Alternatives to Conventional Toxicology Testing

The need for developing alternatives for animal testing for assessing chemical risk has come from ethical considerations, legislation, and recognition that alternative methods can offer better science. Historically, testing on animals was the only method for assessing chemical risk, but now more precise methods are being developed because of the tremendous advances made in the understanding of the mechanisms of toxicity. Currently, models using tissue culture methods for measuring cell death in clonal cell lines, and in skin-equivalent models, have been accepted by regulators. The inherent need in toxicology to predict dose is being met with models for assessing transport and metabolism. More complex responses, such as those exhibited by the immune and nervous systems, pose even greater challenges. To meet these challenges, computer models that simulate cellular interactions will likely be needed in addition to cell culture models. Indeed, an understanding of systems biology coordinated with valid alternative methods has the potential to characterize chemical toxicity: identifying molecular targets; analyzing the effect on downstream pathways; modeling the metabolic response; and predicting the whole-organism response. In summary, tools are now available that have the potential to more accurately assess chemical risk using a humane and efficient approach.The concept of alternative models in toxicity testing had been based on the principle of the 3Rs - replacement, refinement, and reduction - that were described by Russell and Burch (1959). Refinement refers to improving animal welfare by minimizing actual or potential pain and distress throughout the life span of the animal, or using animals lower on the phylogenetic scale. Replacement refers to avoiding or replacing animals in methods where animals have been traditionally used, generally this includes in vitro models, and in silico models based, in part, on information from genomic and proteomic databases. Reduction refers to the most effective experimental design, in other words the right number of animals for the statistical power required and the correct species for the question being asked. As we will discuss in this chapter, alternative methods will have beneficial roles beyond the 3Rs. High-throughput methods and models based on human tissue will enable both industry and government to screen large numbers of chemicals and obtain results that more comprehensively and accurately predict human responsiveness.There are many considerations when developing tests including their scientific basis and predictive capacities, which are important during method development. Additionally, validation criteria must be considered. This chapter will focus on the science of replacement alternatives.