랫드에서 표준 및 사료제한 시험에 의한 fluoroquinolone 항균제 DW-116의 발생독성평가

Development Toxicity Evaluation

임신랫드에서 fluoroquinolone 항균제 DW-116에 의해 유발된 발생독성이 모동물의 사료섭취량 감소에 의한 영양 결핍이 주요 원인인지 아니면 DW-116이 배.태자에 직접적으로 작용하여 유발된것인지를 조사하고자 시험물질을 랫드에 임신 6일에서 16일까지 0 및 500 mg/kg 용량으로 반복 경구투여하였다. 사료제한군은 시험물질 투여군의 모동물의 섭취한 동일한 양의 사료를 제한급여하였다. 모든모동물을 임신 20일째에 제왕절개하였고, 모독성 및 발생독성을 평가하였다. 시험물질 투여군에서는 독성증상과 체중의 감소, 투여 및 투여후 기간의 체중증가 억제, 사료섭취량의 감소를 포함하는 모독성이 부형제대조군및 사료제한군에 비해 현저하게 증가하였다. 또한, 태자사망의 증가, 생존태자의 감소, 태자체중과 태반중량의 감소, 태자기형의 증가 및 골환지연을 포함하는 발생독성도 현저하게 증가하였다. 반면, 사료제한군에서는 모체 및 태자에서 경미한 독성고견만 인정되었고, 태자사망이나 태자기형 등의 심각한 발생독성은 관찰되지 않았다. 결론적으로 시험물질투여군에서 관찰된 발생독성은 사료섭취량의 감소에 의한 모체의 영양결핍에 기인된 것이 아니라 DW-116의 투여에 기인된 직접효과인 것으로 판단된다.

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.