From Food Additives and Contaminants to the Human Exposome: A Precision Toxicology Framework for Next-Generation Food Safety.

Human exposure to foodborne xenobiotics, including environmental contaminants that enter the food chain, is no longer adequately represented by isolated chemicals. Individuals encounter complex and dynamic mixtures of food additives, pesticide residues, veterinary drugs, mycotoxins, processing contaminants, packaging migrants, environmental pollutants, and other dietary chemicals that interact with genetics, metabolism, the gut microbiome, nutritional status, and lifestyle throughout life. The dietary exposome therefore represents a critical interface linking food contaminants, internal chemical exposure, molecular perturbation, and long-term human health. Conventional toxicology provides an indispensable foundation for food safety regulation through hazard characterization and population-based health guidance values but is less equipped to explain interindividual variability in biological response and chronic disease susceptibility. Precision toxicology provides an integrative and mechanism-informed framework that combines high-resolution analytical chemistry, human biomonitoring, exposomics, multiomics, new approach methodologies, and artificial intelligence. This integration enables the characterization of biologically effective exposure, the elucidation of exposure-response relationships, and the identification of interindividual variability in toxicological susceptibility. This perspective proposes a translational framework connecting external exposure → internal dose → biological response → individual susceptibility → health outcome. We position this framework relative to existing exposome, exposure-pathway, and adverse-outcome-pathway frameworks; specify the evidence required at each transition; make its life-course dimension explicit; illustrate it with a worked per- and polyfluoroalkyl substance (PFAS) example; and outline a stepwise route into food risk assessment together with its principal limitations. Such integration could advance food safety science beyond residue detection toward biologically informed exposure assessment, ultimately supporting more evidence-based regulatory decision-making, preventive strategies, and public health protection.