PRINCIPLES OF TOXICOLOGY

240 MUTAGENESIS AND GENETIC TOXICOLOGY
probably are responsible for at least some of the alterations of nucleic acid sequences that are observed
in genotoxic processes.
Over 3500 functional disorders or disease states have been linked to heritable changes in humans,
and the ambient incidence of genetic disease may be as great as 10 percent in newborns. In the case
of some cancers, a change in the genotype of a cell results in a change in phenotype that is grossly
defined by rapid cellular division and a reversion of the cell to a less specialized type (dedifferentiation).
The subsequent generations eventually may form a growing tumor mass within the affected tissue.
This simplified sequence has been termed the somatic cell mutation theory of cancer. While not all
chemically-induced cancers can be explained by this hypothesis, general applicability of the somatic
cell mutation theory is supported by the following points:
• Most demonstrated chemical mutagens are demonstrably carcinogenic in animal studies
• Carcinogen-DNA complexes (adducts) often can be isolated from carcinogen-treated cells
• Heritable defects in DNA-repair capability, such as in the sunlight-induced disease
xeroderma pigmentosum, predispose affected individuals to cancer
• Tumor cells can be “initiated” by carcinogens but may remain in a dormant state for many
cell generations, an observation consistent with permanent DNA structural changes
• Cancer cells generally display chromosomal abnormalities
• Cancers display altered gene expression (i.e., a phenotypic change)
The issue of correlation between genotoxicity or mutagenicity assays and cancer is discussed in greater
detail in subsequent sections of this chapter.
Although genetic changes in somatic cells are of concern because consequences such as cancer
may be debilitating or lethal, mutational changes in germ cells (sperm or ovum) may have even more
serious consequences because of the potential for effects on subsequent human generations. If a lethal
and dominant mutation occurs in a germinal cell, the result is a nonviable offspring, and the change is
not transmissible. On the other hand, a dominant but viable mutation can be transmitted to the next
generation, and it need only be present in single form (heterozygous) to be expressed in the phenotype
of the individual. If the phenotypic change confers evolutionary disadvantage to the individual (e.g.,
renders it less fit), it is unlikely to become established in the gene pool. In contrast, individuals that
are heterozygous for recessive genes represent unaffected carriers that are essentially impossible to
detect in a population. Thus, recessive mutations are of the greatest potential concern. These mutations
may cause effects ranging from minor to lethal whenever two heterozygous carriers produce an
offspring that is homozygous for the recessive trait (i.e., the genes are present in both copies). Figure
12.1 describes the potential consequences of mutagenic events.
Occupational Mutagens, Spontaneous Mutations, and Naturally Occurring Mutagens
In considering the potential adverse effects of chemicals, it is important to recognize that both physical
and chemical mutagens occur naturally in the environment. Radiation is an ubiquitous feature of our
lives, sunlight representing the most obvious example.
Incomplete combustion produces mutagens such as benzo[a]pyrene, and some mutagens occur
naturally in the diet, or may be formed during normal cooking or food processing (e.g., nitrosamines).
In addition, drinking water and swimming-pool water have been shown to contain potential mutagens
that are formed during chlorination procedures. Thus, the genetic events that influence the human
evolutionary process appropriately may be viewed as a combination of normal background incidence
of spontaneous mutations that may be occurring during cellular division, coupled with the exposure
to naturally occurring chemical or physical mutagens.
Mutagenic chemicals in the workplace, or those that are introduced into the environment via
industrial operations, represent a potential contribution to the genetic burden, though the practical
significance of this contribution is not known with precision. It is estimated that over 70,000 synthetic