GENETIC TOXICOLOGY DEFINITION
Genetic toxicology is the study of genetic damage to the hereditary material that results in genetic alterations. Included in this broad definition are chemical and physical agents that cause mutagenicity, or transmissible genetic alterations, and genotoxicity. In contrast to mutagenicity, genotoxicity covers a broader spectrum of endpoints, including DNA damage such as DNA strand breaks and DNA adduct biomarkers (both pro-mutagenic and non-mutagenic), unscheduled DNA synthesis (UDS), and sister chromatid exchanges (SCEs); these are all measures of genotoxicity, as opposed to mutagenicity because they are not themselves transmissible from cell to cell or generation to generation. Genotoxicity also encompasses the mechanisms by which DNA damage occurs and the cellular responses to that damage. All of these 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. Standardized assay outcomes that detect mutations in populations of cells and/or organisms have been applied to systematic hazard classifications of chemicals under the United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Under GHS, the chemical hazards associated with germ cell mutagenicity are assigned to one of two hazard categories: (1) substances known to induce heritable mutations (subcategory 1A) or regarded as if they induce heritable mutations (subcategory 1B) in the germ cells of humans; and (2) substances which cause concern that they may induce heritable mutations in the germ cells of humans (UN, 2015).
It is worth mentioning that in the last decades, there has been an increased emphasis on the role of epigenetic changes that control gene expression through DNA methylation and histone modifications in the production of altered phenotypes (Watson and Goodman, 2002; LeBaron et al., 2010; Dearfield et al., 2017). Although these epigenetic changes can be transmitted between generations, these are also fluid and adaptive, are not mutations by definition as they do not involve changes in DNA sequence, and have not been observed to lead to amended point-of-departure values for risk assessment (Hamilton, 2011; Alyea et al., 2014).
In this chapter, we will discuss the history of the development of the field of genetic toxicology, the cellular pathways that counteract DNA damage on a daily basis, 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. This field of toxicology 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.
HISTORY OF GENETIC TOXICOLOGY
The field of genetic toxicology can be considered to have its roots ...