From Classical Toxicology to Tox21: Some Critical Conceptual and Technological Advances in the Molecular Understanding of the Toxic Response Beginning From the Last Quarter of the 20th Century

Abstract

Toxicology has made steady advances over the last 60+ years in understanding the mechanisms of toxicity at an increasingly finer level of cellular organization. Traditionally, toxicological studies have used animal models. However, the general adoption of the principles of 3R (Replace, Reduce, Refine) provided the impetus for the development of in vitro models in toxicity testing. The present commentary is an attempt to briefly discuss the transformation in toxicology that began around 1980. Many genes important in cellular protection and metabolism of toxicants were cloned and characterized in the 80s, and gene expression studies became feasible, too. The development of transgenic and knockout mice provided valuable animal models to investigate the role of specific genes in producing toxic effects of chemicals or protecting the organism from the toxic effects of chemicals. Further developments in toxicology came from the incorporation of the tools of "omics" (genomics, proteomics, metabolomics, interactomics), epigenetics, systems biology, computational biology, and in vitro biology. Collectively, the advances in toxicology made during the last 30-40 years are expected to provide more innovative and efficient approaches to risk assessment. A goal of experimental toxicology going forward is to reduce animal use and yet be able to conduct appropriate risk assessments and make sound regulatory decisions using alternative methods of toxicity testing. In that respect, Tox21 has provided a big picture framework for the future. Currently, regulatory decisions involving drugs, biologics, food additives, and similar compounds still utilize data from animal testing and human clinical trials. In contrast, the prioritization of environmental chemicals for further study can be made using in vitro screening and computational tools.

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“…As toxicogenomics has matured, it has encompassed other omics technologies for global cellular profiling of a wide variety of biomolecules. 202,203 Using a parallel approach, other technologies, such as proteomics, metabolomics, and lipidomics, can be used to yield an overwhelming quantity of data for the study of a toxicological system. The application of the "correct" technologies depends on the issue at hand and toxicological phenomena under evaluation.…”

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“…Supporters of animal studies within biomedical research claim that 1) it is not possible to discontinue their use, as that would jeopardize human health, and that 2) human-based methods (in silico and in vitro) are used in early steps of biomedical research to inform the animal research community, hence avoiding unnecessary or excessive use of animals. For example, purportedly, if a substance shows high levels of toxicity in vitro it will not progress into animal testing [4]. In the same way, a drug that shows high toxicity in animal testing should not proceed to human trials.…”