PRINCIPLES OF TOXICOLOGY

(in humans) of chromatids are thus separated, forming pairs of daughter chromosomes that are pulled
toward one mitotic spindle or the other. In telophase, the mitotic spindle grows longer, completing the
separation of daughter chromosomes. A new nuclear membrane is formed, and shortly thereafter the
cell constricts at the midpoint between the two nuclei, forming two new cells.
Meiosis is the term for the process by which immature germ cells produce gametes (sperm or ova)
that are haploid. During meiosis, DNA is replicated, producing 46 chromosomes with sister chromatids.
The 46 chromosomes arrange into 23 pairs at the center of the nucleus, and in the first division
the pairs separate. In a second division, the sister chromatids separate, with one chromosome of each
pair being incorporated into four gametes. At the time of fertilization, or zygote formation, the fusion
of gametes once again forms a cell with a full complement of 46 chromosomes.
Genetic Alteration
12.2 GENETIC FUNDAMENTALS AND EVALUATION OF GENETIC CHANGE 245
Tests for genotoxicity in higher organisms may be placed into one of three basic categories: gene
mutation tests, chromosomal aberration tests, and DNA damage tests. These tests are conducted
individually or in combination to identify various types of mutagenic events (Figure 12.3) or other
genotoxic effects. For the purpose of this discussion, the principles of each test category will be
reviewed and specific tests will be discussed by broad phylogenetic classifications. Over 200 individual
test methods have been developed to assess the extent and magnitude of genetic alteration; however,
less than 20 have been validated or are in common use. Numerous mutagenic agents have the
demonstrated capacity to cause genetic change in one or more of these test systems, but no well-documented
cases of human mutation are available. This latter conclusion may change as a result of
improvements in the ability to detect human genetic change. Nevertheless, as discussed in this section,
use of a reasonable battery of tests is capable of identifying almost all of the known human carcinogens,
consistent with the hypothesis that somatic cell mutations are, at least in part, responsible for a large
proportion of human cancers.
A transmissible change in the linear sequence of DNA can result from any one of three basic events:
• Infidelity in DNA replication
• Point mutation
• Chromosomal aberration
Figure 12.3 Types of mutagenic changes (Adapted from Brusick, 1980).