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Less than 1% of environmental chemicals have been evaluated for developmental neurotoxicity (DNT). Current guideline DNT studies are resource intensive and not amenable to screening large numbers of compounds for hazard. As part of evaluating a battery of more rapid and scalable in vitro assays for DNT hazard, 86 compounds were screened for their ability to alter function during cortical network development. Developing rat cortical networks were treated with a concentration series (usually 0.03-30 A mu M) of 86 compounds, 60 of which have known in vivo DNT effects ("DNT Reference Set"). Spontaneous network activity was monitored by microelectrode array recordings over 12 days in vitro, and 17 measures of network activity and synchrony were quantified. Following recordings on days in vitro 12, in-well cell assessment of metabolic activity (Alamar blue) and total cellular content (lactase dehydrogenase) were conducted. Of the 86 compounds tested, 64 perturbed cortical network function in a concentration-dependent manner; 49 of the 60 DNT Reference Set compounds (81.7%) altered network formation. Compounds were ranked by potency (network effect EC50) and selectivity (separation of network and cell viability EC50) for hazard prioritization. Machine learning indicates a combination of an overall network activity metric with a measure of network coordination is key in distinguishing network-disruptive from benign treatments. These data demonstrate that this microelectrode array-based assay for developing cortical network function is amenable to medium-throughput evaluation of environmental substances for DNT hazard and further prioritization. For comprehensive identification of compounds of concern, this assay will be a useful component of a battery of assays targeting independent neurodevelopmental processes.