Framework for classifying chemicals for repeat dose toxicity using NAMs

Doe, JE ORCID: 0000-0001-5393-1421, Botham, P, Holland, D, Gatnik, MF, Giri, V ORCID: 0000-0001-6055-6324, Kang, H, Kalra, P, León Pérez, S ORCID: 0009-0006-7281-5702, Marty, S ORCID: 0000-0002-5404-8515, Moors, S, Raeburn, R, Reale, E ORCID: 0000-0002-0853-0693, Settivari, R ORCID: 0009-0001-2963-5224, Sica, M, Travis, KZ and Wijeyesakere, SJ ORCID: 0000-0002-4275-0438 (2025) Framework for classifying chemicals for repeat dose toxicity using NAMs. Archives of Toxicology, 99 (8). pp. 3223-3246. ISSN 0340-5761

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Abstract

EPAA’s ‘NAM Designathon 2023’ challenge for human toxicity sought to identify a classification system capable of categorising chemicals based on their bioactivity and bioavailability properties determined using non-animal methodologies (Worth et al. 2025). The proposal is made to classify chemicals into three levels of concern: low concern could be used without restriction, medium concern requiring assessment to establish safe use levels and high concern being candidates requiring risk management (Berggren and Worth in Regul Toxicol Pharmacol 142:105431, https://doi.org/10.1016/j.yrtph.2023.105431, 2023). We developed a NAMs based classification system for “human systemic toxicity” mainly focussed on repeat dose toxicity, similar to the assessment carried out in classification for ‘Specific Target Organ Toxicity—Repeated Exposure’ (STOT-RE) based on ECETOC’s Tiered Approach integrating three lines of evidence: In silico predictions, In vitro bioavailability and PBK modelling, In vitro bioactivity assays. The first stage employed an in silico approach, covering several toxicity endpoints across various (Q)SAR in silico models to identify indicators of toxicity. Bioavailability was categorised by simulating 14-day plasma C<inf>max</inf> predictions for a standard dose level using three TK models (Firman et al. in Arch Toxicol 96:817–830, https://doi.org/10.1007/s00204-021-03205-x, 2022). Bioactivity was categorised using a matrix with potency and severity. In vitro data were obtained from ToxCast. Potency makes use of dose response AC50 values. Severity categorisation is based on consideration of the adverse effects associated with the assays. 12 chemicals have been assessed through the framework. Overall, we have demonstrated that the matrix suggested by the EPAA Designathon can be used to categorise chemicals into three different levels of concern but there are areas still to be explored especially for the range of assays used, the framework categorisation being defined, and how such a matrix would fit into a tiered approach, pragmatically, including targeted in vivo studies.

Item Type:	Article
Uncontrolled Keywords:	Animals; Humans; Hazardous Substances; Risk Assessment; Toxicity Tests; Quantitative Structure-Activity Relationship; Biological Availability; Dose-Response Relationship, Drug; Models, Biological; Computer Simulation; Chemical safety assessment; Classification and labelling; New approach methodology (NAM); Next-generation safety assessment; Regulatory toxicology; Risk management; Humans; Toxicity Tests; Dose-Response Relationship, Drug; Animals; Risk Assessment; Computer Simulation; Biological Availability; Hazardous Substances; Quantitative Structure-Activity Relationship; Models, Biological; 3214 Pharmacology and Pharmaceutical Sciences; 3101 Biochemistry and Cell Biology; 32 Biomedical and Clinical Sciences; 31 Biological Sciences; 3 Good Health and Well Being; 1115 Pharmacology and Pharmaceutical Sciences; Toxicology; 3101 Biochemistry and cell biology; 3214 Pharmacology and pharmaceutical sciences
Subjects:	Q Science > QD Chemistry R Medicine > RA Public aspects of medicine > RA1190 Toxicology. Poisions
Divisions:	Pharmacy and Biomolecular Sciences
Publisher:	Springer
Date of acceptance:	16 April 2025
Date of first compliant Open Access:	29 August 2025
Date Deposited:	29 Aug 2025 13:44
Last Modified:	29 Aug 2025 13:45
DOI or ID number:	10.1007/s00204-025-04069-1
URI:	https://researchonline.ljmu.ac.uk/id/eprint/27025

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