当前的气候趋势可能会扩大产毒微藻和伴随的植物毒素的地理分布,使这种毒素中毒成为全球现象。在各种植物毒素中,毒素(STX)是一种神经毒素,在食用受污染的海鲜后,可能会引起哺乳动物严重的神经系统症状。为了得出口服STX引起的急性神经毒性的人类健康风险评估的出发点(POD),采用基于生理学的动力学(PBK)建模促进的体外至体内定量外推(QIVIVE)方法。大鼠PBK模型,老鼠,人类是用文献中的参数建造的,体外实验,和硅预测。通过为这三个物种建立的PBK模型,将STX的现有体外毒性数据转换为体内剂量反应曲线。和POD值从预测的曲线得出,并与报告的体内毒性数据进行比较。发现了啮齿动物和人类之间急性STX毒性的种间差异,它们似乎主要是由于毒物动力学的差异。所描述的方法导致对急性口腔STX暴露的充分预测,表明新的方法方法,当适当整合时,可用于基于3R的化学风险评估范式。
Current climate trends are likely to expand the geographic distribution of the toxigenic microalgae and concomitant phycotoxins, making intoxications by such toxins a global phenomenon. Among various phycotoxins, saxitoxin (STX) acts as a neurotoxin that might cause severe neurological symptoms in mammals following consumptions of contaminated seafood. To derive a point of departure (POD) for human health risk assessment upon acute neurotoxicity induced by oral STX exposure, a physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach was employed. The PBK models for rats, mice, and humans were built using parameters from the literature, in vitro experiments, and in silico predictions. Available in vitro toxicity data for STX were converted to in vivo dose-response curves via the PBK models established for these three species, and POD values were derived from the predicted curves and compared to reported in vivo toxicity data. Interspecies differences in acute STX toxicity between rodents and humans were found, and they appeared to be mainly due to differences in toxicokinetics. The described approach resulted in adequate predictions for acute oral STX exposure, indicating that new approach methodologies, when appropriately integrated, can be used in a 3R-based chemical risk assessment paradigm.