Page 333 - Industrial Ventilation Design Guidebook

5.3 TQXiCiTY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS 289

Genetic Damage
A genetic injury often leads to the formation of inactive protein or inhibi-
tion of synthesis of a certain protein. There are endless possibilities for such
interactions between DNA and chemical compounds because each human cell
contains about 100 000 genes. Genetic damage leads to an inheritable injury
only when it occurs in a germ cell that is involved in fertilization and develop-
ment of a new organism. Genetic damage in a somatic cell may lead to a dele-
terious effect in an individual since it can ultimately lead to a toxic end result
such as cancer.
Most of the compounds that induce alterations in genetic material, i.e.,
mutagens, also induce cancer, i.e., they are also carcinogens. For this reason,
mutagenicity tests have been widely used to predict carcinogenicity. They are
also used for biological monitoring of exposed workers to identify early dam-
age to the genetic material in human cells. It has to be noted, however, that re-
cently mutagenic tests have been heavily criticized for a number of reasons,
and a positive result in a single mutagenic test can never be considered as a
clear indication of carcinogenicity or even mutagenicity. Instead, a combina-
tion of several mutagenicity tests all producing positive results is clearly a
129
cause for concern.
Genetic damage can take place at the level of the chromosome or at the
gene level. In addition, chemicals can also induce alterations in the number of
chromosomes in the cells. Aneuploidy is an excess or a shortage of a single
chromosome. Polyploidia is an excess of a whole set of chromosomes in the
cell.
Chromosomal aberrations represent damage to the chromosomal struc-
ture that can be detected microscopically. The most frequent chromosomal ab-
errations are deletion (lack of a chromosome or its part), duplication (part of
a chromosome has been duplicated), inversion (parts of a chromosome have
changed place within that particular chromosome), and translocation (parts of
chromosomes have changed their position between two chromosomes). Many
of these chromosomal changes are transferred to sister cells when the cell di-
vides, and become, therefore, stable chromosomal aberrations. Cytostatic
drugs and cigarette smoke are examples of chemical exposures known to in-
duce chromosomal aberrations. Chromosomal aberrations themselves do not,
however, give any clue of the causative agents for the changes. 129
Genotoxic compounds can induce a number of different mutations. A
gene or a part of a gene can be missing (deletion), additional genetic material
may become added to a gene (insertion), a gene may be amplified (amplifica-
tion), or a genetic change may concern only one nucleotide, a basic structural
unit of nucleic acid. The latter change causes deletion of one single arnino
acid in a protein encoded by the gene, and may lead to inactivation of a pro-
tein. The result is a frame-shift mutation if a number of nucleotides (usually
one or two) upset the regular arrangement of the three nucleotide-code. This
kind of change alters the amino acids throughout the protein because each
amino acid has its own code consisting of three nucleotides. A number of
chemical compounds bind to DNA, and may cause point mutations. Ionizing
radiation-induced DNA damage typically causes deletions. Table 5.12 lists the
principal assays used in genetic toxicology. 130