替代測試方法之進展及應用-以皮膚致敏為例應用於農藥評估
Development and application of new alternative methods-taking pesticide skin sensitization assessment as an example
Non-animal new alternative methods (NAMs) have gained significant attention due to ethical concerns in recent years. The Adverse Outcome Pathway (AOP) concept is a framework that connects a molecular initiating event (MIE) to an adverse outcome (AO) across various biological levels. By identifying key events (KEs) within different AOPs, scientists can more effectively predict and mitigate adverse outcomes. AOPs provide a mechanistic representation of adverse effects and are utilized to develop more targeted and efficient alternative testing methods for risk assessment. The Organisation for Economic Co-operation and Development (OECD) actively includes NAMs in the development of new chemical testing guidelines and oversees the Integrated Approaches to Testing and Assessment (IATA).
Skin sensitization is crucial for the risk assessment of dermal exposure to chemicals, including pesticides. AOP-based computational models have been developed to minimize animal use for safety evaluations. However, their applicability to pesticides is not well understood. Initially built on the comprehensive SkinSensDB, a curated database of various in chemico, in vivo, and in vitro OECD-recommended KEs for skin sensitization assays, SkinSensPred uses existing data and advanced transfer learning algorithms to enhance the accuracy and reliability of skin sensitizer predictions. The reconfiguration of SkinSensPred has notably improved its effectiveness in predicting pesticide nonsensitizers, making it a valuable tool for safer agricultural practices. Moreover, SkinSensPred has demonstrated its efficacy as an in silico tool for integrated testing strategies (ITS), providing a cost-effective and ethical alternative to traditional testing methods. Performance evaluations of SkinSensPred across different cases have shown high accuracy rates. ITS-SkinSensPred also showed promising performance over existing ITSv1 and ITS v2 for agrochemical products with more than 10% improvement.
Further research is required to optimize the application of KE3 assays for agrochemical active ingredients and finished products. Our recent study assessed individual KE3 in vitro assays, including h-CLAT and U-SENS™, along with the in silico SkinSensPred prediction platform, to evaluate the skin sensitization potential of agrochemical active ingredients and finished products. A tiered testing strategy was proposed, incorporating individual assays and AOP-based integrated testing strategies (ITS). In conclusion, our findings suggested that the proposed tiered test strategy, particularly the ITS approach, represents a scientifically robust and ethically preferable alternative to traditional animal testing, with promising potential for regulatory acceptance in the safety assessment of agrochemical products.