Health Risk Science - Toxicity testing

Toxicity tests are laboratory studies conducted to evaluate the potential of external substances to induce adverse health effects on living systems. Toxicity occurs if the normal physiologic or biochemical pathways in organisms, organ systems, individual organs, tissues, cells, or subcellular units are perturbed. At the level of the whole organism, if the perturbation is of sufficient intensity or if a particular pathway is critical for viability; toxic effects will be manifested in different end-points such as cancer, disease, birth defects, death…etc. Toxic substances could be chemical agent (e.g. lead, asbestos, air pollutants, food additives, pesticides, and most medications), physical agents (ionizing and non-ionizing radiation) or biological agents (such as bacteria and viruses).

Generally, xenobiotics cause toxicity by different mechanisms including cellular injury and cellular death, genetic damage, immunotoxicity. The rational approach for evaluating the risk of substances to humans (and hence establish exposure levels and other regulatory actions) depends on understanding mechanisms of toxicity in experimental animals and in vitro cell culture and identifying the relevant human biochemical and physiologic pathways. Understanding how chemical or physical agents cause toxicity in the living organisms is also critical in developing preventive and therapeutic strategies. Currently, large part of toxicity testing for regulatory purposes is conducted on laboratory animals by exposing them to high doses of chemicals and then evaluating signs that are indicative of toxic effects. Although this is a valid approach, it involves many uncertainties when using the data to estimate effects on humans. For example, animals are exposed to high doses and are observed for overt signs of toxicity, which provides little information about biological changes leading to such effects. Furthermore, animal testing is expensive and time consuming.

Recent advances in genomics, systems biology, computational biology, comparative pharmacokinetics, metabolism, cell and molecular biology permit utilization of in vitro screening tests using cells, cellular components, and tissues rather than whole animals to identify pathways and mechanisms through which chemicals induce critical lesions at the cellular and subcellular levels. In vitro testing systems also enhance the predictability of animal models and in some cases to complement the traditional in vivo systems. Human cell lines, in this regard, are particularly attractive because they offer the possibility of working with a system that maintains several phenotypic and genotypic characteristics of the human cells in vivo. Population-based and human exposure data are important component of toxicity testing since they often complement in vitro tests and may suggest relevant biomarkers that can be monitored in human populations. Biomarkers reveal genetic and molecular changes related to early, intermediate and late end-points associated with exposure to toxic agents.

Just recently, the National Research Council (NRC) has completed a report that outlined the vision for toxicity testing for the 21st century. The report envisions toxicity-testing systems that rely mainly on more understanding of toxic pathways that help explain mechanisms and identify critical cellular pathways of chemical-induced adverse health effects. This new strategy is expected to generate more robust data on the potential risks to humans posed by exposure to environmental agents and to expand capabilities to test chemicals more efficiently and cost-effectively. Furthermore, implementation of the vision will lead to a marked reduction in animal use and focus on doses that are more relevant to those experienced by human populations. The report conclude that achieving this new vision requires a concerted efforts and resources over the next several decades by scientists from government, industry, universities, consulting laboratories, and the public interest community.