Integrating In Vitro Data and Physiologically Based Kinetic Modeling to Predict and Compare Acute Neurotoxic Doses of Saxitoxin in Rats, Mice, and Humans

Current climate trends are likely to expand the geographicdistributionof the toxigenic microalgae and concomitant phycotoxins, making intoxicationsby such toxins a global phenomenon. Among various phycotoxins, saxitoxin(STX) acts as a neurotoxin that might cause severe neurological symptomsin mammals following consumptions of contaminated seafood. To derivea point of departure (POD) for human health risk assessment upon acuteneurotoxicity induced by oral STX exposure, a physiologically basedkinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach wasemployed. The PBK models for rats, mice, and humans were built usingparameters 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 thesethree species, and POD values were derived from the predicted curvesand compared to reported in vivo toxicity data. Interspeciesdifferences in acute STX toxicity between rodents and humans werefound, and they appeared to be mainly due to differences in toxicokinetics.The described approach resulted in adequate predictions for acuteoral STX exposure, indicating that new approach methodologies, whenappropriately integrated, can be used in a 3R-based chemical riskassessment paradigm. Anintegration of PBK modeling-facilitated QIVIVE and in vitro toxicity data is a promising alternative to animaltesting for human health risk assessment upon exposure to phycotoxins.