Welcome back to our series on NAMs. So far, we have looked at how model choice depends on the scientific question, and where NAMs can support nonclinical drug development. In this article, we move beyond pharmaceuticals to look at how human cell-based NAMs could also support environmental, agricultural, and personal care toxicology.
Unlike drug development, where researchers are often focused on a defined drug candidate, chemical safety assessment may involve large numbers of substances with limited existing data (1). Chemicals enter the body through different routes and can be encountered repeatedly or at low exposures, or in combinations that better reflect real-life exposure. Each of these factors can influence which safety assay is most relevant. For instance, if a chemical is likely to be inhaled, the model should be able to reveal effects relevant to the airways and lung biology, such as inflammation, allergic responses, or other respiratory-pathway effects. If a cosmetic product is applied topically, a skin or barrier model will be more relevant than a general cytotoxicity assay.
In chemical safety testing, human cell-based models help researchers ask more relevant, human-specific questions earlier in the assessment process than traditional animal-based approaches. Such questions include: Which chemicals show biological activity? Which biological processes or pathways are affected? Which tissues or developmental stages are vulnerable? Which substances should be prioritized for further testing?
Here, we look at how human cell-based NAMs can support chemical safety evaluation, using developmental neurotoxicity as a case example of how these approaches can help address complex, human-relevant endpoints.
A Wider Role for Human Cell-Based Models
Chemical safety assessment covers a wide range of substances, exposure routes, tissues, and endpoints. Environmental and agricultural toxicology may involve industrial chemicals, pollutants, pesticides, herbicides, flame retardants, metals, air or water contaminants (2,3). Personal care and cosmetic safety assessment may encompass local effects on the skin, hair and scalp, around the eye area, or other exposed tissues over long periods of time, as well as systemic, developmental, and reproductive toxicity risk (4,5).
In each case, the purpose of the model is not to just generate more data, but to generate data relevant to the exposure, tissue, endpoint, or decision context. A basic viability assay might show that a chemical affects cell viability, but it won’t necessarily reveal whether that effect is relevant to a specific tissue, exposure route, or human risk setting. A more useful approach is to choose the model according to the question being asked. For example, if there is a concern about repeated skin exposure, a human skin model with appropriate exposure conditions may provide a more relevant readout than a generic cytotoxicity assay.
What Human Cell-Based Models Can Offer
Human cell-based NAMs offer a broad range of model systems, from relatively simple 2D cultures to more complex 3D models, including spheroids, organoids, co-cultures, and microphysiological systems. These models may be based on primary human cells, immortalized human cell lines, or induced pluripotent stem cell-derived cells.
A complex model is not always the better model; the best choice depends on what the study needs to answer. In environmental and agricultural toxicology, these models can help screen chemicals for effects on pathways that involve oxidative stress, mitochondrial function, endocrine signaling, inflammation, DNA damage, barrier integrity, neurotoxicity, or developmental processes. This is especially useful when many substances need to be assessed and only a subset can move forward into more detailed evaluation.
In personal care and cosmetic safety, human cell-based models are already important because animal testing is restricted or prohibited in many regions, including the EU, UK, Canada, India, Australia, New Zealand, and several U.S. states. Reconstructed human skin, keratinocyte-based assays, immune-related assays, and barrier models can support the assessment of irritation, corrosion, sensitization, phototoxicity, and other local effects. For systemic safety questions, these models can be combined with exposure estimates, in silico tools, and toxicokinetic modeling as part of risk assessment.
Importantly, a positive in vitro response does not automatically mean that a chemical or ingredient is dangerous. The data should be considered alongside exposure, concentration, and biological relevance. What concentration caused the effect? Is that concentration relevant to human exposure? Is the endpoint biologically meaningful? Does the model capture the tissue or process of concern?
Developmental Neurotoxicity as a Test Case
Developmental neurotoxicity, or DNT, provides a useful case example of how NAMs can be applied in chemical safety assessment. DNT is not the only endpoint relevant to chemical safety, and it may be more relevant in some exposure contexts than others. However, it highlights a major challenge in toxicology: the developing brain can be vulnerable prenatally and in early infancy, while the effects of exposure may not become apparent until childhood or later in life. This makes DNT difficult to study using traditional approaches and challenging to incorporate into routine chemical safety decisions. Recognition of developmental neurotoxicity often depends on linking exposure data from pregnancy or early life with neurodevelopmental outcomes observed years later. At the same time, many chemicals have not been systematically evaluated for their effects on brain development. In one widely cited review, the number of industrial chemicals recognized as developmental neurotoxicants doubled from six to 12 between 2006 and 2013, with newly recognized examples including manganese, fluoride, chlorpyrifos, DDT/DDE, tetrachloroethylene, and PBDE flame retardants (6).
The developing nervous system is complex and highly dynamic, relying on tightly coordinated processes such as neural progenitor proliferation, apoptosis, differentiation, migration, neurite outgrowth, synaptogenesis, and neural network formation. These processes are shaped not only by environmental exposures but also by intrinsic genetic susceptibilities that can influence developmental vulnerability. These events occur in a tightly regulated sequence, and disruption at one stage may have long-term consequences. Human cell-based models can help by breaking this complex endpoint into measurable biological processes. For example, neural progenitor models can be used to study proliferation, migration, and differentiation, while human neuronal cultures can support the evaluation of neurite outgrowth, synapse formation, and network activity. Glial models can help explore the roles of astrocytes, oligodendrocytes, and microglia in neurodevelopment and toxicity.
More complex 3D systems, including CNS organoids and brain-region-specific organoids, may be useful when studying chemical effects on tissue organization, developmental patterning, neural maturation, or interactions between different neural cell types. As with any model, these systems need to be used with their limitations in mind. They are not miniature brains and do not fully capture maternal-fetal physiology, whole-body metabolism, vascularization, immune-endocrine interactions, or how early developmental disruption may affect nervous system function over time (7).
Communicating Findings Clearly
As NAMs become more important in chemical safety assessment, scientists also need to communicate clearly how these models are used and what their results mean. This is especially important when scientific evidence is questioned or misunderstood in public debate. Building trust requires strong study design, transparent methods, reproducible protocols, and honest discussion of uncertainty and limitations. It also means explaining risk in context: what was tested, at what concentration, through which exposure route, and how those conditions relate to real-world exposure. For NAMs, clear communication can help the public understand that these models are not a shortcut, but part of a broader evidence-based approach to making safety decisions more human-relevant.
From Model Systems to Safety Decisions
For NAMs to support chemical safety decisions, they need to be reproducible, transferable, well documented, and clear enough to support a defined use.
This is where the NAM lifecycle described for DNT by Blum et al. becomes useful. The process begins with relevant test systems and moves through alignment with regulatory needs, assessment of method readiness, fit-for-purpose validation, Organisation for Economic Co-operation and Development (OECD) recognition, and public availability through contract research organizations that can perform testing under appropriate quality standards (7).
The lessons from DNT are also relevant across environmental, agricultural, and personal care toxicology. The goal is not to replace every existing method at once, but to use human cell-based NAMs where they can provide useful, human-relevant evidence: which chemicals matter, which mechanisms are involved, and where further testing is most needed.
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References
- Deepika D, Bharti K, Sharma S, Kumar S, Pathak RK, Biosca Brull J, et al. Advancing human health risk assessment: the role of new approach methodologies. Frontiers in Toxicology. 2025;7:1632941.
- Stucki AO, Barton-Maclaren TS, Bhuller Y, Henriquez JE, Henry TR, Hirn C, et al. Use of new approach methodologies (NAMs) to meet regulatory requirements for the assessment of industrial chemicals and pesticides for effects on human health. Frontiers in Toxicology. 2022;4:964553.
- Bellinger DC. An overview of environmental chemical exposures and neurodevelopmental impairments in children. Pediatric Medicine. 2018 Dec 1;1(0).
- Sewell F, Alexander-White C, Brescia S, Currie RA, Roberts R, Roper C, et al. New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption. Toxicol Res (Camb). 2024 Apr 1;13(2):tfae044.
- ICCR-19_2025_Outcome Statement. Accessed June 23, 2026. Available at: https://www.iccr-cosmetics.org/
- Grandjean P, Landrigan PJ. Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014 Mar 1;13(3):330–8.
- Blum J, Bartmann K, de Paula Souza J, Fritsche E. Developmental neurotoxicity as a case example for a six-step framework for the sustainable regulatory implementation of NAMs. Curr Opin Toxicol. 2025 Jun 1;42:100528.
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Karen O’Hanlon Cohrt is an independent Science Writer with a PhD in biotechnology from Maynooth University, Ireland (2011). After her PhD, Karen relocated to Denmark where she held postdoctoral positions in mycology and later in human cell cycle regulation, before moving to the world of drug discovery. Karen has been a full-time science writer since 2017, and has since then held numerous contract roles in science communication and editing spanning diverse topics including diagnostics, molecular biology, and gene therapy. Her broad research background provides the technical know-how to support scientists in diverse areas, and this in combination with her passion for learning helps her to keep abreast of exciting research developments as they unfold. Karen is currently based in Ireland, and you can follow her on Linkedin here.
