Genetic toxicology assesses the effects of chemical and physical agents on the hereditary material (DNA) and on the genetic processes of living cells.
Oncogenes are genes that stimulate the transformation of normal cells into cancer cells.
Genetic toxicology assays serve to identify mutagens for purposes of hazard identification, and to characterize dose–response relationships and mutagenic mechanisms.
A broad range of short-term assays for genetic toxicology serve to identify many mutagens and address the relationship between mutagens and cancer-causing agents.
Genetic toxicology is the study of genetic damage to the hereditary material that results in genetic alterations, including mutagenicity, transmissible genetic alterations, and genotoxicity. Genotoxicity covers a broad 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). Genotoxicity also encompasses the mechanisms by which DNA damage occurs and resulting cellular responses. This chapter describes 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 of the mechanisms of mutagenesis, and new methods for the assessment of genetic alterations.
HEALTH IMPACT OF GENETIC ALTERATIONS
Mutations are permanent, transmissible alterations in DNA sequences that result in changes to the amount or structure of genetic material in the cell. Both small (i.e., one or a few base-pair changes of a single gene) and large scale (i.e., changes affecting multiple genes) DNA alterations can lead to mutations. Mutagenicity refers to the induction of mutations; substances that induce mutations are known as mutagens. Clastogenicity refers to the process of inducing chromosomal breaks, and clastogens are substances that induce chromosomal breakage, such as chromosomal deletions and rearrangements. These events can lead to mutations provided they are not lethal to the cell harboring them. Substances that induce loss or gain of whole chromosome(s) are called aneugens, and aneugenicity arises through changes in the ploidy (i.e., aneuploidy) of the normal chromosome complement of the cell. The importance of mutations and chromosomal alterations for human health is evident from their roles in genetic disorders, including birth defects and cancer.
Somatic mutations arise in the genomes of all normal dividing and transformed cells as a result of endogenous and exogenous processes and stressors. An association between mutation and cancer has long been evident, and the average cancer genome contains about 103 to 104 point mutations, 10 to 102 small insertions or deletions, and 1 to 10 large-scale chromosome rearrangements (including copy-number alterations). The so-called “cancer genes” exhibit attributes that confer growth advantages such as the capacity to generate their own mitogenic signals, the evasion ...