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in vitro methods toxicology endocrine disruptors reach organoids alternative methods new approach methodologies (nams) read across microphysiological system organ-on-a-chip drug development preclinical studies investigative toxicology adverse outcome pathways drug developmenent ipsc zebra fish embryo test mini brain eogrts reproductive toxicity nams validazione metodi alternativi decreto legge 4 marzo 2014 directive 2010/63 in vitro tests in vivo tests pesticides qivive ecopa scientific discussion 3rs nam new advanced methodologies www.iss.it/life minibrain stem cells in vitro regulatory annex xi