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Initial Recommendations on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery

OECD·2023·OECD Series on Testing and Assessment
DOI 10.1787/91964ef3-en
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  • The DNT in vitro Battery (DNT-IVB) is a suite of 17 cell-based assays targeting key neurodevelopmental processes and is nearing regulatory implementation for chemical risk assessment.

    “The DNT in vitro Battery (DNT-IVB), a suite of 17 cell-based assays targeting these key processes, is nearing regulatory implementation for chemical risk assessment (Bal-Price et al., 2018b; Fritsche et al., 2018; Masjosthusmann et al., 2020; EFSA, 2021; Sachana et al., 2021a; Sachana et al., 2021b; Carstens et al., 2022; Blum et al., 2023; OECD, 2023; Smirnova et al., 2024).”

    From Challenges and solutions in transitioning to animal-free standards: a comprehensive analysis of components in human cell-based developmental neurotoxicity assays (2026) · cites this paper as OECD, 2023

    The DNT IVB section describes cell-culture assays targeting fundamental neurodevelopmental processes, and section 62 says the current battery contains 17 assays. The paper reports a consensus that the assays are ready for regulatory use, particularly screening and prioritisation, but it does not establish that regulatory implementation is imminent; section 7 also cautions against using the battery to replace in vivo tests for all hazard-based decisions. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The U.S. EPA, EFSA and OECD endorse the integration of the DNT-IVB in risk assessment, with OECD recommendations providing a tiered framework for its regulatory use.

    “The U.S. Environmental Protection Agency (EPA), European Food Safety Authority (EFSA) and the Organization for Economic Co-operation and Development (OECD) endorse its integration in risk assessment with OECD recommendations providing a tiered framework for its regulatory use (EFSA PPR Panel (EFSA Panel on Plant Protection Products and their Residues), OECD, 2023).”

    From Challenges and solutions in transitioning to animal-free standards: a comprehensive analysis of components in human cell-based developmental neurotoxicity assays (2026) · cites this paper as OECD, 2023

  • Of the 17 DNT-IVB assays, seven utilize human cells differentiated into various neural subtypes, while others, such as the synaptogenesis assay and the neural network formation (NNF) assay, incorporate rat-derived cells.

    “Of the 17 DNT-IVB assays, seven utilize human cells differentiated into various neural subtypes, while others, such as the synaptogenesis assay and the neural network formation (NNF) assay, incorporate rat-derived cells (OECD, 2023).”

    From Challenges and solutions in transitioning to animal-free standards: a comprehensive analysis of components in human cell-based developmental neurotoxicity assays (2026) · cites this paper as OECD, 2023

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  181. Crofton KM, Mundy WR, Lein PJ, Bal-Price A, Coecke S, Seiler AE, Knaut H, Buzanska L, Goldberg A. Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals. ALTEX. 2011;28(1):9-15. PMID: 21311847.
  182. Druwe I, Freudenrich TM, Wallace K, Shafer TJ, Mundy WR. 2016. Comparison of Human Induced Pluripotent Stem Cell-Derived Neurons and Rat Primary Cortical Neurons as In Vitro Models of Neurite Outgrowth. Applied in vitro Toxicology. 2(1): 26-36.
  183. Filer DL, Kothiya P, Setzer RW, Judson RS, Martin MT. tcpl: the ToxCast pipeline for high-throughput screening data. Bioinformatics. 2017 Feb 15;33(4):618-620. doi: 10.1093/bioinformatics/btw680. PMID: 27797781. · DOI
  184. Harrill JA, Robinette BL, Mundy WR. Use of high content image analysis to detect chemical-induced changes in synaptogenesis in vitro. Toxicol In Vitro. 2011 Feb;25(1):368-87. doi: 10.1016/j.tiv.2010.10.011. · DOI
  185. Harrill JA, Freudenrich T, Wallace K, Ball K, Shafer TJ, Mundy WR.Testing for developmental neurotoxicity using a battery of in vitro assays for key cellular events in neurodevelopment. Toxicol Appl Pharmacol. 2018 Sep 1;354:24-39.
  186. Inglefield JR, Shafer TJ. Perturbation by the PCB mixture aroclor 1254 of GABA(A) receptor-mediated calcium and chloride responses during maturation in vitro of rat neocortical cells.Toxicol Appl Pharmacol. 2000 Apr 15;164(2):184-95. doi: 10.1006/taap.2000.8898. · DOI
  187. Li S, Zhang L, Huang R, Xu T, Parham F, Behl M, Xia M. Evaluation of chemical compounds that inhibit neurite outgrowth using GFP-labeled iPSC-derived human neurons. Neurotoxicology. 2021 Mar;83:137-145. doi: 10.1016/j.neuro.2021.01.003. Epub 2021 Jan 27.PMID: 33508353. · DOI
  188. McConnell ER, McClain MA, Ross J, Lefew WR, Shafer TJ. Evaluation of multi-well microelectrode arrays for neurotoxicity screening using a chemical training set. Neurotoxicology. 2012 Oct;33(5):1048-57. doi: 10.1016/j.neuro.2012.05.001. · DOI
  189. Mundy WR, Freudenrich TM. Sensitivity of immature neurons in culture to metal-induced changes in reactive oxygen species and intracellular free calcium Neurotoxicology. 2000 Dec;21(6):1135-44.
  190. Mundy WR, Padilla S, Breier JM, Crofton KM, Gilbert ME, Herr DW, Jensen KF, Radio NM, Raffaele KC, Schumacher K, Shafer TJ, Cowden J. Expanding the test set: Chemicals with potential to disrupt mammalian brain development. Neurotoxicol Teratol. 2015 Nov-Dec;52(Pt A):25-35. doi: 10.1016/j.ntt.2015.10.001. Epub 2015 Oct 22. PMID: 26476195. · DOI
  191. Pearce RG, Setzer RW, Strope CL, Wambaugh JF, Sipes NS. httk: R Package for High-Throughput Toxicokinetics. J Stat Softw. 2017 Jul 17;79(4):1-26. doi: 10.18637/jss.v079.i04. PMID: 30220889. · DOI
  192. Ryan KR, Sirenko O, Parham F, Hsieh JH, Cromwell EF, Tice RR, Behl M. Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity. Neurotoxicology. 2016 Mar;53:271-281. doi: 10.1016/j.neuro.2016.02.003. Epub 2016 Feb 4.PMID: 26854185. · DOI
  193. Wetmore BA, Wambaugh JF, Ferguson SS, Sochaski MA, Rotroff DM, Freeman K, Clewell HJ 3rd, Dix DJ, Andersen ME, Houck KA, Allen B, Judson RS, Singh R, Kavlock RJ, Richard AM, Thomas RS. Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment. Toxicol Sci. 2012 Jan;125(1):157-74. doi: 10.1093/toxsci/kfr254. Epub 2011 Sep 26. Reference to additional files of relevance Number of supporting files: 1. Standard Operation Procedure (Section 3.7) Description of general features of the test system source Supply of source cells Rat primary cortical neurons prepared from postnatal day (PND) 0 pups. Pregnant dams are supplied by Charles River Laboratories; delivered to the US Environmental Protection Agency (EPA) facility on gestational day (GD)16 and held in animal colonies until they give birth. Overview of cell source component(s) Primary rat cortical cultures are prepared on site from the neocortex dissected from the central nervous system (CNS) of newborn (PND0) Long-Evans rat pups using a standard protocol (Section 3.7). In a typical culture, cells are isolated from the combined cortices of 3-5 pups, seeded onto a Poly-L-Lysine coated 96- well plate at a density of 10,000 cells/well and are allowed 2 hours to attach. The cells are maintained in a Bal-Price A, Hogberg HT, Crofton KM, Daneshian M, FitzGerald RE, Fritsche E, Heinonen T, Hougaard Bennekou S, Klima S, Piersma AH, Sachana M, Shafer TJ, Terron A, Monnet-Tschudi F, Viviani B, Waldmann T, Westerink RHS, Wilks MF, Witters H, Zurich MG, Leist M. Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity. ALTEX. 2018;35(3):306-352. doi: 10.14573/altex.1712081.PMID: 29485663. · DOI · Paper page
  194. Bell SM, Chang X, Wambaugh JF, Allen DG, Bartels M, Brouwer KLR, Casey WM, Choksi N, Ferguson SS, Fraczkiewicz G, Jarabek AM, Ke A, Lumen A, Lynn SG, Paini A, Price PS, Ring C, Simon TW, Sipes NS, Sprankle CS, Strickland J, Troutman J, Wetmore BA, Kleinstreuer NC. In vitro to in vivo extrapolation for high throughput prioritization and decision making. Toxicol In Vitro. 2018 Mar;47:213- 227. doi: 10.1016/j.tiv.2017.11.016. Epub 2017 Dec 5. PMID: 29203341 · DOI
  195. Crofton KM, Mundy WR, Lein PJ, Bal-Price A, Coecke S, Seiler AE, Knaut H, Buzanska L, Goldberg A. Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals. ALTEX. 2011;28(1):9-15. PMID: 21311847.
  196. Harrill JA, Robinette BL, Mundy WR. Use of high content image analysis to detect chemical-induced changes in synaptogenesis in vitro. Toxicol In Vitro. 2011 Feb;25(1):368-87. doi: 10.1016/j.tiv.2010.10.011. · DOI
  197. Harrill JA, Freudenrich T, Wallace K, Ball K, Shafer TJ, Mundy WR.Testing for developmental neurotoxicity using a battery of in vitro assays for key cellular events in neurodevelopment. Toxicol Appl Pharmacol. 2018 Sep 1;354:24-39.
  198. Filer DL, Kothiya P, Setzer RW, Judson RS, Martin MT. tcpl: the ToxCast pipeline for high-throughput screening data. Bioinformatics. 2017 Feb 15;33(4):618-620. doi: 10.1093/bioinformatics/btw680. PMID: 27797781. · DOI
  199. Mundy WR, Padilla S, Breier JM, Crofton KM, Gilbert ME, Herr DW, Jensen KF, Radio NM, Raffaele KC, Schumacher K, Shafer TJ, Cowden J. Expanding the test set: Chemicals with potential to disrupt mammalian brain development. Neurotoxicol Teratol. 2015 Nov-Dec;52(Pt A):25-35. doi: 10.1016/j.ntt.2015.10.001. PMID: 26476195. · DOI
  200. Pearce RG, Setzer RW, Strope CL, Wambaugh JF, Sipes NS. httk: R Package for High-Throughput Toxicokinetics. J Stat Softw. 2017 Jul 17;79(4):1-26. doi: 10.18637/jss.v079.i04. PMID: 30220889. · DOI

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Authors
OECD
Venue
OECD Series on Testing and Assessment
Publisher
OECD
Published
2023-11-03
ISSN
2077-7876
DOI
10.1787/91964ef3-en
Cited by
24
References
0
Language
en

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