PurposeReducing chemical pressure on human and environmental health is an integral part of the global sustainability agenda. Guidelines for deriving globally applicable, life cycle–based indicators are required to consistently quantify toxicity impacts from chemical emissions as well as from chemicals in consumer products. In response, we elaborate the methodological framework and present recommendations for advancing near-field/far-field exposure and toxicity characterization, and for implementing these recommendations into the scientific consensus model USEtox.MethodsAn expert taskforce was convened by the Life Cycle Initiative hosted by UN Environment to expand existing guidance for evaluating human toxicity impacts from exposure to chemical substances. This taskforce evaluated scientific advances since the original release of USEtox and identified two major aspects that required refinement, namely integrating near-field and far-field exposure, and improving human dose-response modeling. Dedicated efforts have led to a set of recommendations to address these aspects in an update of USEtox, while ensuring consistency with the boundary conditions for characterizing life cycle toxicity impacts and being aligned with recommendations from agencies that regulate chemical exposure. The proposed updated USEtox framework was tested in an illustrative rice production and consumption case study.Results and discussionOn the exposure side, a matrix system is proposed and recommended to integrate far-field exposure from environmental emissions with near-field exposure from chemicals in various consumer product types. Consumer exposure is addressed via sub-models for each product type to account for product type-specific characteristics and exposure settings. Case study results illustrate that product use–related exposure dominates overall life cycle exposure. On the effect side, a probabilistic dose-response approach combined with a decision tree for identifying reliable points of departure is proposed for non-cancer effects, following recent guidance from the World Health Organization. This approach allows for explicitly considering both uncertainty and human variability in toxicity effect factors. Factors reflecting disease severity are proposed to distinguish cancer from non-cancer effects and within the latter to discriminate reproductive/developmental and other non-cancer effects. All proposed aspects have been consistently implemented into the original USEtox framework.ConclusionsThe recommended methodological advancements address several key limitations in earlier approaches. Next steps are to test the new characterization framework in additional case studies and to close remaining research gaps. Our framework is applicable for evaluating chemical emissions and product-related exposure in life cycle assessment, chemical alternatives assessment and chemical substitution, consumer exposure and risk screening, and high-throughput chemical prioritization.