Alternatives to Toxicity Testing in Animals: Challenges and Opportunities

We have learned over time that the development of successful alternative methods in toxicology testing requires the successful integration of three elements: First, there must be a solid foundation of understanding the basic biology and toxicology of the tissues and organs being studied. Second, in vitro platforms must be available that can be modified to make them amenable for toxicity testing. Third, one needs to convince the scientific community, which is skeptical by nature and training (and rightfully so), that the alternative methods fulfill their intended purpose and have been rigorously validated. In vitro mutagenicity screening methods have been used for many years and are a good illustration of these three points. Initially, the basic biology that needed to be understood was that DNA is the molecular basis for heredity and that mutations are, in fact, manifestations of damage to the DNA. Furthermore, several types of mutations (e.g., point mutations, insertions, deletions) require the development of different in vitro models. In vitro platforms, the second element, were adapted from extensive research into the molecular biology of prokaryotes, and later, eukaryotic cells. The third element involved years of assay standardization, replication of results in multiple laboratories, and comparisons with in vivo results. For more complex end points, the development of alternatives has been a daunting task. Even supposedly simple targets for replacement, such as the Draize test for eye irritation, have proved difficult to model in vitro and progress through successful external validation despite major efforts by the European Centre for the Validation of Alternatives (ECVAM), industry trade associations, individual companies, and academia. An extensive list of in vitro models that have been proposed as alternatives to the Draize test has been published E s s a y o n Toxicity Testing in Animals