Chemical Alternatives Assessment: Progress and Perspectives in Hazard Characterization, Exposure Assessment, and Life...

With rapid technological advancement and accelerating industrialization, legacy chemicals and emerging contaminants have caused increasingly severe adverse impacts on ecological environments and human health due to their persistence, bioaccumulation, and toxicity. Developing and scaling up green chemical alternatives is a critical pathway to mitigate exposure risks from conventional hazardous substances and achieve sustainable industrial development. However, to prevent a recurring "pollution-substitution-repollution" cycle, often termed "regrettable substitution", there is an urgent need to establish a scientifically sound and forward-looking chemical alternatives assessment (CAA) framework. This work presents a systematic overview of the evolution of global CAA guidelines and provides an in-depth analysis of recent research advances in assessment methodologies across three core domains, including hazard characterization, exposure assessment, and life cycle assessment (LCA). We highlight that modern CAA is undergoing a profound paradigm shift. Hazard characterization is transitioning from traditional in vivo experiments to predictive toxicology, anchored in new approach methodologies; exposure assessment is evolving from static, conservative assumptions to refined, dynamic coupled multi-media models; and LCA is expanding from end-of-pipe environmental impact auditing to source-level interventions that integrate prospective prediction and green design. By connecting insights across scales, from microscopic molecular mechanisms to macroscopic ecosystem-level outcomes, this study aims to provide relatively comprehensive methodological guidance for chemical alternative assessments. In turn, this work provides both the theoretical foundation for "Safe and Sustainable by Design (SSbD)" chemical development and the practical reference for establishing robust scientific toolkits for prospective chemical classification and regulatory decision-making.