Skip to main content
SpringerLink
Log in

Application of Non-Animal Methods to More Effective Neurotoxicity Testing for Regulatory Purposes

  • Protocol
  • First Online:
Book cover Cell Culture Techniques

Part of the book series: Neuromethods ((NM,volume 145))

Abstract

The identification of chemicals that have the potential to induce developmental or adult neurotoxicity is currently entirely based on animal testing. At the regulatory level, systematic testing of developmental (DNT) and adult (NT) neurotoxicity is not a standard requirement within the EU legislation of chemical safety assessment, except for pesticides where NT testing is required. Both DNT and NT evaluation are only performed when triggered based on structure-activity relationships or evidence of neurotoxicity in systemic adult, developmental, or reproduction studies. However, these triggers are rarely used as to date only a limited amount of chemicals have been tested for either DNT or NT effects. Furthermore, the animal-based regulatory DNT or NT studies are unsuitable for screening large number of chemicals, since they are low throughput and costly and use large number of animals. Therefore, new, reliable, and efficient screening and assessment tools are needed for better identification, prioritization, and evaluation of chemicals with potential to induce neurotoxicity. A new framework is proposed for the development of a mechanistically informed IATA (Integrated Approaches to Testing and Assessment) which would integrate various sources of information (e.g., in vitro approaches, in silico modeling, mechanistic knowledge built in the relevant adverse outcome pathways, etc.) as well as in vivo animal and human data, speeding up the evaluation of thousands of compounds present in industrial, agricultural, and consumer products that lack safety data on NT and DNT potential.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Harry GJ, Billingsley M, Bruinink A et al (1998) In vitro techniques for the assessment of neurotoxicity. Environ Health Perspect 106(Suppl 1):131–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Harry J, Kulig B, Ray D et al (2001) Neurotoxicity risk assessment for human health: principles and approaches. Available from: http://www.inchem.org/documents/ehc/ehc/ehc223.htm#_223318000

  3. Coecke S, Goldberg AM, Allen S et al (2007) Workgroup report: incorporating in vitro alternative methods for developmental neurotoxicity into international hazard and risk assessment strategies. Environ Health Perspect 115(6):924–931

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hogberg HT, Kinsner-Ovaskainen A, Coecke S et al (2010) mRNA expression is a relevant tool to identify developmental neurotoxicants using an in vitro approach. Toxicol Sci 113(1):95–115

    Article  CAS  PubMed  Google Scholar 

  5. Hogberg HT, Kinsner-Ovaskainen A, Hartung T et al (2009) Gene expression as a sensitive endpoint to evaluate cell differentiation and maturation of the developing central nervous system in primary cultures of rat cerebellar granule cells (CGCs) exposed to pesticides. Toxicol Appl Pharmacol 235(3):268–286

    Article  CAS  PubMed  Google Scholar 

  6. Krug AK, Balmer NV, Matt F et al (2013) Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87(12):2215–2231

    Article  CAS  PubMed  Google Scholar 

  7. Rice D, Barone S Jr (2000) Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 108(Suppl 3):511–533

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stiles J, Jernigan TL (2010) The basics of brain development. Neuropsychol Rev 20(4):327–348

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yang D, Kania-Korwel I, Ghogha A et al (2014) PCB 136 atropselectively alters morphometric and functional parameters of neuronal connectivity in cultured rat hippocampal neurons via ryanodine receptor-dependent mechanisms. Toxicol Sci 138(2):379–392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adinolfi M (1985) The development of the human blood-CSF-brain barrier. Dev Med Child Neurol 27(4):532–537

    Article  CAS  PubMed  Google Scholar 

  11. Bal-Price AK, Coecke S, Costa L et al (2012) Advancing the science of developmental neurotoxicity (DNT): testing for better safety evaluation. ALTEX 29(2):202–215

    Article  PubMed  Google Scholar 

  12. Smirnova L, Hogberg HT, Leist M et al (2014) Developmental neurotoxicity – challenges in the 21st century and in vitro opportunities. ALTEX 31(2):129–156

    PubMed  PubMed Central  Google Scholar 

  13. Bal-Price AK, Hogberg HT, Buzanska L et al (2010) In vitro developmental neurotoxicity (DNT) testing: relevant models and endpoints. Neurotoxicology 31(5):545–554

    Article  CAS  PubMed  Google Scholar 

  14. Makris SL, Raffaele K, Allen S et al (2009) A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect 117(1):17–25

    Article  CAS  PubMed  Google Scholar 

  15. OECD (1981) Test guideline 403. OECD guideline for testing of chemicals. Acute Inhalation Toxicity

    Google Scholar 

  16. OECD (1987) Test guideline 402. OECD guideline for testing of chemicals. Acute Dermal Toxicity

    Google Scholar 

  17. OECD (2002) Test guideline 420. OECD guideline for testing of chemicals. Acute Oral Toxicity – Fixed Dose Procedure

    Google Scholar 

  18. OECD (2002) Test guideline 423. OECD guideline for testing of chemicals. Acute Oral Toxicity – Acute Toxic Class Method

    Google Scholar 

  19. OECD (2008) Test guideline 436. OECD guideline for testing of chemicals. Acute Inhalation Toxicity – Acute Toxic Class Method

    Google Scholar 

  20. OECD (2008) Test guideline 425. OECD guideline for testing of chemicals. Acute Oral Toxicity – Up-and-Down Procedure

    Google Scholar 

  21. OECD (1998) Test guideline 408. OECD guideline for testing of chemicals. Repeated Dose 90-day Oral Toxicity Study in Rodents

    Google Scholar 

  22. OECD (2008) Test guideline 407. OECD guideline for testing of chemicals. Repeated Dose 28-day Oral Toxicity Study in Rodents

    Google Scholar 

  23. OECD (2009) Test guideline 452. OECD guideline for testing of chemicals. Chronic Toxicity Studies

    Google Scholar 

  24. Bjorling-Poulsen M, Andersen HR, Grandjean P (2008) Potential developmental neurotoxicity of pesticides used in Europe. Environ Health 7:50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. OECD (2007) Test guideline 426. OECD guideline for testing of chemicals. Developmental Neurotoxicity Study

    Google Scholar 

  26. OECD (1997) Test guideline 424. OECD guideline for testing of chemicals. Neurotoxicity Study in Rodents

    Google Scholar 

  27. OECD (1995) Test guideline 418. OECD guideline for testing acute neurotoxicity of organophosphorus substances in laying hens

    Google Scholar 

  28. OECD (1995) Test guideline 419. OECD guideline for testing delayed neurotoxicity of organophosphorus substances in laying hens

    Google Scholar 

  29. OECD (2011) Test guideline 443. Extended one-generation reproductive toxicity study

    Google Scholar 

  30. OECD (2004) Series on testing and assessment number 20, Guidance document for neurotoxicity testing

    Google Scholar 

  31. EPA (2009) OPPTS 870.6200 Neurotoxicity Screening Battery [EPA 712–C–98–238]. Available from: https://www.regulations.gov/document?D=EPA-HQ-OPPT-2009-0156-0041

  32. U.S. Government Publishing Office (2018) 40 CFR § 799.9620 – TSCA neurotoxicity screening battery. Available from: https://www.govinfo.gov/app/details/CFR-2018-title40-vol35/CFR-2018-title40-vol35-sec799-9620

  33. Rovida C, Hartung T (2009) Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals – a report by the transatlantic think tank for toxicology (t(4)). ALTEX 26(3):187–208

    Article  PubMed  Google Scholar 

  34. Tsuji R, Crofton KM (2012) Developmental neurotoxicity guideline study: issues with methodology, evaluation and regulation. Congenit Anom (Kyoto) 52(3):122–128

    Article  Google Scholar 

  35. Aschner M, Ceccatelli S, Daneshian M et al (2017) Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. ALTEX 34(1):49–74

    PubMed  Google Scholar 

  36. Fritsche E, Grandjean P, Crofton KM et al (2018) Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes. Toxicol Appl Pharmacol 354:3–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Grandjean P, Landrigan PJ (2006) Developmental neurotoxicity of industrial chemicals. Lancet 368(9553):2167–2178

    Article  CAS  PubMed  Google Scholar 

  38. Crofton KM, Mundy WR, Lein PJ et al (2011) Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals. ALTEX 28(1):9–15

    PubMed  Google Scholar 

  39. Bal-Price A, Crofton KM, Sachana M et al (2015) Putative adverse outcome pathways relevant to neurotoxicity. Crit Rev Toxicol 45(1):83–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bal-Price A, Hogberg HT, Crofton KM et al (2018) Recommendation on test readiness criteria for new approach methods in toxicology: exemplified for developmental neurotoxicity. ALTEX 35(3):306–352

    Article  PubMed  PubMed Central  Google Scholar 

  41. Fritsche E, Alm H, Baumann J et al (2015) Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods. External Scientific Report. EFSA supporting publication. EN-778

    Google Scholar 

  42. Gassmann K, Abel J, Bothe H et al (2010) Species-specific differential AhR expression protects human neural progenitor cells against developmental neurotoxicity of PAHs. Environ Health Perspect 118(11):1571–1577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. NRC (2007) In: NRCN (ed) Toxicity testing in the 21st century: a vision and a strategy. The National Academies Press, Washington, D.C.

    Google Scholar 

  44. Bal-Price A, Pistollato F, Sachana M et al (2018) Strategies to improve the regulatory assessment of developmental neurotoxicity (DNT) using in vitro methods. Toxicol Appl Pharmacol 354:7–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fritsche E, Gassmann K, Schreiber T (2011) Neurospheres as a model for developmental neurotoxicity testing. Methods Mol Biol 758:99–114

    Article  CAS  PubMed  Google Scholar 

  46. Moors M, Cline JE, Abel J et al (2007) ERK-dependent and -independent pathways trigger human neural progenitor cell migration. Toxicol Appl Pharmacol 221(1):57–67

    Article  CAS  PubMed  Google Scholar 

  47. Moors M, Rockel TD, Abel J et al (2009) Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing. Environ Health Perspect 117(7):1131–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Breier JM, Gassmann K, Kayser R et al (2010) Neural progenitor cells as models for high-throughput screens of developmental neurotoxicity: state of the science. Neurotoxicol Teratol 32(1):4–15

    Article  CAS  PubMed  Google Scholar 

  49. Aschner M, Costa L (2005) Role of glia in neurotoxicity. Vol. RC347.5.R65. CRC Press, New York

    Google Scholar 

  50. Fritsche E, Cline JE, Nguyen NH et al (2005) Polychlorinated biphenyls disturb differentiation of normal human neural progenitor cells: clue for involvement of thyroid hormone receptors. Environ Health Perspect 113(7):871–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pistollato F, Canovas-Jorda D, Zagoura D et al (2017) Nrf2 pathway activation upon rotenone treatment in human iPSC-derived neural stem cells undergoing differentiation towards neurons and astrocytes. Neurochem Int 108:457–471

    Article  CAS  PubMed  Google Scholar 

  52. Yla-Outinen L, Heikkila J, Skottman H et al (2010) Human cell-based micro electrode array platform for studying neurotoxicity. Front Neuroeng 3:111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Amin H, Maccione A, Marinaro F et al (2016) Electrical responses and spontaneous activity of human iPS-derived neuronal networks characterized for 3-month culture with 4096-electrode arrays. Front Neurosci 10:121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pistollato F, Canovas-Jorda D, Zagoura D et al (2017) Protocol for the differentiation of human induced pluripotent stem cells into mixed cultures of neurons and glia for neurotoxicity testing. J Vis Exp. 124. https://doi.org/10.3791/55702

  55. Pistollato F, Louisse J, Scelfo B et al (2014) Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: effects of CREB pathway inhibition. Toxicol Appl Pharmacol 280(2):378–388

    Article  CAS  PubMed  Google Scholar 

  56. Zagoura D, Canovas-Jorda D, Pistollato F et al (2017) Evaluation of the rotenone-induced activation of the Nrf2 pathway in a neuronal model derived from human induced pluripotent stem cells. Neurochem Int 106:62–73

    Article  CAS  PubMed  Google Scholar 

  57. Yang Y, Jiang S, Yan J et al (2015) An overview of the molecular mechanisms and novel roles of Nrf2 in neurodegenerative disorders. Cytokine Growth Factor Rev 26(1):47–57

    Article  CAS  PubMed  Google Scholar 

  58. Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116(1):1–9

    Article  CAS  PubMed  Google Scholar 

  59. Coecke S, Balls M, Bowe G et al (2005) Guidance on good cell culture practice. A report of the second ECVAM task force on good cell culture practice. Altern Lab Anim 33(3):261–287

    Article  CAS  PubMed  Google Scholar 

  60. Pamies D, Bal-Price A, Simeonov A et al (2017) Good cell culture practice for stem cells and stem-cell-derived models. ALTEX 34(1):95–132

    PubMed  Google Scholar 

  61. Pistollato F, Bremer-Hoffmann S, Healy L et al (2012) Standardization of pluripotent stem cell cultures for toxicity testing. Expert Opin Drug Metab Toxicol 8(2):239–257

    Article  CAS  PubMed  Google Scholar 

  62. Harrill JA, Freudenrich T, Wallace K et al (2018) Testing for developmental neurotoxicity using a battery of in vitro assays for key cellular events in neurodevelopment. Toxicol Appl Pharmacol 354:24–39

    Article  CAS  PubMed  Google Scholar 

  63. Mundy WR, Radio NM, Freudenrich TM (2010) Neuronal models for evaluation of proliferation in vitro using high content screening. Toxicology 270(2–3):121–130

    Article  CAS  PubMed  Google Scholar 

  64. Druwe I, F TM, Wallace K et al (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

    Article  CAS  Google Scholar 

  65. Ryan KR, Sirenko O, Parham F et al (2016) Neurite outgrowth in human induced pluripotent stem cell-derived neurons as a high-throughput screen for developmental neurotoxicity or neurotoxicity. Neurotoxicology 53:271–281

    Article  CAS  PubMed  Google Scholar 

  66. Breier JM, Radio NM, Mundy WR et al (2008) Development of a high-throughput screening assay for chemical effects on proliferation and viability of immortalized human neural progenitor cells. Toxicol Sci 105(1):119–133

    Article  CAS  PubMed  Google Scholar 

  67. Harrill JA, Freudenrich TM, Robinette BL et al (2011) Comparative sensitivity of human and rat neural cultures to chemical-induced inhibition of neurite outgrowth. Toxicol Appl Pharmacol 256(3):268–280

    Article  CAS  PubMed  Google Scholar 

  68. Kuegler PB, Zimmer B, Waldmann T et al (2010) Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing. ALTEX 27(1):17–42

    PubMed  Google Scholar 

  69. Hogberg HT, Sobanski T, Novellino A et al (2011) Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32(1):158–168

    Article  CAS  PubMed  Google Scholar 

  70. Mundy WR, Robinette B, Radio NM et al (2008) Protein biomarkers associated with growth and synaptogenesis in a cell culture model of neuronal development. Toxicology 249(2–3):220–229

    Article  CAS  PubMed  Google Scholar 

  71. Schultz L, Zurich MG, Culot M et al (2015) Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models. Toxicol In Vitro 30(1 Pt A):138–165

    Article  CAS  PubMed  Google Scholar 

  72. Costa LG (1998) Neurotoxicity testing: a discussion of in vitro alternatives. Environ Health Perspect 106(Suppl 2):505–510

    Article  PubMed  PubMed Central  Google Scholar 

  73. Frank CL, Brown JP, Wallace K et al (2018) Defining toxicological tipping points in neuronal network development. Toxicol Appl Pharmacol 354:81–93

    Article  CAS  PubMed  Google Scholar 

  74. Novellino A, Scelfo B, Palosaari T et al (2011) Development of micro-electrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng 4:4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Valdivia P, Martin M, LeFew WR et al (2014) Multi-well microelectrode array recordings detect neuroactivity of ToxCast compounds. Neurotoxicology 44:204–217

    Article  CAS  PubMed  Google Scholar 

  76. Vassallo A, Chiappalone M, De Camargos Lopes R et al (2017) A multi-laboratory evaluation of microelectrode array-based measurements of neural network activity for acute neurotoxicity testing. Neurotoxicology 60:280–292

    Article  CAS  PubMed  Google Scholar 

  77. Geier MC, James Minick D, Truong L et al (2018) Systematic developmental neurotoxicity assessment of a representative PAH superfund mixture using zebrafish. Toxicol Appl Pharmacol 354:115–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ruszkiewicz JA, Pinkas A, Miah MR et al (2018) C. elegans as a model in developmental neurotoxicology. Toxicol Appl Pharmacol 354:126–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sipes NS, Padilla SKnudsen TB (2011) Zebrafish: as an integrative model for twenty-first century toxicity testing. Birth Defects Res C Embryo Today 93(3):256–267

    Article  CAS  PubMed  Google Scholar 

  80. Noyes PD, Haggard DE, Gonnerman GD et al (2015) Advanced morphological – behavioral test platform reveals neurodevelopmental defects in embryonic zebrafish exposed to comprehensive suite of halogenated and organophosphate flame retardants. Toxicol Sci 145(1):177–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lapenna S, Fuart-Gatnik M, Worth A (2010) Review of QSAR models and software tools for predicting acute and chronic systemic toxicity. JRC Scientific and Technical report

    Google Scholar 

  82. Crofton KM (1996) A structure-activity relationship for the neurotoxicity of triazole fungicides. Toxicol Lett 84(3):155–159

    Article  CAS  PubMed  Google Scholar 

  83. Pessah IN, Hansen LG, Albertson TE et al (2006) Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2+ channel complex type 1 (RyR1). Chem Res Toxicol 19(1):92–101

    Article  CAS  PubMed  Google Scholar 

  84. Nevalainen T, Kolehmainen E (1994) New QSAR models for polyhalogenated aromatics. Environ Toxicol Chem 13(10):1699–1706

    Article  CAS  Google Scholar 

  85. Pessah IN, Cherednichenko G, Lein PJ (2010) Minding the calcium store: ryanodine receptor activation as a convergent mechanism of PCB toxicity. Pharmacol Ther 125(2):260–285

    Article  CAS  PubMed  Google Scholar 

  86. El Yazal J, Rao SN, Mehl A et al (2001) Prediction of organophosphorus acetylcholinesterase inhibition using three-dimensional quantitative structure-activity relationship (3D-QSAR) methods. Toxicol Sci 63(2):223–232

    Article  PubMed  Google Scholar 

  87. Stenberg M, Hamers T, Machala M et al (2011) Multivariate toxicity profiles and QSAR modeling of non-dioxin-like PCBs – an investigation of in vitro screening data from ultra-pure congeners. Chemosphere 85(9):1423–1429

    Article  CAS  PubMed  Google Scholar 

  88. ECHA (2008) Guidance on information requirements and chemical safety assessment. Chapter R, 8. Available from: https://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

  89. Paradis A, Leblanc DDumais N (2016) Optimization of an in vitro human blood-brain barrier model: application to blood monocyte transmigration assays. MethodsX 3:25–34

    Article  PubMed  Google Scholar 

  90. Zhang L, Zhu H, Oprea TI et al (2008) QSAR modeling of the blood-brain barrier permeability for diverse organic compounds. Pharm Res 25(8):1902–1914

    Article  CAS  PubMed  Google Scholar 

  91. Kortagere S, Chekmarev D, Welsh WJ et al (2008) New predictive models for blood-brain barrier permeability of drug-like molecules. Pharm Res 25(8):1836–1845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Abreu PA, Castro HC, Paes-de-Carvalho R et al (2013) Molecular modeling of a phenyl-amidine class of NMDA receptor antagonists and the rational design of new triazolyl-amidine derivatives. Chem Biol Drug Des 81(2):185–197

    Article  CAS  PubMed  Google Scholar 

  93. Rayne S, Forest K (2010) Quantitative structure-activity relationship (QSAR) studies for predicting activation of the ryanodine receptor type 1 channel complex (RyR1) by polychlorinated biphenyl (PCB) congeners. J Environ Sci Health A Tox Hazard Subst Environ Eng 45(3):355–362

    Article  CAS  PubMed  Google Scholar 

  94. Guerra A, Páez JACampillo NE (2008) Artificial neural networks in ADMET modeling: prediction of blood–brain barrier permeation. Mol Inform 27(5):586–594

    CAS  Google Scholar 

  95. Zhang YY, Liu H, Summerfield SG et al (2016) Integrating in silico and in vitro approaches to predict drug accessibility to the central nervous system. Mol Pharm 13(5):1540–1550

    Article  CAS  PubMed  Google Scholar 

  96. Hewitt M, Madden JC, Rowe PH et al (2007) Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier. SAR QSAR Environ Res 18(1–2):57–76

    Article  CAS  PubMed  Google Scholar 

  97. Giaginis C, Zira A, Theocharis S et al (2009) Application of quantitative structure-activity relationships for modeling drug and chemical transport across the human placenta barrier: a multivariate data analysis approach. J Appl Toxicol 29(8):724–733

    Article  CAS  PubMed  Google Scholar 

  98. OECD (2013) Series on testing and assessment no. 184. Guidance document on developing and assessing adverse outcome pathways

    Google Scholar 

  99. Ankley GT, Bennett RS, Erickson RJ et al (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29(3):730–741

    Article  CAS  PubMed  Google Scholar 

  100. Bal-Price A, Meek MEB (2017) Adverse outcome pathways: application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther 179:84–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bal-Price A, Crofton KM, Leist M et al (2015) International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes. Arch Toxicol 89(2):269–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sachana M, Rolaki ABal-Price A (2018) Development of the Adverse Outcome Pathway (AOP): chronic binding of antagonist to N-methyl-d-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children. Toxicol Appl Pharmacol 354:153–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. OECD (2017) Guidance document on the reporting of defined approaches to be used within integrated approaches to testing and assessment OECD series on testing and assessment. Vol. 255

    Google Scholar 

  104. OECD (2017) Guidance document on the reporting of defined approaches and individual information sources to be used within Integrated Approaches to Testing and Assessment (IATA) for skin sensitisation OECD series on testing and assessment. Vol. 256

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. European Commission Joint Research Centre, Ispra, Italy

    Anna Bal-Price & Francesca Pistollato

Authors
  1. Anna Bal-Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francesca Pistollato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Bal-Price .

Editor information

Editors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    Michael Aschner

  2. Department of Environment/STE 100, University of Washington, Seattle, WA, USA

    Lucio Costa

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Bal-Price, A., Pistollato, F. (2019). Application of Non-Animal Methods to More Effective Neurotoxicity Testing for Regulatory Purposes. In: Aschner, M., Costa, L. (eds) Cell Culture Techniques. Neuromethods, vol 145. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9228-7_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9228-7_15

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-4939-9227-0

  • Online ISBN: 978-1-4939-9228-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation