PRINCIPLES OF TOXICOLOGY - Biology East Borneo

262 MUTAGENESIS AND GENETIC TOXICOLOGYand Carcinogens (ICPEMC), the World Health Organization, and the Commission for EuropeanCommunities. 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 germinalcells (sperm and ovum). On the basis of evidence in animals demonstrating germinal cell effects, itis imperative to develop human screening methods capable of detecting such effects. Thereinlies 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 havesupported the philosophy that if uncertainty is to occur in extrapolation it should favor the side ofsafety. This concept is particularly important in the consideration of whether or not thresholdcharacteristics may exist. In the case of carcinogens, discussed further in the next chapter, goodevidence supports the view that genotoxic (DNA-damaging) carcinogens may be distinct fromepigenetic carcinogens (those that induce or potentiate cancer by means other than direct DNAinteraction). 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 chemicalsshould include routine tests of nonpregnant females and males, as well as the more traditionalmonitoring of pregnant and lactating women. For example, vinyl chloride, mentioned earlier in relationto its suggested role in angiosarcoma of the liver, has been correlated with an increased incidence ofnervous system malformations in infants fathered by exposed workers. It has also been demonstratedto 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 indicesof mutagenic capacity in humans and animals.Monitoring of male populations may prove particularly important in that the spermatogeniccycle is continuous in adults and therefore poses continuous opportunities for genetic damage tobe expressed as damaged chromosomes. Since the female carries the full lifetime complement ofova at birth, susceptibility to propagation of genetic alteration during cell division is reducedexcept in those periods of division following conception. By the same token, the cessation ofexposure 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 orovum, then fetal death frequently occurs. Greater than 50 percent of spontaneous abortions inhumans show chromosomal defects.Once mutagenic potential is established for a compound, the risks posed by exposure underexpected conditions must be assessed. As discussed, complications may be encountered in situationswhere mutagenic effects are due to “multihit” phenomena and therefore reflect threshold-typeresponses. A more complete discussion on risk assessment is presented in Chapter 18.12.6 SUMMARYModification of genetic material by mutagenic agents poses a serious environmental and occupationalthreat. 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 modificationsin gene expression, which results in tumorigenesis.• Germ cell (sperm, ovum) mutagens may exert their effects through decreased fertility, birthdefects, spontaneous abortion, or through changes that may not become evident for severalsubsequent generations (such hidden mutagenic effects remain essentially undetectableexcept 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.