Complex mixtures derived from natural products and thermal processing (e.g., wood pyrolysis derived flavors, roasted coffee/tea, baked goods and botanicals) can contain one or more constituents with genotoxic potential. Such constituents are not intentionally added to mixtures and typically occur at very low levels–so low that they are insufficient to pose a genotoxic hazard in the mixture. Recent regulatory decisions have highlighted these challenges, particularly when constituent-level genotoxicity hazards are identified despite negative whole-mixture in vivo genotoxicity data. Emerging literature and scientific discussion support use of in vivogenotoxicity data to derive quantitative points of departure for considerations for risk characterization. In some cases, this approach may be more conservative than those based on traditional 2-year carcinogenicity bioassays. Two recent expert workshops (i.e., BfR and EFSA) emphasized the need for additional case studies to refine and validate this evolving paradigm. This poster synthesizes the current state of the science, includes key take aways from stakeholder perspectives from these workshops, and integrates these insights into a transparent and structured approach for evaluating the genotoxicity of mixtures containing genotoxicants yet producing negative in vivo whole mixture results. Opportunities to consolidate and update guidance, reduce interpretative ambiguity, and advance 3R objectives by potentially decreasing reliance on 2-year carcinogenicity bioassays when robust in vivo genotoxicity data are available, are discussed. Collectively, the proposed approach provides a pragmatic and health-protective method to reconcile constituent-based hazards with whole mixture evidence when available. Abstract Acknowledgements: The authors thank all collaborators and colleagues whose insights and technical assistance supported the development of this work.