Current opinion in toxicology最新文献

Replacement, reduction, and refinement, known as the 3Rs, is a well-known and broadly applied concept in biomedical science. Since its formal introduction in 1959, application of the 3Rs have refined approaches to reduce or eliminate distress, reduced overall use through repeated measures approaches and use of appropriate numbers of animals, or have replaced animals altogether. However, adoption of the 3Rs is not always easy, due in part to initial lack of awareness of the importance of animal well-being to the outcome of scientific investigation, a lack of understanding of use of results from in vivo model verses in vitro models, lack of effective communication about model benefits, or other technical issues with the development or use of an assay. In understanding the history of the 3Rs, we can learn from or avoid previous challenges as we look to the future of the application of the 3Rs. For instance, there is little doubt that awareness and use of the 3Rs influenced the concept of new approach methods (NAMs), a term describing assays that include traditional in vitro cultures, microphysiological systems, and in silico approaches, and is certainly part of the 3Rs future and the ultimate replacement of an animal-based assay.

Developmental toxicity outcomes in humans and animals often exhibit variability; hence, the demand for predictive non-animal alternatives, particularly human cell-based models, are increasing. Despite advancements in genomic toxicology, which have facilitated the identification of toxicity mechanisms and potential biomarkers, existing transcriptome analysis-based methods have yet to yield highly predictive in vitro developmental toxicity assays. One possible reason is that assays at a single time point could not capture the entire dynamic signal network during developmental processes. This article addresses the challenges in comprehensive gene expression analysis and introduces novel in vitro developmental toxicity assays focused on the time-dependent dynamics of signaling pathway responses crucial to human development.

A variety of new approach methodologies (NAMs) have already been developed for acute systemic and short-term toxicity, including in vitro, in silico, and omics methods. To advance their regulatory implementation, we suggest that beta testing of these methods in regulatory settings is urgently needed. There are several limitations to the use of NAMs for acute systemic and short-term toxicity, such as the lack of definitions for applicability domains, skewed reference data for validation, and the absence of representation of kinetic processes and multi-organ complexity. These limitations may lead to risks associated with the ordinary regulatory implementation, such as the application of methods to substances outside of their intended applicability domain or reduced predictivity due to a lack of mechanistic information or consideration of kinetics. We argue that this could be avoided by beta testing. Further benefits of beta testing would be the filling of in vivo data gaps and potentially improved validation with regard to human relevance of methods. In order to enhance the improvement, familiarisation, and acceptance of NAMs in the near future, it is essential for such concept of beta testing to rely on feedback loops between method testers and developers.