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Spontaneous activity in neuronal cultures on microelectrode arrays (MEAs) is sensitive to effects of drugs, chemicals, and particles. Multi-well MEA (mwMEA) systems have increased throughput of MEAs, enabling their use for chemical screening. The present experiments examined a subset of EPA's ToxCast compounds for effects on spontaneous neuronal activity in primary cortical cultures using 48-well MEA plates. A first cohort of 68 compounds was selected from the ToxCast Phase I and II libraries; 37 were positive in one or more of 20 individual ToxCast Novascreen assays related to ion channels (NVS_IC), with the remainder selected based on known neuroactivity. A second cohort of 25 compounds was then tested with 20 originating from the ToxCast Phase I and II libraries (not hits in NVS_IC assays) and 5 known negatives from commercial vendors. Baseline activity (1 h) was recorded prior to exposing the networks to compounds for 1 h, and the weighted mean firing rate (wMFR) was determined in the absence and presence of each compound. Compounds that altered activity by greater than the weighted change of DMSO-treated wells plus 2SD were considered "hits". Of the first set of 68 compounds, 54 altered wMFR by more than the threshold, while in the second set, 13/25 compounds were hits. MEAs detected 30 of 37 (81.1%) compounds that were hits in NVS_IC assays, as well as detected known neurotoxicants that were negative in NVS_IC assays, primarily pyrethroids and GABA(A) receptor antagonists. Conversely, wMFR of cortical neuronal networks on MEAs was insensitive to nicotinic compounds, as only one neonicotinoid was detected by MEAs; this accounts for the bulk of non-concordant compounds between MEA and NVS_IC assays. These data demonstrate that mwMEAs can be used to screen chemicals efficiently for potential neurotoxicity, and that the results are concordant with predictions from ToxCast NVS_IC assays for interactions with ion channels. Published by Elsevier Inc.