PRINCIPLES OF TOXICOLOGY

262 MUTAGENESIS AND GENETIC TOXICOLOGY
and Carcinogens (ICPEMC), the World Health Organization, and the Commission for European
Communities. In the past, most estimates of genotoxic risks were more qualitative than quantitative,
and the emphasis has rested on somatic effects (e.g., those leading to cancers) rather than on germinal
cells (sperm and ovum). On the basis of evidence in animals demonstrating germinal cell effects, it
is imperative to develop human screening methods capable of detecting such effects. Therein
lies one of the premier challenges to genetic toxicology and occupational medicine.
The uncertainties of accurate extrapolation of mutagenicity test data to a human hazard model have
supported the philosophy that if uncertainty is to occur in extrapolation it should favor the side of
safety. This concept is particularly important in the consideration of whether or not threshold
characteristics may exist. In the case of carcinogens, discussed further in the next chapter, good
evidence supports the view that genotoxic (DNA-damaging) carcinogens may be distinct from
epigenetic carcinogens (those that induce or potentiate cancer by means other than direct DNA
interaction). For the purposes of this discussion, mutagens are assumed to exert nonthreshold effects.
That is, even as one approaches zero dose, there is still a calculable risk of DNA effects.
The concern for the potential mutagenic hazards in the workplace from exposure to chemicals
should include routine tests of nonpregnant females and males, as well as the more traditional
monitoring of pregnant and lactating women. For example, vinyl chloride, mentioned earlier in relation
to its suggested role in angiosarcoma of the liver, has been correlated with an increased incidence of
nervous system malformations in infants fathered by exposed workers. It has also been demonstrated
to cause elevations in chromosomal aberration in the occupationally exposed. 1,2-dibromo-3-chloropropane
(DBCP), a pesticide linked to sterility in exposed male workers, causes increases in indices
of mutagenic capacity in humans and animals.
Monitoring of male populations may prove particularly important in that the spermatogenic
cycle is continuous in adults and therefore poses continuous opportunities for genetic damage to
be expressed as damaged chromosomes. Since the female carries the full lifetime complement of
ova at birth, susceptibility to propagation of genetic alteration during cell division is reduced
except in those periods of division following conception. By the same token, the cessation of
exposure in the male should allow for recovery from a mutagenic event in premeiotic spermatocytes,
providing that spermatogonia are not affected. If chromosome damage occurs in sperm or
ovum, then fetal death frequently occurs. Greater than 50 percent of spontaneous abortions in
humans show chromosomal defects.
Once mutagenic potential is established for a compound, the risks posed by exposure under
expected conditions must be assessed. As discussed, complications may be encountered in situations
where mutagenic effects are due to “multihit” phenomena and therefore reflect threshold-type
responses. A more complete discussion on risk assessment is presented in Chapter 18.
12.6 SUMMARY
Modification of genetic material by mutagenic agents poses a serious environmental and occupational
threat. Chemical or physical mutagens may induce cancer or lead to germ cell alteration.
• The mutagens that lead to cancer alter the DNA of somatic cells so as to cause modifications
in gene expression, which results in tumorigenesis.
• Germ cell (sperm, ovum) mutagens may exert their effects through decreased fertility, birth
defects, spontaneous abortion, or through changes that may not become evident for several
subsequent generations (such hidden mutagenic effects remain essentially undetectable
except when expressed as a gross malformation).
Many screening tests have been developed to investigate the mutagenic potential of chemical agents.
• These assays use bacteria, insects, mammals, and various cells in culture.