title: Expanding the test set: Chemicals with potential to disrupt mammalian brain development.
abstract: High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery. In contrast, evaluation of the predictive ability of a comprehensive test battery requires a set of chemicals that have been shown to alter brain development after in vivo exposure ("test set"). Because only a small number of substances have been well documented to alter human neurodevelopment, we have proposed an expanded test set that includes chemicals demonstrated to adversely affect neurodevelopment in animals. To compile a list of potential developmental neurotoxicants, a literature review of compounds that have been examined for effects on the developing nervous system was conducted. The search was limited to mammalian studies published in the peer-reviewed literature and regulatory studies submitted to the U.S. EPA. The definition of developmental neurotoxicity encompassed changes in behavior, brain morphology, and neurochemistry after gestational or lactational exposure. Reports that indicated developmental neurotoxicity was observed only at doses that resulted in significant maternal toxicity or were lethal to the fetus or offspring were not considered. As a basic indication of reproducibility, we only included a chemical if data on its developmental neurotoxicity were available from more than one laboratory (defined as studies originating from laboratories with a different senior investigator). Evidence from human studies was included when available. Approximately 100 developmental neurotoxicity test set chemicals were identified, with 22% having evidence in humans.
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address: mundy.william@epa.gov.
authors.forename: William R
authors.initials: WR
authors.lastname: Mundy
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Padilla
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Breier
authors.affiliation: National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Gilbert
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Herr
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Jensen
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Radio
authors.affiliation: Office of Solid Waste and Emergency Response, U.S. Environmental Protection Agency, Washington, DC, USA.
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Raffaele
authors.affiliation: Region 7, U.S. Environmental Protection Agency, Lenexa, KS, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Schumacher
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
authors.affiliation: National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cowden
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development*; D023381:Endpoint Determination; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008322:Mammals / Q000254:growth & development; D009498:Neurotoxins / Q000032:analysis*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology / Q000523:psychology; D015203:Reproducibility of Results; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D009498:Neurotoxins
keywords: Brain; Development; Neurotoxicity; Reference chemicals; Toxicity testing