Fig. 1.

The Road to NAMs. Early animal use included a wide variety of animals to investigate physiology, pharmacology, putative therapies, and medical devices. The 3Rs concept increased awareness of animal use and encouraged replacement, reduction, and refinement of animals. As more advanced technologies were developed (i.e., genetic modification of rodents) and adoption of 3Rs became widespread, some animal use decreased (as indicated by blue arrowhead). There was also increased use of lower phylogenetic species (i.e., worms, flies) and development of in silico models at this time. NAMs were introduced and continue to be developed, used, and validated. In the future, it is likely that NAMs use will continue to increase while decreasing, although not eliminating, animal use.