Mutations from Chemical Exposure

Mutagens are chemical species that alter DNA to produce traits that can be inherited. Mutation is a natnral process that occurs randomly, but from an environmental perspective, the mutations of concern are those cansed by xenobiotic substances in the environment. Because mutagens also often canse cancer and birth defects (see Section 2.14), they are of major toxicological concern. 

FIGURE 2.18 Examples of simple alkylating agents capable of causing mutations, including Al-methyl-Al-nitrosurea, commonly used as a model compound for alkylation studies Melphalan, a chemotherapeutic agent used to treat cancer dimethylnitrosamine and methyl methanesulfonate. 

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Germ-line mutations in a tumor suppressor gene, with neoplasia from chemical exposure... 

The initiated cell can remain in a static nondividing state (2) the initiated cell may acquire mutations incompatible with cell viability or normal function and thus the cell will be deleted through apoptotic mechanisms or (3) the cell, stimulated by intrinsic factors and/or from chemical exposure, may undergo cell division resulting... 

A. I Cette mutations are chan in the sequence of dei ribonucleic acid (ONA) within a gene. In veterinary titedicine, gene rrxjtations resulting from chemical exposures are rare. 

This chapter has emphasized the role of DNA mutations in the pathways leading to cancer. However, a number of chemicals are cancopromoting purely because of their ability to activate certain enzymes, where there exists no direct or indirect influence on DNA mutations. This functional class of compounds promotes or prevents cancer orJy when present on a chronic basis, i.e, at elevated levels every day for many years. The notion that bile salt metabolites may result in chronic stimulation of protein kinase C was discussed earlier. The related event of fiber decreasing exposure of the colon to bile salts was also outlined. The chronic exposure theory applies to the phorbol esters that are present in certain plants. People who drink tea made from the plant Croton flaveti tend to acquire esophageal cancer. This cancer results from chronic exposure to phorbol esters, which occurs in the leaf extract or in an oil prepared from the plant (croton oil). The phorbol esters enter the cell, bind to protein kinase C, and activate this enzyme. Activated protein kinase C, in turn, activates the MAP kinase cascade (Ueda et aL, 1996). The continual activation of protein kinase C, when combined with mutations in specific proto-oncogenes, may lead to cancer and sustain the cells in the cancerous state. 

Since the use of radioisotopes in nuclear power stations, in anti-cancer radiotherapy or in nuclearweapons, noxious effects of ionizing radiation on human cells are better known. According to the amount and distribution of exposure, ionizing radiation can locally eliminate tumors, but can also damage normal tissues. The biological effects of such radiation result from chemical processes as ionization or excitation of the biological macromolecules, such as DNA, either in a direct way or in an indirect way via water molecule radiolysis (Chapter 12). In both cases, many radical species appear then, which have various consequences on cellular scales such as mutations of DNA, cellular death, or cancer. 

Current data support a clonal origin of most cancers because most tumors arise from a single cell as a result of a spontaneous mutation or after exposure to an oncogenic virus or chemical carcinogen these tumors then expand to a detectable level while continually shedding viable cells. The ability to cure the cancer then depends on numerous variables, the most important being the presence of viable metastasis. The application of chemotherapy arose out of the appreciation that cancer is not commonly a localized process and is thus not amenable to control... 

Tobacco smoking, occupational exposure to certain chemical dyes, and inflammatory reactions to parasitic and other infections account for the majority of the bladder cancer cases in the world. The burden of DNA sequence alterations is expected to increase in cells exposed to mutagenic agents from these exposures, such as 4-aminobiphenyl and other aromatic amines derived from tobacco smoke and dye mixtures, or nitric oxide released during inflammatory responses. Forty to fifty percent of bladder tumors contain mutant p53 alleles, and in a number of cases two distinct, nonsilent point mutations have been found in the same tumor. 

Applying toxicity data How do toxicologists predict health risks to people Toxicity data might be available from studies of routine chemical exposure in the workplace, as well as from medical records of accidental chemical contact. Toxicity testing is often carried out using bacteria and cell cultures. Toxicologists observe the effect of chemical doses on bacteria. If mutations occur, the chemical is considered potentially harmful. 

The desire for quantitative data from cell culture mutation assay is explicit in the reporting of results that show the induced mutant fraction as a function of chemical exposure. For this quantitation to be valid, the mutation assay must be completely unbiased. 

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