Toward Human-relevant Toxicology: A Decision-oriented Roadmap Integrating Modern Tools for the Safety Evaluation of Novel Foods, Functional Ingredients, and Nutraceuticals

Ensuring the safety of novel foods, functional ingredients, and nutraceuticals is increasingly challenging as global food systems shift toward sustainable, health-aligned innovations. This review synthesizes conventional and next-generation approaches in food toxicology to outline a mechanistic, human-relevant, and decision-oriented framework for evaluating novel foods, nutraceuticals, and ingredients. Emphasis is placed on integrating multidisciplinary tools, including regulatory benchmarks, state-of-the-art analytical protocols, and in vitro and in silico systems, which are reshaping safety assessment pipelines. The dynamic regulatory context is examined, with a focus on the European Food Safety Authority's updated requirements for novel foods and its tiered toxicological strategy for assessing genotoxicity, toxicity, allergenicity, and chemical risk. Emerging scientific and technological trends are highlighted as the main drivers of a more predictive and ethically aligned toxicological paradigm. These include high-throughput cellular assays, omics-enabled molecular profiling, physiologically relevant in vitro models, computational prediction tools, and technologies for chemical and bioactivity characterization. Together, these advances support a modern, mechanism-based approach to safety evaluation. The review demonstrates how integrating these tools can strengthen science-based decision-making, enhance regulatory confidence, and promote responsible innovation in the advancement of next-generation foods and functional ingredients.