Ready for regulatory use: NAMs and NGRA for chemical safety assurance

Main Article Content

Paul L. Carmichael
Maria T. Baltazar
Sophie Cable
Stella Cochrane
Matthew Dent
Hequn Li
Alistair Middleton
Iris Muller
Georgia Reynolds
Carl Westmoreland
Andrew White


New approach methodologies (NAMs) that do not use experimental animals are, in certain settings, entirely appropriate for assuring the safety of chemical ingredients, although regulatory adoption has been slow. In this opinion article we discuss how scientific advances that utilize NAMs to certify systemic safety are available now and merit broader acceptance within the framework of next generation risk assessments (NGRA).

Article Details

How to Cite
Carmichael, P. L., Baltazar, M. T., Cable, S., Cochrane, S., Dent, M., Li, H., Middleton, A., Muller, I., Reynolds, G., Westmoreland, C. and White, A. (2022) “Ready for regulatory use: NAMs and NGRA for chemical safety assurance”, ALTEX - Alternatives to animal experimentation, 39(3), pp. 359–366. doi: 10.14573/altex.2204281.
Food for Thought ...

Allen, T., Goodman, J., Gutsell, S. et al. (2014). Defining molecular initiating events in the adverse outcome pathway framework for risk assessment. Chem Res Toxicol 27, 2100-2112. doi:10.1021/tx500345j

Baltazar, M. T., Cable, S., Carmichael, P. L. et al. (2020). A next-generation risk assessment case study for coumarin in cosmetic products. Toxicol Sci 176, 236-252. doi:10.1093/toxsci/kfaa048

Berggren, E., White, A., Ouedraogo, G. et al. (2017). Ab initio chemical safety assessment: A workflow based on exposure considerations and non-animal methods. Comput Toxicol 4, 31-44. doi:10.1016/j.comtox.2017.10.001

Bernauer, U., Bodin, L., Chaudhry, Q. et al. (2021). The SCCS notes of guidance for the testing of cosmetic ingredients and their safety evaluation, 11th revision, 30-31 March 2021, SCCS/1628/21. Regul Toxicol Pharmacol 127, 105052. doi:10.1016/j.yrtph.2021.105052

Bowes, J., Brown, A., Hamon, J. et al. (2012). Reducing safety-related drug attrition: The use of in vitro pharmacological profiling. Nat Rev Drug Discov 11, 909-922. doi:10.1038/nrd3845

Bury, D., Alexander-White, C., Clewell, H. et al. (2021). New framework for a non-animal approach adequately assures the safety of cosmetic ingredients – A case study on caffeine. Regul Toxicol Pharmacol 123, 104931. doi:10.1016/j.yrtph.2021.104931

Collinge, M., Schneider, P., Dingzhou Li, D. et al. (2020). Cross-company evaluation of the human lymphocyte activation assay. J. Immunotoxicol 17, 51-58. doi:10.1080/1547691X.2020.1725694

Deisenroth, C., DeGroot, D., Zurlinden, T. et al. (2020). The alginate immobilization of metabolic enzymes platform retrofits an estrogen receptor transactivation assay with metabolic competence. Toxicol Sci 178, 281-301. doi:10.1093/toxsci/kfaa147

Dent, M., Amaral, R., Da Silva, P. et al. (2018). Principles underpinning the use of new methodologies in the risk assessment of cosmetic ingredients. Comput Toxicol 7, 20-26. doi:10.1016/j.comtox.2018.06.001

Dent, M., Li, H., Carmichael P. L. et al. (2019). Employing dietary comparators to perform risk assessments for anti-androgens without using animal data. Toxicol Sci 167, 375-384. doi:10.1093/toxsci/kfy245

Dent, M., Vaillancourt P. E., Thomas R. S. et al. (2021). Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients. Regul Toxicol Pharmacol 125, 105026. doi:10.1016/j.yrtph.2021.105026

Donnellan, L. (2020). Animal welfare in the European Union: The cosmetics regulation. In R. Moldovan (ed.), The European Union: Policies, Perspectives and Politics (Book Chapter, 187-215). Hauppauge, NY USA: Nova Science Publishers.

Drasler, B., Sayre, P., Steinhäuser, K. et al. (2017). In vitro approaches to assess the hazard of nanomaterials. NanoImpact 8, 99-116. doi:10.1016/j.impact.2017.08.002

Escher, S. E., Aguayo-Orozco, A., Benfenati, E. et al. (2022). Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action. Toxicol In Vitro 79, 105269. doi:10.1016/j.tiv.2021.105269

Fentem, J., Malcomber, I., Maxwell, G. et al. (2021). Upholding the EU’s commitment to ‘animal testing as a last resort’ under REACH requires a paradigm shift in how we assess chemical safety to close the gap between regulatory testing and modern safety science alternatives to laboratory animals. Altern Lab Anim 49, 122-132. doi:10.1177/02611929211040824

Hall, B., Tozer, S., Safford, B. et al. (2007). European consumer exposure to cosmetic products, a framework for conducting population exposure assessments. Food Chem Toxicol 45, 2097-2108. doi:10.1016/j.fct.2007.06.017

Harrill, J., Shah, I. and Woodrow Setzer, R. W. (2019). Considerations for strategic use of high-throughput transcriptomics chemical screening data in regulatory decisions. Curr Opin Toxicol 15, 64-75. doi:10.1016/j.cotox.2019.05.004

Harrill, J. A., Logan, J. and Everett, D. E. (2021). High-throughput transcriptomics platform for screening environmental chemicals. Toxicol Sci 181, 68-89. doi:10.1093/toxsci/kfab009

Hartung, T. and Corsini, E. (2013). Immunotoxicology: Challenges in the 21st century and in vitro opportunities. ALTEX 30, 411-426. doi:10.14573/altex.2013.4.411

Hatherell, S., Baltazar M. T., Reynolds, J. et al. (2020). Identifying and characterizing stress pathways of concern for consumer safety in next-generation risk assessment. Toxicol Sci 176, 11-33. doi:10.1093/toxsci/kfaa054

Hopperstad, K., DeGroot, D. E., Zurlinden, T. et al. (2022). Chemical screening in an estrogen receptor transactivation assay with metabolic competence. Toxicol Sci 187, 112-126. doi:10.1093/toxsci/kfac019

Kimura, Y., Yasuno, R., Watanabe, M. et al. (2020). An international validation study of the IL-2 Luc assay for evaluating the potential immunotoxic effects of chemicals on T cells and a proposal for reference data for immunotoxic chemicals. Toxicol In Vitro 66, 104832. doi:10.1016/j.tiv.2020.104832

Li, H., Reynolds, J., Sorrell, I. et al. (2022). PBK modelling of topical application and characterisation of the uncertainty of Cmax estimate: A case study approach. Toxicol Appl Pharmacol 442, 115992. doi:10.1016/j.taap.2022.115992

Middleton, A. M., Reynolds, J., Cable, S. et al. (2022). Are non-animal systemic safety assessments protective? A toolbox and evaluation strategy. Toxicol Sci Jul 13, kfac068. doi:10.1093/toxsci/kfac068

Moxon, T. E., Li, H., Lee, M. Y. et al. (2020). Application of physiologically based kinetic (PBK) modelling in the next generation risk assessment of dermally applied consumer products, Toxicol In Vitro 63, 104746. doi:10.1016/j.tiv.2019.104746

NRC – National Research Council (2007). Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC, USA: The National Academies Press. doi:10.17226/11970

Nyffeler, J., Willis, C., Lougee, R. et al. (2020). Bioactivity screening of environmental chemicals using imaging-based high-throughput phenotypic profiling. Toxicol Appl Pharmacol 389, 114876. doi:10.1016/j.taap.2019.114876

Olson, H., Betton, G., Robinson, D. et al. (2000). Concordance of the toxicity of pharmaceuticals in humans and in animals, Regul Toxicol Pharmacol 32, 56-67. doi:10.1006/rtph.2000.1399

Paul Friedman, K., Gagne, M., Loo, L.-H. et al. (2020). Utility of in vitro bioactivity as a lower bound estimate of in vivo adverse effect levels and in risk-based prioritization. Toxicol Sci 173, 202-225. doi:10.1093/toxsci/kfz201

Pearce, R. G., Setzer, R. W., Strope, C. L. et al. (2017). httk: R package for high-throughput toxicokinetics. J Stat Softw 79, 1-26. doi:10.18637/jss.v079.i04

Pessina, A., Bonomi, A., Casati, S. et al. (2007). Mitochondrial function, apoptosis and cell cycle delay in the WEHI-3B leukaemia cell line and its variant ciprofloxacin-resistant WEHI-3B/CPX. Cell Prolif 40, 568-579. doi:10.1111/j.1365-2184.2007.00456.x

Phillips, J. R., Svoboda, D. L., Tandon, A. et al. (2018). BMDExpress 2: Enhanced transcriptomic dose-response analysis workflow. Bioinformatics 35, 1780-1782. doi:10.1093/bioinformatics/bty878

Proença, S., Escher, B. I., Fischer, F. C. et al. (2021). Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models. Toxicol In Vitro 73, 105133. doi:10.1016/j.tiv.2021.105133

Punt, A., Firman, J., Boobis, A. et al. (2020). Potential of ToxCast data in the safety assessment of food chemicals. Toxicol Sci 174, 326-340. doi:10.1093/toxsci/kfaa008

Punt, A., Louisse, J., Beekmann, K. et al. (2022). Predictive performance of next generation human physiologically based kinetic (PBK) model predictions based on in vitro and in silico input data. ALTEX 39, 221-234. doi:10.14573/altex.2108301

Rajagopal, R., Baltazar, M. T., Carmichael, P. L. et al. (2022). Beyond AOPs: A mechanistic evaluation of NAMs in DART testing. Front Toxicol 4, 838466. doi:10.3389/ftox.2022.838466

Rampa, K. M., Van De Venter, M., Koekemoer, T. C. et al. (2021). Exploring four South African Croton species for potential anti-inflammatory properties: In vitro activity and toxicity risk assessment. J Ethnopharmacol 10, 282. doi:10.1016/j.jep.2021.114596

Reynolds, J., Malcomber, S. and White, A. (2020). A Bayesian approach for inferring global points of departure from transcriptomics data. Comput Toxicol 16, 100138. doi:10.1016/j.comtox.2020.100138

Reynolds, G., Reynolds, J., Gilmour, N. et al. (2021). A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products. Regul Toxicol Pharmacol 127, 105075. doi:10.1016/j.yrtph.2021.105075

Rusyn, I., Sakolish, C. and Kato, Y. (2022). Microphysiological systems evaluation: Experience of TEX-VAL tissue chip testing ConsortiumTox sciences. Toxicol Sci, in press. doi:10.1093/toxsci/kfac061

SCCS – Scientific Committee on Consumer Safety (2021). SCCS Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation, 11th revision, 30-31 March 2021, SCCS/1628/21. doi:10.1016/j.yrtph.2021.105052

Singer, J. W., Al-Fayoumi, S., Taylor, J. et al. (2019). Comparative phenotypic profiling of the JAK2 inhibitors ruxolitinib, fedratinib, momelotinib, and pacritinib reveals distinct mechanistic signatures. PLoS One 27, 14. doi:10.1371/journal.pone.0222944

Solan, M. E. and Lavado, R. (2021). The use of in vitro methods in assessing human health risks associated with short-chain perfluoroalkyl and polyfluoroalkyl substances (PFAS). J Appl Toxicol 6, 4270. doi:10.1002/jat.4270

Thomas, R. S., Bahadori, T., Buckley T. J. et al. (2019). The next generation blueprint of computational toxicology at the U.S. Environmental Protection Agency. Toxicol Sci 169, 317-332. doi:10.1093/toxsci/kfz058

Tolosa, L., Martínez-Sena, T., Schimming, J. P. et al. (2021). The in vitro assessment of the toxicity of volatile, oxidisable, redox-cycling compounds: Phenols as an example. Arch Toxicol 95, 2109-2121. doi:10.1007/s00204-021-03036-w

Wetmore, B. A., Wambaugh, J. F., Allen, B. et al. (2015). Incorporating high-throughput exposure predictions with dosimetry-adjusted in vitro bioactivity to inform chemical toxicity testing. Toxicol Sci 148, 121-136. doi:10.1093/toxsci/kfv171

Williams, D. P., Lazic, S. E., Foster, A. J. et al. (2020). Predicting drug-induced liver injury with Bayesian machine learning. Chem Res Toxicol 33, 239-248. doi:10.1021/acs.chemrestox.9b00264

Yang, C., Barlow, S. B., Muldoon Jacobs, K. L. et al. (2017). Thresholds of toxicological concern for cosmetics-related substances: New database, thresholds, and enrichment of chemical space. Food Chem Toxicol 109, 170-193. doi:10.1016/j.fct.2017.08.043

Zuang, V., Dura, A., Asturiol Bofill, D. et al. (2021). Non-animal methods in science and regulation. EUR 30553 EN, Publications Office of the European Union, Luxembourg, 2021, ISBN 978-92-76-28396-6. doi:10.2760/163367

Most read articles by the same author(s)