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What Is Genetic Toxicology?
History of Genetic Toxicology
Health Impact of Genetic Alterations
Cancer and Genetic Risk Assessments
Cancer Risk Assessment
Genetic Risk Assessment
Mechanisms of Induction of Genetic Alterations
Assays for Detecting Genetic Alterations
Introduction to Assay Design
Structural Alerts and In Silico Assays
DNA Damage and Repair Assays
Gene Mutations in Prokaryotes
Genetic Alterations in Nonmammalian Eukaryotes
Gene Mutations in Mammals
Gene Mutations In Vitro
Gene Mutations In Vivo
Transgenic Assays
Mammalian Cytogenetic Assays
Germ Cell Mutagenesis
Development of Testing Strategies
Human Population Monitoring
New Approaches for Genetic Toxicology
Conclusions
Acknowledgments
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What is Genetic Toxicology?
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Genetic toxicology is a branch of the field of toxicology that assesses the effects of chemical and physical agents on the hereditary material (DNA) and on the genetic processes of living cells. Such effects can be assessed directly by measuring the interaction of agents with DNA or more indirectly through the assessment of DNA repair or the production of gene mutations or chromosome alterations. Given the risk assessment framework of this chapter, it is important at the outset to distinguish between genotoxicity and mutagenicity. Genotoxicity covers a broader spectrum of endpoints than mutagenicity. For example, unscheduled DNA synthesis (UDS), sister chromatid exchanges (SCEs), and DNA strand breaks are measures of genotoxicity, not mutagenicity because they are not themselves transmissible from cell to cell or generation to generation. Mutagenicity on the other hand refers to the production of transmissible genetic alterations. In the last few years, there has been an increased emphasis on the role of epigenetic changes in the production of altered phenotypes. Such changes can be transmitted and so it is appropriate to include epigenetic changes such as alterations in DNA methylation or in histones involved in the control of gene expression as genotoxic endpoints. However, they are not mutations by definition because they do not involve changes in DNA sequence (Hamilton, 2011).
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This chapter discusses the history of the development of the field of genetic toxicology, the use of genetic toxicology data in cancer and genetic risk assessments, the mechanisms underlying genetic toxicology assays, the assays that can be used for detecting genotoxic endpoints, the use of the same assays for better understanding mechanisms of mutagenesis, and new methods for the assessment of genetic alterations. The field is evolving rapidly, and a review of its past and present state will set the stage to allow for a consideration of what are likely next major landmarks.