnancy at oral dosages up to 1000 mg/kg/day did not induce teratogenic toxicity in regard to fetal mortality and morphology.

• Toxicological Research
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• v.23 no.2
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• pp.151-158
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• 2007

tert-Butyl acetate is an organic solvent used for coatings, industrial cleaning, and surface treatment applications. This study investigated the potential adverse effects of tert-butyl acetate on pregnant dams and embryo-fetal development after maternal exposure on gestational days 6 through 19 in rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 500, 1,000, 1,500, and 2,000 mg/kg/day. All dams were subjected to a caesarean section on day 20 of gestation and their fetuses were examined for any external, visceral, and skeletal abnormalities. At 2,000 mg/kg, treatment-related clinical signs, including piloerection, abnormal gait, decreased locomotor activity, loss of fur, reddish tear, anorexia, nasal discharge, vocalization and coma, were observed in a dose-dependent manner. All dams died between the 2nd day and 5th day of treatment due to a severe systemic toxicity. At 1,500 mg/kg, minimal maternal toxicity including an increase in the incidence of decreased locomotor activity and loss of fur, and an increase in the weights of adrenal glands and liver was observed. On the contrary, no significant adverse effect on the embryo-fetal development was detected. There were no adverse effects on either pregnant dams or embryo-fetal development at <1,000 mg/kg. These results show that a 14-day repeated oral dose of tert-butyl acetate in rats caused a minimal maternal toxicity including increases in the incidence of clinical signs and the weights of adrenal glands and liver, but no embryotoxicity and teratogenicity at 1,500 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level (NOAEL) of tert-butyl acetate is estimated to be 1,000 mg/kg per day for dams and 1,500 mg/kg per day for embryo-fetal development.

• Toxicological Research
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• v.17 no.2
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• pp.83-90
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• 2001

The background control data were compiled from rat developmental toxicity studies con-ducted at Toxicology Research Center, KRICT during the 1993-1999 period. These data were assembled in order to provide background in formation for the maternal and fetal data collected in 13 developmental toxicity studies using Sprague-Dawley rats. A total of 325 mated females were used in these studies during the seven-year period and overall pregnancy rate of these females was 93.8%. The present background control data included body weights, food consumption, hematological values, and organ weights of pregnant females, caesarean section data, and fetal examination data. These data can be used not only as a historical database for the meaningful interpretation of data from reproductive and developmental toxicity studies, but also as a contribution to biological characterization oj Sprague-Dawley rats.

• Biomolecules & Therapeutics
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• v.6 no.2
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• pp.151-158
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• 1998

Aspalatone, a new antithrombotic agent, was administered orally to pregnant Sprague-Dawley rats during the organogenetic period at dose levels of 0, 20, 100 and 500 mg/kg/day. All dams were subjected to caesarean section on day 20 of pregnancy. Effects of test substance on dams and embryonic development of F1 fetuses were examined There were treatment-related decreases in body weight and food consumption in the 500 mg/kg group. There was a increase in the spleen weight in the 100 and 500 mg/kg groups. Develo-pmental toxicity was evident as decreased fetal body weights and increased fetal malformations in the 500 mg/ kg group. External and skeletal malformations of fetuses occurred at an incidence of 1 and 8.2%, respectively. In addition, there was a delay in ossification of sternebrae and sacrocaudal vertebrae in the 500 mg/kg group. The results show that the no observed adverse effect dose level (NOAEL) for maternal toxicity was 20 mg/kg/ day and for developmental toxicity was 100 mg/kg/day.

• Communications for Statistical Applications and Methods
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• v.29 no.2
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• pp.239-250
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• 2022

In many applications, we frequently encounter correlated multiple outcomes measured on the same subject. Joint modeling of such multiple outcomes can improve efficiency of inference compared to independent modeling. For instance, in developmental toxicity studies, fetal weight and number of malformed pups are measured on the pregnant dams exposed to different levels of a toxic substance, in which the association between such outcomes should be taken into account in the model. The number of malformations may possibly have many zeros, which should be analyzed via zero-inflated count models. Motivated by applications in developmental toxicity studies, we propose a Bayesian joint modeling framework for continuous and count outcomes with excess zeros. In our model, zero-inflated Poisson (ZIP) regression model would be used to describe count data, and a subject-specific random effects would account for the correlation across the two outcomes. We implement a Bayesian approach using MCMC procedure with data augmentation method and adaptive rejection sampling. We apply our proposed model to dose-response analysis in a developmental toxicity study to estimate the benchmark dose in a risk assessment.

• Environmental Mutagens and Carcinogens
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• v.21 no.2
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• pp.77-81
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• 2001

Kamijadowhan (KMD), an oriental herbal medicine used for anti-angiogenic effect, was extracted with 80% ethanol from mixture of source materials and lyophilized. KMD was orally administered to plugpositive pregnant rats from gestational days 12 to 20, dividing into three groups including vehicle-treated control, 0.5 g/kg or 3 g/kg KMD-treated groups. Dam weight during gestation and post-gestation, weight of pre- and post-weaning offsprings in male and female, and reproductive and developmental endpoints including incisor eruption, eye opening and testes descent were measured. No significant alterations in development of physical landmarks in offspring, maternal weight gain during gestation and post-gestation, and offspring weight were observed in KMD-treated group. The measurement of organ weight at post-gestational days 21 was not changed in dams. In 0.5 g/kg KMD-treated rats, kidney weights in male and female offsprings were significantly increased, and the body weight in male offspring was also increased. Liver and brain weights were not changed. Taken together, these data suggest that KMD may not significantly cross the placenta and produce no reproductive and developmental toxicity at maternally non-toxic dosages.

• Proceedings of the Korean Institute of Information and Commucation Sciences Conference
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• 2022.05a
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• pp.273-275
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• 2022

The use of drugs by pregnant women poses a potential risk to the fetus. Therefore, it is essential to classify drugs that pregnant women should prohibit. However, the fetal toxicity of most drugs has not been identified. This takes a lot of time and cost. In silico approaches, such as virtual screening, can identify compounds that may present a high risk to the fetus for a wide range of compounds at the low cost and time. We collected class information of each drug from the hazard classification lists for prescribing drugs in pregnancy by the government of Korea and Australia. Using the structural and chemical features of each drug, various machine learning models were constructed to predict fetal toxicity of drugs. For all models, the quantitative performance evaluation was performed. Based on the attention algorithm, important molecular substructures of compounds were identified in the process of predicting the fetal toxicity of the drug by the proposed model. From the results, we confirmed that drugs with a high risk of fetal toxicity can be predicted for a wide range of compounds by machine learning. This study can be used as a pre-screening tool for fetal toxicity predictions, as it provides key molecular substructures associated with the fetal toxicity of compounds.

• Toxicological Research
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• v.16 no.2
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• pp.117-124
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• 2000

The objective of this experiment is to investigate neurobehavioral and developmental effects of fumonisin B1 (FB1) after prenatal FB1 administration in rats. FB1 (0.8 or 1.6 mg/kg) was orally exposed to pregnant rats during gestational days 13 to 20, whereas the vehicle alone was administered to control group. Maternal and offspring body weights, physical landmarks of incisor eruption, eye opening, testes descending and vaginal opening, open field activity, running wheel activity, and complex maze performance were included as endpoints for developmental and neurobehavioral measurement. Maternal body weights were not signfficantly altered after FB1 exposure. Percentage of maternal weight gain difference between control and 1.6 mg/kg FBI groups was about 4%. Pre- and post-weanling weight of offsprings after prenatal exposure to FB1 was not signfficantly changed, suggesting that FB1 at 0.8 or 1.6 kg/kg doses may not cross the placenta. Significant gender difference in running wheel activity on postnatal days 57 to 63 and complex maze performance on postnatal days 75 to 78 was observed.

• Journal of Life Science
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• v.11 no.5
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• pp.447-456
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• 2001

We have recently demonstrated that the fluoroquinolone antibacterial DW-116 caused a significant developmental toxicity in rats. The present study was conducted to determine whether the development toxicity induced by DW-116 treatment was the result of malnutrition fro reduced food intake or the direct effects of test chemical on conceptuses. The test chemical was administered by gavage to pregnant rats from gestational days 6 through 16 at dose levels of 0 and 500 mg/kg/day. A pair-feeding study was also performed in which the pregnant rats received the same amount of diet consumed by the DW-116-treated pregnant rats. All dams were subjected to caesarean section on day 20 of gestation and their fetuses were examined for examined for external, visceral, and skeletal abnormalities. In this treatment group, the maternal toxicities included increased abnormal clinical signs, decreased maternal body weight, suppressed body weight gain during treatment and posttreatment periods, and reduced food intake. The significant developmental toxicities included increased fetal deaths, decreased live fetuses, reduced fetal body weight and placental weight, increased incidence of fetal abnormalities, and increased fetal ossification delay. In this pair-fed group, however, slight maternal toxicities including decreased body weight and suppressed body weight gain during treatment period were observed in comparison with the control group, and minimal development toxicities including reduced fetal and placental weights and increased fetal ossification delay were found. The number of fetal deaths and live fetuses, and the incidences of malformed fetuses and litters with affected fetuses were comparable to the control values. Based on the results, it could be concluded that the development toxicity observed in the treatment group is attributable to the direct effects of Dw-116 treatment, but not to the maternal malnutrition from reduced food consumption during pregnancy.