Safety Assessment of Newly Expressed Proteins in Genetically Modified Crops: A Decade of Regulatory Case Studies

This review synthesizes regulatory and scientific evidence accumulated over the past decade supporting the safety of newly expressed proteins (NEPs) in genetically modified (GM) crops. Using five case studies representing diverse protein classes, including dicamba monooxygenase (DMO), protoporphyrinogen IX oxidase (PPO), Cry1B.2/Cry1B.3, Mpp75Aa1.1, and Vip3Cb1, it illustrates how science-based, case-by-case, weight-of-evidence approaches are applied in food and feed safety assessment and ecological risk assessment (ERA) for regulatory submissions. These examples demonstrate how hazard identification, hazard characterization, and exposure assessment are integrated across proteins with diverse biological functions, structural characteristics, and levels of familiarity. It further examines the safety relevance of protein processing and sequence variation arising from protein engineering or biological processing and discusses the scientific basis supporting bridging and read-across approaches, including phylogenetic relationships, sequence similarity, structural conservation, domain architecture, and functional equivalence. The increasing application of safe-by-design principles and bridging strategies is highlighted as an important advancement enabling efficient, scientifically robust evaluations while reducing unnecessary testing. The review also discusses the convergence of food/feed safety assessment and ERA and future directions. Overall, accumulated evidence from NEPs commercialized to date in GM crops has not identified hazards for the assessed safety endpoints and supports the continued evolution and modernization of protein safety assessment frameworks.