Are New Approach Methodologies (NAMs) the Holy Grail of toxicology?

New Approach Methodologies (NAMs), including organoids, microphysiological systems, and computer modeling, are gaining increased popularity for toxicological testing and even mechanistic research. With the use of human cells, the primary objectives of NAMs are to develop more human-relevant test systems and to reduce, and ultimately eliminate, animal experiments. There are many advantages of using NAMs for biological research. For example, NAMs can be used to test the dose- and time-dependent toxicity of numerous chemicals and mixtures in a cost-effective way and reduce animal use. Although these are worthwhile goals when considering the big picture, the problems lie in the details. First, in vivo insight is needed to build and refine NAMs, including computer modeling. Second, primary human cells are difficult to obtain reliably and in sufficient quantities; substitutes such as immortalized cell lines or induced pluripotent stem cells have the advantage of being more robust and available in unlimited numbers, but their basal and stress-induced gene expression profiles are quite different compared with primary cells. Third, critical aspects such as metabolic competency, the presence of various cell types in an organ, spatial aspects, oxygen gradients, and the role of inflammatory cells are very difficult to replicate in vitro. Therefore, in vivo experiments are necessary to verify results obtained with NAMs. Importantly, the results of both NAMs and the in vivo animal experiments need to be translatable to human disease processes. The advantages and limitations of NAMs are being discussed using the challenges of investigating mechanisms of drug hepatotoxicity as an example.