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Expanding the test set: Chemicals with potential to disrupt mammalian brain development.
| Neurotoxicology and Teratology | Mundy WR, Padilla S, Breier JM, Crofton KM, Gilber ME, Herr DW, Jensen KF, Radio NM, Raffaele KC, Schumacher K, Shafer TJ, Cowden J. | 52(Pt A):25-35.
Brain Cognitive Function Review

Abstract

Highlights

  • The manuscript describes results from a literature review of peer-reviewed studies and regulatory documents. The purpose of the literature review was to evaluate the amount of evidence available for chemicals that have been reported to alter brain development in test animals and/or humans. This information can be used for the development of a set of chemicals to assess which screening technologies and alternative testing techniques best predict potential neurotoxicity.
  • Out of 400 chemicals reviewed, approximately 100 had evidence of developmental neurotoxicity. Of these 100 chemicals, 21 had evidence in human studies
  • These chemicals will be useful for testing and evaluating the new high-throughput screening assays.

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: Mundy WR1, Padilla S2, Breier JM2, Crofton KM3, Gilbert ME2, Herr DW2, Jensen KF2, Radio NM2, Raffaele KC4, Schumacher K5, Shafer TJ, 2 Cowden J3.

  1. National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
  2. National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
  3. National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
  4. Office of Solid Waste and Emergency Response, U.S. Environmental Protection Agency, Washington, DC, USA.
  5. Region 7, U.S. Environmental Protection Agency, Lenexa, KS, USA.

*Original abstract online at https://www.sciencedirect.com/science/article/abs/pii/S0892036215300362?via%3Dihub