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Safety Assessments via NAM

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Safety Assessments via NAM
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Economic Value Model
Predictive toxicology analysis
with human liver-chip.
Credit: Lorna Ewart et al, Nature.

NAM are transforming toxicology and safety assessment by providing human-relevant models for predicting compound toxicity, skin sensitization, endocrine disruption, and mixture toxicology. This section explores how regulatory agencies and industries are adopting these methods to improve chemical risk assessment and reduce reliance on animal testing.

Endocrine Disruption Assessment
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The Tox21 estrogen receptor pathway battery identified compounds interfering with human hormones using robotic screening results. The EPA accepted this computational model as an alternative to rodent assays, validating the use of robotically derived data. This provides a recognized non-animal alternative for hazard identification regarding endocrine disruptors.1 2 3

Skin Sensitization Hazard & Potency Prediction
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The OECD TG 497 guideline combined multiple NAM, such as peptide reactivity and keratinocyte activation assays, to classify skin sensitization. The performance was validated as equal to or better than mouse assays, even for chemicals not previously tested in animals. This established a regulatory framework for animal-free safety testing of skin sensitizers.4 5 6 7 8

BER for PFAS Risk Assessment
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Regulators used in vitro assays to calculate human equivalent doses and derive a Bioactivity-Exposure Ratio (BER) for emerging PFAS compounds. The BER served as a validated protective surrogate in the absence of traditional animal data. This enabled risk-based prioritization of chemicals based on biological perturbation likelihood.9 10 11

Mixture Toxicology via NAM
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NAM-based defined approaches were extended to complex mixtures such as pesticide formulations to assess their collective toxicity. Panels of in chemico and in vitro assays demonstrated they could accurately identify and rank sensitization potential. This impact advanced the understanding of combined exposure effects without resorting to animal testing.12 13 14

Reconstructed Human Skin Models
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Reconstructed human skin models have been validated by the OECD as replacements for the Draize rabbit skin irritation test. These models are now standard in the EU and increasingly adopted globally for testing cosmetics and chemicals. Their use eliminates animal testing for skin irritation and corrosion endpoints in multiple jurisdictions.15 16

Corneal and Eye Irritation Models
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Validated alternatives to the Draize rabbit eye test, such as EpiOcular and SkinEthic HCE, assess the eye irritation potential of chemicals and consumer products. These human-relevant models provide accurate safety assessments for a wide range of industrial applications. They offer a validated non-animal alternative that is both more ethical and biologically relevant.17 18

References
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  1. Rosa LCS, Sarhan M, Silva A, et al., Toxic Alerts of Endocrine Disruption Revealed by Explainable Artificial Intelligence, Environment & Health, 2025
    Reviews the use of explainable AI to identify toxic alerts of endocrine disruption, advancing non-target analysis of environmental contaminants. ↩︎

  2. National Institute of Environmental Health Sciences (NIEHS), Tox21: Chemical testing in the 21st century, NIEHS/NIH, 2017
    Outlines the Tox21 program’s strategic roadmap for chemical testing, emphasizing high-throughput screening and computational toxicology to assess health risks. ↩︎

  3. U.S. Environmental Protection Agency (EPA), Use of New Approach Methodologies, EPA, 2024
    Details the EPA’s Endocrine Disruptor Screening Program’s adoption of new approach methodologies (NAMs) to reduce vertebrate animal testing. ↩︎

  4. Ankli PP, Parween S, Béatrice B, et al., Skin Sensitisation Case Study: Comparison of Defined Approaches including OECD 497 Guidance, bioRxiv, 2024
    Presents a case study comparing defined approaches for skin sensitization, demonstrating the practical application of OECD TG 497 guidance. ↩︎

  5. Alépée N, Tourneix F, van Vliet E, et al., Advancing Skin Sensitization Potency Categorization Using U-SENS™ in OECD TG 497, ALTEX, 2026
    Evaluates the implementation of the U-SENS™ assay within integrated testing strategies, showing it enhances flexibility without compromising predictive capacity for skin sensitization. ↩︎

  6. Casati S, et al., Standardisation and international adoption of defined approaches for skin sensitisation, Frontiers in Toxicology, 2022
    Discusses the standardization and international regulatory adoption of defined approaches for skin sensitization testing. ↩︎

  7. Chilton ML, et al., Evaluating the ability of defined approaches to predict the human skin sensitisation potential of chemicals previously untested in new approach methodologies, Regulatory Toxicology and Pharmacology, 2025
    Evaluates the predictive ability of defined approaches for chemicals previously untested in NAMs, supporting broader regulatory acceptance. ↩︎

  8. Organisation for Economic Co-operation and Development (OECD), Case Study on the Use of Integrated Approaches for Testing and Assessment for skin sensitisation, OECD, 2023
    Provides a case study demonstrating the next-generation risk assessment framework for skin sensitization using integrated approaches. ↩︎

  9. Corsini E, et al., S13-02 NAMs to investigate chemical-induced immunotoxicity: the cases of PFAS and BPA analogs, Toxicology Letters, 2025
    Investigates chemical-induced immunotoxicity using NAMs, specifically focusing on the cases of PFAS and BPA analogs. ↩︎

  10. Health Canada, Use of new approach methods (NAMs) in risk assessment, Government of Canada, 2023
    Explains how Health Canada and Environment and Climate Change Canada are integrating NAMs into chemical risk assessment frameworks. ↩︎

  11. Lin HC, Chiu WA, et al., Sensitivity Analysis of the Inputs for Bioactivity-Exposure Ratio Calculations in a NAM-Based Systemic Safety Toolbox, NAM Journal, 2025
    Analyzes the sensitivity of inputs for bioactivity-exposure ratio (BER) calculations, validating NAM-based systemic safety toolboxes. ↩︎

  12. NC3Rs, iPSC derived cardiomyocytes for cardiac toxicity assessment, NC3Rs, 2021
    Highlights the use of human iPSC-derived cardiomyocytes to replace animal-derived primary cells for cardiotoxicity screening and hazard identification. ↩︎

  13. Organisation for Economic Co-operation and Development (OECD), Case Study on the Use of Integrated Approaches for Testing and Assessment for skin sensitisation of Diethanolamine, OECD, 2023
    Details a specific case study applying next-generation risk assessment for the skin sensitization of diethanolamine using integrated approaches. ↩︎

  14. Stucki AO, et al., Chemical testing using new approach methodologies, Frontiers in Toxicology, 2022
    Editorial overview of the current state and future directions of chemical testing using new approach methodologies (NAMs) to meet regulatory requirements. ↩︎

  15. Costa Gagosian VS, et al., In Vitro Skin Models as Non-Animal Methods for Dermal Drug Development and Safety Assessment, Pharmaceutics, 2025
    Reviews the application of in vitro reconstructed human skin models as validated non-animal methods for dermal drug development and safety assessment. ↩︎

  16. Yun YE, Jung YJ, Choi YJ, Choi JS, Cho YW, Artificial Skin Models for Animal-Free Testing, Journal of Pharmaceutical Investigation, 2018
    Explores the development and application of 3D reconstructed artificial skin models as effective alternatives to animal testing. ↩︎

  17. Kim SH, Jo SH, Kim BK, Park SH, Tissue Engineered Mini-Cornea Model for Eye Irritation Test, Tissue Engineering and Regenerative Medicine, 2022
    Describes the development and validation of a tissue-engineered mini-cornea model as a reliable alternative for eye irritation testing. ↩︎

  18. Abdalkader RK, Fujita T, Corneal epithelium models for safety assessment in drug development: Present and future directions, Experimental Eye Research, 2023
    Reviews the present state and future directions of corneal epithelium models for safety assessment in drug development. ↩︎