PRINCIPLES OF TOXICOLOGY

250 MUTAGENESIS AND GENETIC TOXICOLOGY
formed, which may result in an alteration of some measurable cellular function. The phenotypic
changes that can be monitored by this type of test include auxotrophic changes (i.e., acquired
dependence on a formerly endogenously synthesized substance), altered proteins, color differences,
and lethality. It is extremely difficult to detect those alterations in mammalian DNA caused by insertions
or deletions of one or a few bases, except in rare instances where the specific protein product is known
and its formation can be monitored. It is somewhat easier in bacterial or prokaryotic systems, and this
has led to the use of bacterial or in vitro screening assays to detect potential mutagens. These issues
are discussed in greater detail in Brusick (1980, 1994).
Chromosomal aberrations, the third type of genetic change, may be present as chromatid gaps or
breaks, symmetrical exchange (exchange of corresponding segments between arms of a chromosome),
or asymmetric interchange between chromosomes. Point mutations can result in altered products of
gene expression, but chromosomal aberration or alteration in chromosome numbers passed on through
germ cells can have disastrous consequences, including embryonic death, teratogenesis, retarded
development, behavioral disorders, and infertility. Some naturally occurring abnormalities of human
chromosomal structure or number are shown in Table 12.2. The frequency of these events may be
increased by mutagenic agents. Because these genetic lesions may be visualized by microscopy, they
are referred to as macrolesions. One type of macrolesion is caused by an incomplete separation of
replicated chromosomes during cell division. This is characterized by the abnormal chromosome
numbers that result in the daughter cells and may be recognized as a change in the number of haploid
chromosome sets (ploidy changes) or in the gain or loss of single chromosomes (aneuploidy). A second
type of macrolesion caused by damage to chromosome structure (clastogenic effects) is categorized
by the abnormal chromosome morphology that results.
Two theories are currently available to explain the mechanism of chromosome aberration. One is
the classic “breakage-first” hypothesis. This theory assumes that the initial lesion is a break in the
chromosomal backbone that is indicative of a broken DNA strand. Several possibilities exist following
such an event: (1) the ends may repair normally and rejoin to form a normal chromosome; (2) the ends
TABLE 12.2 Examples of Human Genetic Disorders
Chromosome Abnormalities
Cri-du-chat syndrome (partial deletion of chromosome 5)
Down’s syndrome (triplication of chromosome 21)
Klinefelter’s syndrome (XXY sex chromosome constitution; 47 chromosomes)
Turner’s syndrome (X0 sex chromosome constitution; 45 chromosomes)
Dominant Mutations
Chondrodystrophy
Hepatic porphyria
Huntington’s chorea
Retinoblastoma
Recessive Mutations
Al binism
Cystic fibrosis
Diabetes mellitus
Fanconi’s syndrome
Hemophilia
Xeroderma pigmentosum
Complex Inherited Traits
Anencephal y
Club foot
Spina bifida
Other congenital defects