OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

311 cluding: neural proliferation, differentiation, migration, neurite outgrowth, synaptogenesis, myelin formation, and neural network formation and function. Many of these human cell-based assays have been used to study small numbers of chemicals (n < 15; e.g., Harrill et al., 2011; He et al., 2012; Rempel et al., 2015; Baumann et al., 2016; Brown et al., 2016) or to derive mechanistic information for limited numbers of chemicals (e.g., Gassmann et al., 2010; Balmer et al., 2012; Balmer and Leist, 2014; Barenys et al., 2016). Only a few have been utilized to screen larger numbers (n > 15) of compounds (e.g., Stiegler et al., 2011; Zimmer et al., 2012; Culbreth et al., 2012; McConnell et al., 2012; Krug et al., 2013; Valdivia et al., 2014; Mundy et al., 2015; Hoelting et al., 2016; Nyffeler et al., 2016). On the scientific premise that alternative methods are available and can be assembled into a larger DNT screening battery, a joint OECD/EFSA workshop was held in Brussels on October 18 and 19, 2016 that aimed to facilitate the use of such methods in regulatory decision making. Specific objectives of this workshop were: 1. Development of a consensus that the proposed testing battery of alternative DNT methods is ready to be applied right now, and could be used in a fit-for-purpose manner for either screening and prioritization, or as a first starting point to conduct targeted testing in a tiered testing approach in the process of hazard identification and characterization for specific chemical risk assessment. 2. Identification of the next steps necessary to encourage the regulatory use of the alternative methods depending on their level of readiness. 3. Outline what could become an integrated approach to testing and assessment (IATA) for the purposes of screening and prioritization or hazard assessment. The meeting was co-chaired by Ellen Fritsche (Leibniz Research Institute for Environmental Medicine, IUF) and Kevin Crofton (US Environmental Protection Agency, US EPA). Meeting participants and their affiliations are reported in the supplementary file at https://doi.org/10.14573/altex.1701171s. Scientists from 15 countries across the world, representing stakeholders from regulatory agencies, non-governmental organizations (NGOs), academia and industry, reached a consensus that current data requirements for in vivo developmental neurotoxicity (DNT) testing are not sufficient to screen and characterize potentially hazardous compounds. In addition, there was agreement on the need to develop a standardized in vitro testing battery to generate additional data on the effects of chemicals on the developing nervous system. The need for more effective DNT screening is driven by the scientific fact that the developing nervous system might be more sensitive to exposures to some chemical classes of hazardous substances. In addition, recent societal concerns have been raised linking the rise in children’s neurodevelopmental impairments (e.g., learning disabilities) to chemical exposures. Despite a clear deficit in knowledge concerning DNT effects, only approximately 140 in vivo guideline studies (according to OECD 426 & EPA OPPTS 870.630) have been conducted to date, leaving a huge data gap on the DNT potential of chemicals within the universe of thousands of compounds present in industrial, agricultural and consumer products. This deficit is mainly due to the fact that currently accepted guideline studies are at present not mandatory data requirements and are extremely timeand costintensive. Additionally, they can result in methodological and scientific uncertainties. This includes the challenges in extrapolation of findings from rats to humans that result from timing differences in brain development, toxicokinetics, and inherent difficulties in the use of non-homologous functional tests (Tsuji and Crofton, 2012; Dorman et al., 2001; Kaufmann, 2003). For these reasons, DNT has been regarded as an area in need of the development of alternative methods in order to establish a timeand cost-efficient predictive testing strategy. A series of workshops held over the past decade (Lein et al., 2007; Crofton et al., 2011; Bal-Price et al., 2012, 2015a) have fostered the development of in vitro assays or methods using alternative model organisms that assess the impact of chemicals on cellular processes critical to normal brain development, inMeeting report