Nawaji Tasuku, Mizoguchi Naohiro, Adachi Ryuta, Teraoka Hiroki
Chemicals Evaluation and Research Institute, Japan (CERI), 3-2-7 Miyanojin, Kurume, Fukuoka 839-0801, Japan.
School of Veterinary Medicine, Rakuno Gakuen University, 582 Bunkyodai-Midorimachi, Ebetsu, Hokkaido 069-8501, Japan.
Curr Res Toxicol. 2024 Jul 14;7:100187. doi: 10.1016/j.crtox.2024.100187. eCollection 2024.
To study the effects of drugs on embryo/fetal development (EFD), developmental and reproductive toxicity studies in zebrafish () embryos is expected to be an accepted alternative method to animal studies using mammals. However, there is a lack of clarity in the relationship between the concentration of developmental toxicity agents in whole embryos or larvae (Ce) and that in aqueous solution (Cw), and also between the amount of drug exposure required to cause developmental toxicity in zebrafish embryos or larvae and that required in mammals. Here, we measured Ce for developmental toxicity agents every 24 h starting at 24 h post fertilization (hpf). We found a high correlation ( : 0.87-0.96) between log [Ce/Cw] and the -octanol-water distribution coefficient at pH 7 (logD) of each drug at all time points up to 120 hpf. We used this relationship to estimate the Ce values of the 21 positive-control reference drugs listed in ICH guidelines on reproductive and developmental toxicity studies (ICH S5). We then calculated the area under the Ce-time curve in zebrafish (zAUC) for each drug from the regression equation between log [Ce/Cw] and logD and compared it with the AUC at the no-observed-adverse-effect level in rats and rabbits and at the effective dose in humans described in ICH S5. The log of the calculated zAUC for the 14 drugs identified as positive in the zebrafish developmental toxicity test was relatively highly positively correlated with the log [AUC] for rats, rabbits, and humans. These findings provide important and positive information on the applicability of the zebrafish embryo developmental toxicity test as an alternative method of EFD testing. (267 words).
为研究药物对胚胎/胎儿发育（EFD）的影响，斑马鱼胚胎发育和生殖毒性研究有望成为替代哺乳动物动物研究的一种可接受的方法。然而，全胚胎或幼虫中发育毒性剂的浓度（Ce）与水溶液中浓度（Cw）之间的关系，以及斑马鱼胚胎或幼虫中引起发育毒性所需的药物暴露量与哺乳动物中所需的暴露量之间的关系尚不清楚。在此，我们从受精后24小时（hpf）开始，每24小时测量一次发育毒性剂的Ce。我们发现，在高达120 hpf的所有时间点，log [Ce/Cw]与每种药物在pH 7时的正辛醇-水分配系数（logD）之间存在高度相关性（r：0.87 - 0.96）。我们利用这种关系估算了国际人用药品注册技术协调会（ICH）生殖和发育毒性研究指南（ICH S5）中列出的21种阳性对照参考药物的Ce值。然后，我们根据log [Ce/Cw]与logD之间的回归方程，计算了每种药物在斑马鱼中的Ce-时间曲线下面积（zAUC），并将其与ICH S5中描述的大鼠和兔子未观察到不良反应水平时的AUC以及人类有效剂量时的AUC进行比较。在斑马鱼发育毒性试验中被确定为阳性的14种药物的计算zAUC的对数与大鼠、兔子和人类的log [AUC]相对高度正相关。这些发现为斑马鱼胚胎发育毒性试验作为EFD测试替代方法的适用性提供了重要且积极的信息。 （267字）
