26th Lauriston S. Taylor Lecture: developing mechanistic data for incorporation into cancer and genetic risk assessments: old problems and new approaches.

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The theme that runs through this 26th Taylor Lecture is the question of how can data on the mechanism of induction of genetic alterations by radiations and chemicals be used to support the development of risk estimates, particularly at low exposure levels. The premise is that chromosomal alterations are involved in the development of tumors and birth defects, and that data generated for genetic alterations can be interpreted in terms of these adverse health outcomes. The general conclusions are that chromosomal alterations can be induced by ionizing radiations by a single energy loss event in a target of the size of a DNA molecule and that aberrations generally result from misrepair or failure to repair the induced lesions (generally assumed to be double-strand breaks). Chromosomal alterations induced by chemicals are produced almost exclusively by replication errors on a damaged DNA template. Thus, cell cycle stage and DNA repair and replication fidelity will be influential on overall sensitivity to aberration induction. These same features are also important in considerations of genetic susceptibility-alterations in cell cycle control or DNA repair or replication fidelity can alter sensitivity. The differences in mechanism of induction of chromosomal aberrations by ionizing radiation and chemicals is most important when considering cells at risk and comparative sensitivities among species and cell types. Models of cancer induction have gradually evolved from initiation, promotion, and progression models to multistep genetic models to the most recent one of six acquired characteristics. This evolution has passed the level of concentration of research from single gene, single cell to multiple genes (pathways), and whole tissues. The latter areas of concentration are ideal for addressing with the new genomics, proteomics, and computational modeling approaches. The attention is still on the role of genetic alterations in cancer and hereditary effects and the mechanism of their formation--it is the approaches to address these that are changing.