Division of Toxicology, Wageningen University and Research, Stippeneng 4, Wageningen, Gelderland 6708 WE, The Netherlands.
Environ Sci Technol. 2023 Aug 1;57(30):10974-10984. doi: 10.1021/acs.est.3c01987. Epub 2023 Jul 21.
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 to extrapolation (QIVIVE) approach was employed. The PBK models for rats, mice, and humans were built using parameters from the literature, experiments, and predictions. Available toxicity data for STX were converted to 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 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.
当前的气候趋势可能会扩大产毒微藻和伴随的藻毒素的地理分布，使此类毒素引起的中毒成为一种全球性现象。在各种藻毒素中，石房蛤毒素 (STX) 是一种神经毒素，哺乳动物食用受污染的海鲜后可能会产生严重的神经症状。为了确定口服 STX 暴露引起急性神经毒性的人类健康风险评估的起始点 (POD)，采用了基于生理的动力学 (PBK) 建模辅助定量到推断 (QIVIVE) 方法。使用文献、实验和预测中的参数为大鼠、小鼠和人类建立了 PBK 模型。通过为这三个物种建立的 PBK 模型将 STX 的可用毒性数据转换为剂量反应曲线，并从预测曲线中得出 POD 值，并将其与报告的毒性数据进行比较。发现啮齿动物和人类之间急性 STX 毒性存在种间差异，这似乎主要是由于毒代动力学的差异所致。所描述的方法对急性口服 STX 暴露进行了充分的预测，表明当适当整合时，新的方法学可以用于基于 3R 的化学风险评估范式。
