title: Comparison of the acute inhibitory effects of Tetrodotoxin (TTX) in rat and human neuronal networks for risk assessment purposes.
abstract: Tetrodotoxin (TTX) is an extremely toxic marine neurotoxin. TTX inhibits voltage-gated sodium channels, resulting in a potentially lethal inhibition of neurotransmission. Despite numerous intoxications in Asia and Europe, limited (human) toxicological data are available for TTX. Additionally, the degree of interspecies differences for TTX is not well established, hampering the use of available (animal) data for human risk assessment and establishing regulatory limits for TTX concentrations in (shell)fish. We therefore used micro-electrode array (MEA) recordings as an integrated measure of neurotransmission to demonstrate that TTX inhibits neuronal electrical activity in both primary rat cortical cultures and human-induced pluripotent stem cell (hIPSC)-derived iCell®neurons in co-culture with hIPSC-derived iCell®astrocytes, with IC50values of 7 and 10nM, respectively. From these data combined with LD50values and IC50concentrations of voltage-gated sodium channels derived from literature it can be concluded that interspecies differences are limited for TTX. Consequently, we used experimental animal data to derive a human acute reference dose of 1.33μg/kg body weight, which corresponds to maximum concentration of TTX in shellfish of 200μg/kg.
authors.affiliation: Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands.
authors.forename: Emma E J
authors.initials: EE
authors.lastname: Kasteel
authors.affiliation: Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands. Electronic address: r.westerink@uu.nl.
authors.forename: Remco H S
authors.initials: RH
authors.lastname: Westerink
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007928:Lethal Dose 50; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D018570:Risk Assessment; D009435:Synaptic Transmission / Q000187:drug effects; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000633:toxicity*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism
chemical_list: D009498:Neurotoxins; D061566:Voltage-Gated Sodium Channels; D013779:Tetrodotoxin
keywords: Acute reference dose (ARfD); Human risk assessment; Interspecies extrapolation; Marine neurotoxin; Tetrodotoxin (TTX)