PRINCIPLES OF TOXICOLOGY

12 Mutagenesis and Genetic Toxicology
MUTAGENESIS AND GENETIC TOXICOLOGY
CHRISTOPHER M. TEAF and PAUL J. MIDDENDORF
Genetic toxicology combines the study of physically or chemically induced changes in the hereditary
material (deoxyribonucleic acid or DNA) with the prediction and the prevention of potential adverse
effects. Modification of the human genetic material by chemical agents or physical agents (e.g.,
radiation) represents one of the most serious potential consequences of exposure to toxicants in the
environment or the workplace. Nevertheless, despite increasing research interest in this area, the
number of agents or processes that are known to cause such changes is quite limited. This chapter
presents information regarding the following areas:
• Types and characteristics of genetic alteration
• Common research methods for the assessment of genetic change
• Practical significance of test results from animal and human studies in the identification of
potential mutagens
• Theoretical relationships between mutagenesis and carcinogenesis
12.1 INDUCTION AND POTENTIAL CONSEQUENCES OF GENETIC CHANGE
Historical Perspective
The term mutation is defined as a transmissible change in the genetic material of an organism. This
actual heritable change in the genetic constitution of a cell or an individual is referred to as a genotypic
change because the genetic material has been altered. While all mutational changes result in alteration
of the genetic material in the parent cells, not all are immediately expressed in cell progeny as
functional, or phenotypic, changes. Thus, it is possible to have genetic change that is not associated
with a transmissible change. These distinctions are discussed in greater detail in subsequent sections.
Potential environmental and occupational mutagens may be classified as physical, biological, or
chemical agents. Ames and many subsequent researchers have identified representative chemical
mutagens in at least 10 classes of compounds, including the following: cyclic aromatics, ethers,
halogenated aliphatics, nitrosamines, selected pesticides, phthalate esters, selected phenols, selected
polychlorinated biphenyls, and selected polycyclic aromatics (PAHs). Despite nearly 50 years of
research concerning chemical-induced genetic change, ionizing radiation still represents the best
described example of a dose-dependent mutagen and was first demonstrated in the 1920s. Chemical
mutagenesis was first demonstrated in the 1940s, and many of the characteristics of radiation-induced
mutation are believed to be common to chemically induced mutation. This is particularly true for
molecules known as free radicals, which are formed in radiation events and some chemical toxic events.
Radicals contain unpaired electrons, are strongly electrophilic, and extraordinarily reactive, features
that are well correlated with both mutagenic and carcinogenic potency. Such reactive molecules
Principles of Toxicology: Environmental and Industrial Applications, Second Edition, Edited by Phillip L. Williams,
Robert C. James, and Stephen M. Roberts.
ISBN 0-471-29321-0 © 2000 John Wiley & Sons, Inc.
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