title: In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures.
abstract: Exposure to tricresyl phosphates (TCPs), via for example contaminated cabin air, has been associated with health effects including the so-called aerotoxic syndrome. While TCP neurotoxicity is mainly attributed to ortho-isomers like tri-ortho-cresyl phosphate (ToCP), recent exposure and risk assessments indicate that ToCP levels in cabin air are very low. However, the neurotoxic potential of non-ortho TCP isomers and TCP mixtures is largely unknown. We therefore measured effects of exposure (up to 48h) to different TCP isomers, mixtures and the metabolite of ToCP (CBDP: cresyl saligenin phosphate) on cell viability and mitochondrial activity, spontaneous neuronal electrical activity, and neurite outgrowth in primary rat cortical neurons. The results demonstrate that exposure to TCPs (24-48h, up to 10μM) increases mitochondrial activity, without affecting cell viability. Effects of acute TCP exposure (30min) on neuronal electrical activity are limited. However, electrical activity is markedly decreased for the majority of TCPs (10μM) following 48h exposure. Additional preliminary data indicate that exposure to TCPs (48h, 10μM) did not affect the number of neurites per cell or average neurite length, except for TmCP and the analytical TCP mixture (Sigma) that induced a reduction of average neurite length. The combined neurotoxicity data demonstrate that the different TCPs, including ToCP, are roughly equipotent and a clear structure-activity relation is not apparent for the studied endpoints. The no-observed-effect-concentrations (1μM) are well above current exposure levels indicating limited neurotoxic health risk, although exposures may have been higher in the past. Moreover, prolonged and/or repeated exposure to TCPs may exacerbate the observed neurotoxic effects, which argues for additional research.
authors: Neurotoxicology Research Group, Toxicology Division, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht University, NL-3508 TD Utrecht, The Netherlands.
authors: Daniel J
authors: DJ
authors: Duarte
authors: Neurotoxicology Research Group, Toxicology Division, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht University, NL-3508 TD Utrecht, The Netherlands.
authors: Joost M M
authors: JMM
authors: Rutten
authors: Neurotoxicology Research Group, Toxicology Division, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht University, NL-3508 TD Utrecht, The Netherlands.
authors: Martin
authors: M
authors: van den Berg
authors: Neurotoxicology Research Group, Toxicology Division, Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht University, NL-3508 TD Utrecht, The Netherlands. Electronic address: r.westerink@uu.nl.
authors: Remco H S
authors: RHS
authors: Westerink
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D008928:Mitochondria / Q000187:drug effects; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010755:Organophosphates / Q000633:toxicity*; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors; D014317:Tritolyl Phosphates / Q000633:toxicity*
chemical_list: D010755:Organophosphates; D014317:Tritolyl Phosphates
keywords: Aerotoxic syndrome; Hazard characterization; In vitro neurotoxicity; Microelectrode array (MEA) recordings; Neurite outgrowth; Tricresyl phosphates