title: Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use.
abstract: There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e., alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of > 50 endpoint-specific control compounds was identified. For further test development, an additional "test" set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the > 100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.
authors.affiliation: Albert Einstein College of Medicine, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.affiliation: Department of Neuroscience, Karolinska Institutet Stockholm, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ceccatelli
authors.affiliation: Center for Alternatives to Animal Testing-Europe (CAAT-Europe), University of Konstanz, Germany.
authors.forename: Mardas
authors.initials: M
authors.lastname: Daneshian
authors.affiliation: Leibniz Research Institute for Environmental Medicine (IUF), Düsseldorf, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
authors.affiliation: Center for Alternatives to Animal Testing-Europe (CAAT-Europe), University of Konstanz, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hasiwa
authors.affiliation: Center for Alternatives to Animal Testing-Europe (CAAT-Europe), University of Konstanz, Germany.|Center for Alternatives to Animal Testing (CAAT), The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartung
authors.affiliation: Center for Alternatives to Animal Testing (CAAT), The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Helena T
authors.initials: HT
authors.lastname: Hogberg
authors.affiliation: Center for Alternatives to Animal Testing-Europe (CAAT-Europe), University of Konstanz, Germany.|In vitro Toxicology and Biomedicine, Dept inaugurated by the Doerenkamp-Zbinden Foundation at the University of Konstanz, Konstanz, Germany.|Konstanz Research School Chemical Biology (KoRS-CB), Konstanz University.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.affiliation: Exponent Inc.,San Francisco, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Li
authors.affiliation: United States Environmental Protection Agency (USEPA), NHEERL, Research Triangle Park, NC, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Mundi
authors.affiliation: United States Environmental Protection Agency (USEPA), NHEERL, Research Triangle Park, NC, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Padilla
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.|Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
authors.affiliation: European Commission Joint Research Centre, Institute for Health and Consumer Protection, Ispra, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bal-Price
authors.affiliation: Federal Institute for Risk Assessment (BfR), Berlin, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Seiler
authors.affiliation: Neurotoxicology Research Group, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.
authors.forename: Remco H
authors.initials: RH
authors.lastname: Westerink
authors.affiliation: Axiogenesis AG, Köln, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Zimmer
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, USA.|Department of Molecular Biosciences, University of California, Davis, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Lein
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D003226:Congresses as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D015386:Hazardous Substances; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000209:etiology; D009498:Neurotoxins / Q000032:analysis*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D015386:Hazardous Substances; D009498:Neurotoxins
keywords: AOP; neurotoxicity; specificity; test development; validation