Mapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental neurotoxicity (DNT) testing
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Abstract
On occasion of the DNT5 meeting in Konstanz, Germany (April-2024), participants brainstormed on future challenges concerning a regulatory implementation of the developmental neurotoxicity (DNT) in vitro test battery (DNT-IVB). The five discussion topics below outline some of the key issues, opportunities and research directions for the next several years: (1) How to contextualize DNT hazard with information on potential maternal toxicity or other toxicity domains (non-DNT)? Several approaches on how to use cytotoxicity data from NAMs were discussed. (2) What opportunities exist for an immediate or near-future application of the DNT-IVB, e.g. as a prioritisation step or add-on to other information? Initial examples are already emerging; the data can be used even if the battery is not converted to a defined approach. (3) How to establish data interpretation procedures for multi-dimensional endpoints that reduce dimensionality and are suitable for classification? A decision framework is required on how to use the DNT-IVB in a regulatory context. Machine-learning (AI-approaches) may provide novel classification models. (4) How can a battery of molecular initiating events (MIEs) be smartly linked to the DNT-IVB? At what tier of an overall strategy would MIEs be evaluated, and how would one optimally balance cost vs information yield. (5) What is the way forward to scientific validation of DNT NAMs and the DNT-IVB? A large set of animal data would be required for conventional approaches, while mechanistic information may establish relevance in other ways.
Plain language summary
A meeting on developmental neurotoxicity (DNT) testing was held in Konstanz, Germany in April 2024 (DNT5 meeting). A major topic of discussion at the conference was the DNT in vitro test battery (DNT-IVB), and how this set of cell-based animal-free test methods may be used in a regulatory context. Opportunities for future developments were addressed in discussion groups: The combination of specific DNT readouts with less specific cytotoxicity data was discussed. Another group of participants addressed opportunities for an immediate or near-future application of the DNT-IVB. One of the discussion groups concluded that a decision framework is required on how to use the DNT-IVB in a regulatory context. Moreover, the use of signalling assays (evaluating the interaction of test compounds with receptors, enzymes and transporters) in combination with the IVB was discussed. Finally, ideas and concepts for the way forward to scientific validation of the DNT-IVB were collected.
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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, 49-74. doi:10.14573/altex.1604201
Bal-Price, A., Crofton, K. M., Leist, M. et al. (2015). International stakeholder network (istnet): Creating a developmental neurotoxicity (dnt) testing road map for regulatory purposes. Arch Toxicol 89, 269-287. doi:10.1007/s00204-015-1464-2
Bal-Price, A., Hogberg, H. T., Crofton, K. M. et al. (2018). Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity. ALTEX 35, 306-352. doi:10.14573/altex.1712081
Barenys, M., Gassmann, K., Baksmeier, C. et al. (2017). Epigallocatechin gallate (egcg) inhibits adhesion and migration of neural progenitor cells in vitro. Arch Toxicol 91, 827-837. doi:10.1007/s00204-016-1709-8
Bartmann, K., Bendt, F., Dönmez, A. et al. (2023). A human ipsc-based in vitro neural network formation assay to investigate neurodevelopmental toxicity of pesticides. ALTEX 40, 452-470. doi:10.14573/altex.2206031
Basketter, D., Darlenski, R. and Fluhr, J. W. (2008). Skin irritation and sensitization: Mechanisms and new approaches for risk assessment. Skin Pharmacol Physiol 21, 191-202. doi:10.1159/000135635
Basketter, D., Beken, S., Bender, H. et al. (2020). Building confidence in skin sensitisation potency assessment using new approach methodologies: Report of the 3rd epaa partners forum, brussels, 28th october 2019. Regul Toxicol Pharmacol 117, 104767. doi:10.1016/j.yrtph.2020.104767
Blum, J., Masjosthusmann, S., Bartmann, K. et al. (2023). Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals. Chemosphere 311, 137035. doi:10.1016/j.chemosphere.2022.137035
Blum, J., Brüll, M., Hengstler, J. (2025). The long way from raw data to NAM based information: Overview on data layers and processing steps. ALTEX 42, 167-180. doi:10.14573/altex.2412171
Burbank, M., Kukic, P., Ouedraogo, G. et al. (2024). In vitro pharmacologic profiling aids systemic toxicity assessment of chemicals. Toxicol Appl Pharmacol 492, 117131. doi:10.1016/j.taap.2024.117131
Callegaro, G., Kunnen, S. J., Trairatphisan, P. et al. (2021). The human hepatocyte txg-mapr: Gene co-expression network modules to support mechanism-based risk assessment. Arch Toxicol 95, 3745-3775. doi:10.1007/s00204-021-03141-w
Carstens, K. E., Carpenter, A. F., Martin, M. M. et al. (2022). Integrating data from in vitro new approach methodologies for developmental neurotoxicity. Toxicol Sci 187, 62-79. doi:10.1093/toxsci/kfac018
Carstens, K. E., Freudenrich, T., Wallace, K. et al. (2023). Evaluation of per- and polyfluoroalkyl substances (pfas) in vitro toxicity testing for developmental neurotoxicity. Chem Res Toxicol 36, 402-419. doi:10.1021/acs.chemrestox.2c00344
Chaput, L., Guillaume, V., Singh, N. et al. (2020). Fasttargetpred: A program enabling the fast prediction of putative protein targets for input chemical databases. Bioinformatics 36, 4225-4226. doi:10.1093/bioinformatics/btaa494
Cherianidou, A., Seidel, F., Kappenberg, F. et al. (2022). Classification of developmental toxicants in a human ipsc transcriptomics-based test. Chem Res Toxicol 35, 760-773. doi:10.1021/acs.chemrestox.1c00392
Chesnut, M., Paschoud, H., Repond, C. et al. (2021). Human ipsc-derived model to study myelin disruption. Int J Mol Sci 22, doi:10.3390/ijms22179473
Colaianna, M., Ilmjärv, S., Peterson, H. et al. (2017). Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay. Arch Toxicol 91, 365-391. doi:10.1007/s00204-016-1690-2
Crofton, K. M., Paparella, M., Price, A. et al. (2024). A developmental neurotoxicity adverse outcome pathway (dnt-aop) with voltage gate sodium channel (vgsc) inhibition as a molecular initiating event (mie). EFSA j 22, e8954. doi:10.2903/j.efsa.2024.8954
Culbreth, M., Nyffeler, J., Willis, C. et al. (2021). Optimization of human neural progenitor cells for an imaging-based high-throughput phenotypic profiling assay for developmental neurotoxicity screening. Front Toxicol 3, 803987. doi:10.3389/ftox.2021.803987
Dach, K., Bendt, F., Huebenthal, U. et al. (2017). Bde-99 impairs differentiation of human and mouse npcs into the oligodendroglial lineage by species-specific modes of action. Sci Rep 7, 44861. doi:10.1038/srep44861
Delp, J., Gutbier, S., Klima, S. et al. (2018). A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays. ALTEX 35, 235-253. doi:10.14573/altex.1712182
Dobreniecki, S., Mendez, E., Lowit, A. et al. (2022). Integration of toxicodynamic and toxicokinetic new approach methods into a weight-of-evidence analysis for pesticide developmental neurotoxicity assessment: A case-study with DL- and L-glufosinate. Regul Toxicol Pharmacol 131, 105167. doi:10.1016/j.yrtph.2022.105167
Dreser, N., Madjar, K., Holzer, A. K. et al. (2020). Development of a neural rosette formation assay (rofa) to identify neurodevelopmental toxicants and to characterize their transcriptome disturbances. Arch Toxicol 94, 151-171. doi:10.1007/s00204-019-02612-5
EC (2008). Regulation (ec) no 1272/2008 of the european parliament and of the council of 16 december 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing directives 67/548/eec and 1999/45/ec, and amending regulation (ec) no 1907/2006 (text with eea relevance). Official Journal of the European Union L 353/1,
Fritsche, E., Crofton, K. M., Hernandez, A. F. et al. (2017). Oecd/efsa workshop on developmental neurotoxicity (dnt): The use of non-animal test methods for regulatory purposes. ALTEX - Alternatives to animal experimentation 34, 311-315. doi:10.14573/altex.1701171
Fritsche, E., Grandjean, P., Crofton, K. M. 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. doi:10.1016/j.taap.2018.02.004
Gabbert, S., Mathea, M., Kolle, S. N. et al. (2022). Accounting for precision uncertainty of toxicity testing: Methods to define borderline ranges and implications for hazard assessment of chemicals. Risk Anal 42, 224-238. doi:10.1111/risa.13648
Grillberger, K., Cöllen, E., Trivisani, C. I. et al. (2023). Structural insights into neonicotinoids and n-unsubstituted metabolites on human nachrs by molecular docking, dynamics simulations, and calcium imaging. Int J Mol Sci 24, doi:10.3390/ijms241713170
Guan, Z., Wang, X., Dong, Y. et al. (2015). Dntp deficiency induced by hu via inhibiting ribonucleotide reductase affects neural tube development. Toxicol 328, 142-151. doi:10.1016/j.tox.2014.12.001
Harrill, J. A., Everett, L. J., Haggard, D. E. et al. (2021). High-throughput transcriptomics platform for screening environmental chemicals. Toxicol Sci 181, 68-89. doi:10.1093/toxsci/kfab009
Holzer, A. K., Suciu, I., Karreman, C. et al. (2022). Specific attenuation of purinergic signaling during bortezomib-induced peripheral neuropathy in vitro. Int J Mol Sci 23, doi:10.3390/ijms23073734
Jaklin, M., Zhang, J. D., Schäfer, N. et al. (2022). Optimization of the teratox assay for preclinical teratogenicity assessment. Toxicol Sci 188, 17-33. doi:10.1093/toxsci/kfac046
Jaworska, J. and Hoffmann, S. (2010). Integrated testing strategy (its) - opportunities to better use existing data and guide future testing in toxicology. ALTEX 27, 231-242. doi:10.14573/altex.2010.4.231
Jochum, K., Miccoli, A., Sommersdorf, C. et al. (2024). Comparative case study on nams: Towards enhancing specific target organ toxicity analysis. Arch Toxicol 98, 3641-3658. doi:10.1007/s00204-024-03839-7
Judson, R., Houck, K., Martin, M. et al. (2016). Analysis of the effects of cell stress and cytotoxicity on in vitro assay activity across a diverse chemical and assay space. Toxicol Sci 153, 409. doi:10.1093/toxsci/kfw148
Judson, R., Houck, K., Paul Friedman, K. et al. (2020). Selecting a minimal set of androgen receptor assays for screening chemicals. Regul Toxicol and Pharmacol 117, 104764. doi:10.1016/j.yrtph.2020.104764
Kadarmideen, H. N. and Watson-Haigh, N. S. (2012). Building gene co-expression networks using transcriptomics data for systems biology investigations: Comparison of methods using microarray data. Bioinf 8, 855-861. doi:10.6026/97320630008855
Kadereit, S., Zimmer, B., Thriel, C. v. et al. (2012). Compound selection for in vitro modeling of developmental neurotoxicity. FBL 17, 2442-2460. doi:10.2741/4064
Keßel, H. E., Masjosthusmann, S., Bartmann, K. et al. (2023). The impact of biostatistics on hazard characterization using in vitro developmental neurotoxicity assays. ALTEX - Alternatives to animal experimentation 40, 619-634. doi:10.14573/altex.2210171
Klose, J., Tigges, J., Masjosthusmann, S. et al. (2021). Tbbpa targets converging key events of human oligodendrocyte development resulting in two novel aops. ALTEX - Alternatives to animal experimentation 38, 215-234. doi:10.14573/altex.2007201
Klose, J., Pahl, M., Bartmann, K. et al. (2022). Neurodevelopmental toxicity assessment of flame retardants using a human dnt in vitro testing battery. Cell Biol Toxicol 38, 781-807. doi:10.1007/s10565-021-09603-2
Klose, J., Li, L., Pahl, M. et al. (2023). Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol 39, 319-343. doi:10.1007/s10565-022-09730-4
Koch, K., Bartmann, K., Hartmann, J. et al. (2022). Scientific validation of human neurosphere assays for developmental neurotoxicity evaluation. Front Toxicol 4, 816370. doi:10.3389/ftox.2022.816370
Krebs, A., Waldmann, T., Wilks, M. F. et al. (2019). Template for the description of cell-based toxicological test methods to allow evaluation and regulatory use of the data. ALTEX 36, 682-699. doi:10.14573/altex.1909271
Kreir, M., Putri, D., Tekle, F. et al. (2024). Development of a new hazard scoring system in primary neuronal cell cultures for drug-induced acute neuronal toxicity identification in early drug discovery. Front Pharmacol 15, 1308547. doi:10.3389/fphar.2024.1308547
Kreutz, A., Oyetade, O. B., Chang, X. et al. (2024). Integrated approach for testing and assessment for developmental neurotoxicity (dnt) to prioritize aromatic organophosphorus flame retardants. Toxics 12, doi:10.3390/toxics12060437
Krug, A. K., Balmer, N. V., Matt, F. et al. (2013). Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87, 2215-2231. doi:10.1007/s00204-013-1072-y
Langfelder, P. and Horvath, S. (2008). Wgcna: An r package for weighted correlation network analysis. BMC Bioinf 9, 559. doi:10.1186/1471-2105-9-559
Leist, M., Efremova, L. and Karreman, C. (2010). Food for thought ... Considerations and guidelines for basic test method descriptions in toxicology. ALTEX 27, 309-317. doi:10.14573/altex.2010.4.309
Leist, M., Hasiwa, N., Daneshian, M. et al. (2012). Validation and quality control of replacement alternatives – current status and future challenges. Toxicol Res 1, 8-22. doi:10.1039/C2TX20011B
Leist, M., Hasiwa, N., Rovida, C. et al. (2014). Consensus report on the future of animal-free systemic toxicity testing. ALTEX 31, 341-356. doi:10.14573/altex.1406091
Loser, D., Grillberger, K., Hinojosa, M. G. et al. (2021a). Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nach receptors relevant for neuronal signaling. Arch Toxicol 95, 3695-3716. doi:10.1007/s00204-021-03168-z
Loser, D., Hinojosa, M. G., Blum, J. et al. (2021b). Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons. Arch Toxicol 95, 2081-2107. doi:10.1007/s00204-021-03031-1
Loser, D., Schaefer, J., Danker, T. et al. (2021c). Human neuronal signaling and communication assays to assess functional neurotoxicity. Arch Toxicol 95, 229-252. doi:10.1007/s00204-020-02956-3
Maertens, A., Golden, E., Luechtefeld, T. H. et al. (2022). Probabilistic risk assessment - the keystone for the future of toxicology. ALTEX 39, 3-29. doi:10.14573/altex.2201081
Magel, V., Blum, J., Dolde, X. et al. (2024). Inhibition of neural crest cell migration by strobilurin fungicides and other mitochondrial toxicants. Cells 13, 2057. doi:10.3390/cells13242057
Martin, M. M., Baker, N. C., Boyes, W. K. et al. (2022). An expert-driven literature review of "negative" chemicals for developmental neurotoxicity (dnt) in vitro assay evaluation. Neurotoxicol Teratol 93, 107117. doi:10.1016/j.ntt.2022.107117
Masjosthusmann, S., Barenys, M., El-Gamal, M. et al. (2018). Literature review and appraisal on alternative neurotoxicity testing methods. EFSA Supporting Publ 15, 1410E. doi:10.2903/sp.efsa.2018.EN-1410
Masjosthusmann, S., Siebert, C., Hübenthal, U. et al. (2019). Arsenite interrupts neurodevelopmental processes of human and rat neural progenitor cells: The role of reactive oxygen species and species-specific antioxidative defense. Chemosphere 235, 447-456. doi:10.1016/j.chemosphere.2019.06.123
McDiarmid, A. H., Gospodinova, K. O., Elliott, R. J. R. et al. (2024). Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for alzheimer's disease. Brain Commun 6, fcae101. doi:10.1093/braincomms/fcae101
Meier, M. J., Harrill, J., Johnson, K. et al. (2024). Progress in toxicogenomics to protect human health. Nat Rev Genet doi:10.1038/s41576-024-00767-1
Meisig, J., Dreser, N., Kapitza, M. et al. (2020). Kinetic modeling of stem cell transcriptome dynamics to identify regulatory modules of normal and disturbed neuroectodermal differentiation. Nucleic Acids Res 48, 12577-12592. doi:10.1093/nar/gkaa1089
Miller, M. M., McMullen, P. D., Andersen, M. E. et al. (2017). Multiple receptors shape the estrogen response pathway and are critical considerations for the future of in vitro-based risk assessment efforts. Critical Rev in Toxicol 47, 570-586. doi:10.1080/10408444.2017.1289150
Nyffeler, J., Chovancova, P., Dolde, X. et al. (2018). A structure-activity relationship linking non-planar pcbs to functional deficits of neural crest cells: New roles for connexins. Arch Toxicol 92, 1225-1247. doi:10.1007/s00204-017-2125-4
Ockleford, C., Adriaanse, P., Hougaard Bennekou, S. et al. (2018). Scientific opinion on pesticides in foods for infants and young children. EFSA j 16, e05286. doi:10.2903/j.efsa.2018.5286
OECD (2005). Guidance document on the validation and international acceptance of new or updated test methods for hazard assessment. Oecd series on testing and assessment. No. 34. OECD Publishing, Paris. doi:10.1787/e1f1244b-en
OECD (2017a). Report on considerations from case studies on integrated approaches for testing and assessment (iata) - first review cycle (2015). Oecd series on testing and assessment. No. 250. OECD Publishing, Paris. doi:10.1787/9789264274815-en
OECD (2017b). Guidance document on the reporting of defined approaches to be used within integrated approaches to testing and assessment. Oecd series on testing and assessment. No. 255. OECD Publishing, Paris. doi:10.1787/9789264274822-en
OECD (2018a). Developmental neurotoxicity study (oecd tg 426). Oecd series on testing and assessment. No. 545. OECD Publishing, Paris. doi:10.1787/9789264304741-27-en
OECD (2018b). Test no. 443: Extended one-generation reproductive toxicity study. Oecd guidelines for the testing of chemicals, section 4. No. 443. OECD Publishing, Paris. doi:10.1787/9789264185371-en
OECD (2022a). Case study on the use of integrated approaches for testing and assessment for developmental neurotoxicity hazard characterisation of imidacloprid and the metabolite desnitro-imidacloprid. Series on testing and assessment. No. 366. OECD Publishing, Paris.
OECD (2022b). Per- and polyfluoroalkyl substances and alternatives in coatings, paints and varnishes (cpvs): Report on the commercial availability and current uses. Oecd series on risk management of chemicals, section 4. No. 497. OECD Publishing, Paris. doi:10.1787/6745457d-en
OECD (2022c). Case study on the use of integrated approaches for testing and assessment for developmental neurotoxicity hazard characterisation of acetamiprid. Series on testing and assessment. No. 365. OECD Publishing, Paris.
OECD (2022d). Case study on the use of integrated approaches for testing and assessment for dnt to prioritize a class of organophosphorus flame retardants. Series on testing and assessment. No. 364. OECD Publishing, Paris.
OECD (2022e). Case study for the integration of in vitro data in the developmental neurotoxicity hazard identification and characterisation using flufenacet. Series on testing and assessment. No. 363. OECD Publishing, Paris.
OECD (2022f). Case study for the integration of in vitro data in the developmental neurotoxicity hazard identification and characterisation using deltamethrin as a prototype chemical. Series on testing and assessment. No. 362. OECD Publishing, Paris.
OECD (2023a). Initial recommendations on evaluation of data from the developmental neurotoxicity (dnt) in-vitro testing battery. Oecd series on testing and assessment. No. 377. OECD Publishing, Paris. doi:10.1787/91964ef3-en
OECD (2023b). Guideline no. 497: Defined approaches on skin sensitisation. Oecd guidelines for the testing of chemicals, section 4. No. 497. OECD Publishing, Paris. doi:10.1787/b92879a4-en
OECD (2024). Test no. 467: Defined approaches for serious eye damage and eye irritation. Oecd guidelines for the testing of chemicals, section 4. No. 467. OECD Publishing, Paris. doi:10.1787/28fe2841-en
Pallocca, G., Grinberg, M., Henry, M. et al. (2016). Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol 90, 159-180. doi:10.1007/s00204-015-1658-7
Pamies, D., Ekert, J., Zurich, M. G. et al. (2024). Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility. Stem Cell Rep 19, 604-617. doi:10.1016/j.stemcr.2024.03.009
Paparella, M., Bennekou, S. H. and Bal-Price, A. (2020). An analysis of the limitations and uncertainties of in vivo developmental neurotoxicity testing and assessment to identify the potential for alternative approaches. Reprod Toxicol 96, 327-336. doi:10.1016/j.reprotox.2020.08.002
Penschuck, S., Flagstad, P., Didriksen, M. et al. (2006). Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (mam) model of schizophrenia. Eur J Neurosci 23, 279-284. doi:10.1111/j.1460-9568.2005.04536.x
Rovida, C., Escher, S. E., Herzler, M. et al. (2021). Nam-supported read-across: From case studies to regulatory guidance in safety assessment. ALTEX 38, 140-150. doi:10.14573/altex.2010062
Schmeisser, S., Miccoli, A., von Bergen, M. et al. (2023). New approach methodologies in human regulatory toxicology – not if, but how and when! Environ Int 178, 108082. doi:10.1016/j.envint.2023.108082
Schüttler, A., Altenburger, R., Ammar, M. et al. (2019). Map and model-moving from observation to prediction in toxicogenomics. Gigascience 8, doi:10.1093/gigascience/giz057
Seiler, A. E. and Spielmann, H. (2011). The validated embryonic stem cell test to predict embryotoxicity in vitro. Nat Protoc 6, 961-978. doi:10.1038/nprot.2011.348
Shah, I., Setzer, R. W., Jack, J. et al. (2016). Using toxcast™ data to reconstruct dynamic cell state trajectories and estimate toxicological points of departure. Environ Health Perspect 124, 910-919. doi:10.1289/ehp.1409029
Shinde, V., Hoelting, L., Srinivasan, S. P. et al. (2017). Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: Introduction of the stop-tox(ukn) and stop-tox(ukk) tests. Arch Toxicol 91, 839-864. doi:10.1007/s00204-016-1741-8
Smirnova, L., Hogberg, H. T., Leist, M. et al. (2014). Developmental neurotoxicity - challenges in the 21st century and in vitro opportunities. ALTEX 31, 129-156. doi:10.14573/altex.1403271
Smirnova, L., Hogberg, H. T., Leist, M. et al. (2024). Revolutionizing developmental neurotoxicity testing – a journey from animal models to advanced in vitro systems. ALTEX 41, 152-178. doi:10.14573/altex.2403281
Suciu, I., Delp, J., Gutbier, S. et al. (2023). Definition of the neurotoxicity-associated metabolic signature triggered by berberine and other respiratory chain inhibitors. Antioxidants (Basel) 13, doi:10.3390/antiox13010049
Tal, T., Myhre, O., Fritsche, E. et al. (2024). New approach methods to assess developmental and adult neurotoxicity for regulatory use: A parc work package 5 project. Front Toxicol 6, 1359507. doi:10.3389/ftox.2024.1359507
van der Zalm, A. J., Barroso, J., Browne, P. et al. (2022). A framework for establishing scientific confidence in new approach methodologies. Arch Toxicol 96, 2865-2879. doi:10.1007/s00204-022-03365-4
Vincent, F., Loria, P. M., Weston, A. D. et al. (2020). Hit triage and validation in phenotypic screening: Considerations and strategies. Cell Chem Biol 27, 1332-1346. doi:10.1016/j.chembiol.2020.08.009
Vincent, F., Nueda, A., Lee, J. et al. (2022). Phenotypic drug discovery: Recent successes, lessons learned and new directions. Nature Reviews Drug Discovery 21, 899-914. doi:10.1038/s41573-022-00472-w
Vrijenhoek, N. G., Wehr, M. M., Kunnen, S. J. et al. (2022). Application of high-throughput transcriptomics for mechanism-based biological read-across of short-chain carboxylic acid analogues of valproic acid. ALTEX 39, 207–220. doi:10.14573/altex.2107261
Waldmann, T., Rempel, E., Balmer, N. V. et al. (2014). Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol 27, 408-420. doi:10.1021/tx400402j
Waldmann, T., Grinberg, M., König, A. et al. (2017). Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol 30, 905-922. doi:10.1021/acs.chemrestox.6b00259
Walter, K. M., Dach, K., Hayakawa, K. et al. (2019). Ontogenetic expression of thyroid hormone signaling genes: An in vitro and in vivo species comparison. PLoS One 14, e0221230. doi:10.1371/journal.pone.0221230
Wang, X., Guan, Z., Dong, Y. et al. (2018). Inhibition of thymidylate synthase affects neural tube development in mice. Reprod Toxicol 76, 17-25. doi:10.1016/j.reprotox.2017.12.007