Application of toxicogenomics to study mechanisms of genotoxicity and carcinogenicity.

Specific genotoxic events such as gene mutations and/or chromosome damage are considered hallmarks of cancer. The genotoxicity testing battery enables relatively simple, rapid and inexpensive hazard identification, namely by assessing a chemical's ability to cause genetic damage in cells. In addition, the 2-year rodent carcinogenicity bioassay provides an assessment of a risk associated with the chemical to develop cancer in animals. Although the link between genotoxicity and carcinogenicity is well documented, this relationship is complicated due to the impact of non-genotoxic mechanisms of carcinogenesis and by character of the in vitro genotoxicity assays and specific endpoints making the interpretation of test results in light of human risk and relevance difficult. In particular, the specificity of test results has been questioned. Therefore, the development of novel scientific approaches bridging genotoxicity and carcinogenicity testing via understanding underlying mechanisms is extremely important for facilitating cancer risk assessment. In this respect, toxicogenomics approaches are considered promising as these have the potential of providing generic insight in molecular pathway responses. The goal of this report thus is to review recent progress in the development and application of toxicogenomics to the derivation of genomic biomarkers associated with mechanisms of genotoxicity and carcinogenesis. Furthermore, the potential for application of genomic approaches to hazard identification and risk assessment is explored.