Info

*Chinese.

{The U.S. data are taken from the Connecticut Tumor Registry because it is the oldest continued cancer registry based on a defined population in this country.

{Maori.

**African Americans. (From Doll145)

*Chinese.

{The U.S. data are taken from the Connecticut Tumor Registry because it is the oldest continued cancer registry based on a defined population in this country.

{Maori.

**African Americans. (From Doll145)

to mutagens occurs from chemicals in our diet, water, and air, from products that we use as cosmetics and drugs, and from cigarette smoking. As noted before, several mutagenic substances have been identified in cigarette smoke. Mutagens are also found among the natural products contained in foods such as products elaborated by molds (e.g., aflatoxin) or by edible plants that synthesize a variety of toxins, presumably to ward off insects, as well as among synthetic chemicals such as pesticides, industrial pollutants, and weed killers.146 In short, we live in a sea of mutagens and carcinogens. Identification of potentially mutagenic substances in our environment is a major public health and political issue. Of the myriad of potential mutagens and carcinogens in our diet, only a few have been studied in detail. In addition, more than 65,000 synthetic chemicals are produced in the United States, and about 1000 new chemicals are introduced each year.147 Only a small number of these were examined for mutagenic and carcinogenic potential before being marketed. Obviously, this is a major epidemiologic problem and one that has a major economic impact on private industry as well as on the consumer and taxpayer. What is needed are accurate, rapid, and economically feasible tests to predict the mutagenic and carcinogenic potential of the numerous chemicals in our environment. In practice, however, it has not been possible to develop a "perfect" short-term test. A number of false positives and false negatives result from using these tests.

More than 100 short-term tests for mutage-nicity and carcinogenicity have been developed. Some of the most widely used are bacterial mutagenesis (the Ames test), mutagenesis in cell culture systems, direct measurement of damage to DNA or chromosomes in exposed cells, and malignant transformation of cell cultures.148 One of the most popular of the short-term tests is the Ames test, developed by Bruce Ames and colleagues.147 The basis of this assay is the ability of a chemical agent to induce a genetic reversion of a series of Salmonella typhimurium tester strains, which contain either a base substitution or a frameshift mutation, from histidine requiring (his-) to histidine nonrequiring (his+). These strains have been specially developed for this assay by selecting clones that have a decreased cell surface barrier to uptake of chemicals and a decreased excision repair system. Other advantages of this system are the small genome of the bacteria (4 x 106 base pairs), the large number of cells that can be exposed per culture dish (about 109), and the positive selection of the mutated organisms (i.e., only the mutated organisms will grow under the test conditions). This system has great sensitivity: only about 1 in 1000 to 1 in 10,000 of the mutated bacteria need to be detected to give a positive test, and nanogram amounts of a potent mutagen can be detected as a positive. Both base substitution and frameshift mutagens can be detected, and, using the appropriate tester strains, the type of mutagen can be deduced because frameshift mutagens usually revert only frameshift mutations of the tester strains and not base substitution mutations, and vice versa. Because many mutagens must be metabolized to be active, aliver homogenate fraction containing microsomes is usually added to the incubation to provide the drug metabolizing enzymes.

The potential of various chemical agents to mutagenize mammalian cells has also been used as a short-term test. Frequently, mutation at the hypoxanthine-guanine phosphoribosyltransfer-

ase (HGPRT) locus is used as a marker; the end point of the assay is loss of sensitivity to purine antimetabolites that must be activated by HGPRT to be effective, thus leading to the selection of HGPRT- clones. Cultured fibroblast cell lines such as Chinese hamster V79 or ovary (CHO) cells are frequently used in this way.

Agents that damage DNA can often be detected by examining an index of genotoxicity, such as unscheduled DNA synthesis, sister chromatid exchange, or chromosome breakage in cultured cells exposed to the agents in question.

Carcinogenic potential has also been estimated by the ability of chemicals to "transform" smooth, well-organized monolayers of normal diploid fibroblasts into cells that grow piled up on one another (transformed foci) or into a cell type that can grow suspended in soft agar (normal fibroblasts do not usually grow on soft agar). Sometimes the putative malignant cells are then injected into immunosuppressed or immunode-ficient ("nude") mice to further demonstrate that they are malignant. All of these estimates of carcinogenic potential are fraught with danger in that a significant number of false negatives or false positives can occur.

No single short-term test is foolproof; however, if definitive evidence of genotoxicity has been obtained in more than one test, a chemical is highly suspect. An agent found to be mutagenic, DNA damaging, and a chromosome breaker is almost certain to also be carcinogenic.148 Final proof of mutagenicity and carcinogenicity involves the chronic exposure of whole animals to the test chemical. Although the short-term in vitro tests have several advantages, a number of important components, such as absorption, pharmacokinetics, tissue distribution, metabolism, age or sex effects, and species specificity, cannot be duplicated in vitro. Tests in whole animals take a long time and, unfortunately, are very expensive.

One key question remains: how does one estimate the danger of low-dose exposures? More importantly, how does one estimate the risk of low-dose exposure over a lifetime? These are extremely difficult questions to answer, but in practical terms, as long as an individual's DNA-repair enzymes are working (see Chapter 2), there probably is some low level of exposure below which DNA lesions can be removed efficiently without permanent damage. The low level of mutation in human genes seems to argue in support of this conclusion.149 If one could, in fact, measure the amount of DNA-adduct formation (i.e., the amount of DNA bases bound to carcinogen) after exposure to various doses of carcinogen, one could probably get a much better estimate of the risks involved in exposure to various amounts of carcinogenic agents.150 A shift in the dose-response curve with low doses of carcinogen could occur for several reasons, all of which make linear extrapolations of dose-response data from animal studies tenuous. Some of these reasons relate to differences in metabolism, distribution, and overall pharmacokinetics among species.

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