Generic Trigger Sm 50 Exhaust

[Juanjo Pollreisz]

Researchersare now confronting the difficulties of understanding the etiology and pathogenesis of multifactorial, multistep disease processes, and they are just beginning to recognize general principles that may operate in most typical cases of cancer. There is awareness of the relationship between the dose of carcinogens and the resulting tumor response, and recognition of the importance of the metabolism of a carcinogen into reactive intermediates that may cause damage. Cellular mechanisms such as DNA replication may provide opportunities for carcinogens to transform genetic information, and targets in DNA may include specific genes or sites at which chromosomes are prone to breakage. Enhancing factors, such as promoters, may increase the likelihood of cancer development. Variations in human susceptibility to cancer make evaluation of the activity of specific carcinogens difficult, although it is clear that certain human tissues or certain individuals are more susceptible to cancer than others. Certain familial tendencies or acquired illnesses are also thought to predispose people to cancer.

In this chapter, the evidence on the carcinogenicity of diesel engine exhausts and the methods used to make quantitative risk estimates from these data are evaluated. Specific evidence concerning carcinogenesis of diesel exhaust in experimental systems is reviewed, and relationships between this information and reviews in other chapters are identified. Current knowledge as well as areas of ignorance influence efforts to estimate human risks by extrapolation from the experimental data on animals. A discussion of these issues serves as an outline for making such estimates in the future.

Chemical carcinogenesis is a very complex topic. Thus, this review is selective in its consideration of carcinogenesis, focusing on several general concepts rather than on specific details. The constructive role of studying cancer development in animal models is considered, and certain aspects of the general principles operating in most typical cases of carcinogenesis are examined. The review also touches on unusual cases that appear not to fit the typical pattern of cancer development. It considers the evidence for and the problems associated with evaluating a disease that develops as the result of a multistep process. Finally, the factors that define individual variations in susceptibility are discussed, and features of carcinogen metabolism and translocation are reviewed.

Experimental animal models have been employed to reproduce tumors of the histologic types and organs of origin that commonly occur in humans. Such models permit direct experimental study of factors that influence the development of the most common cancers in humans and the mechanisms of action of particular carcinogens. Examples of valuable animal models and their applications are listed in table 1. Some unique insights have been derived from comparisons of the properties of animal tissues in which the tumor response is a good model for the human disease, to tissues of other species in which the response is very different from that of humans.

Studies of particular tissues have been facilitated by using organ cultures (Saffiotti and Harris 1979). In this technique, pieces of intact tissue representative of the sampled organ are grown in culture. Many features of the tissue that exist in vivo, including the interrelationship between the epithelial components and the supportive cells, are preserved. Such cultures can be used to assess morphological features, macromolecular synthesis, and responses to hormones as well as capacity to metabolize carcinogens and to repair DNA damage. Use of organ cultures has been a principal approach used for analysis of properties related to carcinogenesis in human tissues.

Although direct experimentation with the objective of inducing carcinogenesis is clearly unethical in humans, a broader, deeper information base is needed on the properties of human cells and tissues that relate to carcinogenesis. This goal has been approached by undertaking culture studies of human cells and tissues obtained at immediate autopsies or from surgical specimens (Harris and Trump 1983).

Studying the properties of human tissues in vitro allows examination of the human diversity in cancer development. For example, in vitro techniques can be used to explore the individual variability in metabolizing carcinogens, repairing DNA damage, responding to various hormones, and perhaps even to determine the degree to which various nutrients serve as cofactors in carcinogenesis.

Although in vitro carcinogenesis with human cells in culture is rather new, transformation of normal cells to neoplastic ones has been accomplished with a number of cell types. Results from such studies permit the direct comparison of the stages in the presumed multistep process of carcinogenesis in humans and in animals. For example, the apparently greater difficulty in transforming human cells than animal cells may parallel the comparative susceptibility to cancer of these various species. If the determinants of the various stages in carcinogenesis are successfully characterized in human cells, it may be possible to develop improved methods for early detection of preneoplastic or early neoplastic lesions.

Some human tissues have been maintained as viable xenotransplants in nude mice (Valerio et al. 1981). Such models are an ethically acceptable method for in vivo study of the process of carcinogenesis in human tissue (Shimosato et al. 1980). This model may provide for direct comparisons of features of carcinogenesis between humans and experimental animals that are commonly used in bioassays. Such information would clearly be valuable in determining the risks to humans of agents demonstrated as carcinogenic in animal bioassays.

It is a well-recognized clinical observation that cancer typically occurs in tissues that have a high rate of cell proliferation or in tissues in which cell proliferation occurs in response to injury. Conversely, cancer is extremely rare in adult tissues or cell types in which cell proliferation does not occur. It was the opinion of classical pathologists that chronic irritation or injury was the etiologic factor for the development of cancer. Subsequently, a variety of specific carcinogenic etiologic agents have been recognized. Nonetheless, cell proliferation plays a significant role in the evolution of cancers (Grisham et al. 1983). This is well illustrated in the case of liver cancers induced in rats by chemical carcinogens. Typical liver carcinogens at effective doses are also hepatotoxic, and they induce restorative hyperplasia to replace cells lost as the result of the toxicity.

The influence of cell proliferation as a contributing factor in the development of cancer presumably results from effects on the mitotic process and on DNA synthesis. Replicating DNA is vulnerable for a variety of reasons. First, replicating DNA is affected to a greater extent by chemical carcinogens than is nonreplicating DNA (Cordeiro-Stone et al. 1982). Second, replication of DNA that contains carcinogen adducts may cause incorporation of incorrect nucleotides at sites of altered or excised bases. Third, some carcinogens may modify nucleotide precursors, and altered precursors may be incorporated into DNA. Fourth, DNA replication itself occurs with a low, but nonzero, error rate. Situations that increase cell replication are likely to cause mutations strictly as the result of these errors.

Mammalian cells have a number of mechanisms to repair DNA damage and to reduce the likelihood of errors during DNA replication. Treatments of cells or animals with chemical carcinogens or radiation cause the onset of DNA repair processes. In studies in which cell proliferation has been inhibited and DNA repair has been allowed to remove some or most carcinogen-induced DNA adducts, the transforming effects of the carcinogen damage have been reduced (Ikenaga and Kakunaga 1977). In contrast, in patients with defective DNA repair processes, such as the genetically determined syndrome known as xeroderma pigmentosum, increased incidences of tumors have been observed (Setlow 1978; Hanawalt and Sarasin 1986). Thus, DNA repair processes appear to be protective against tumor development, whereas defects of DNA repair appear to be associated with increased risks of cancer.

There appears to be a critical interrelationship between the repair and replication of DNA as factors in the etiology of cancer (Kakunaga 1975). If DNA replication proceeds within a damaged region prior to repair, there is a substantial risk of error-making during replication, which may cause a mutation to occur as the result of alteration of the base sequence of the complementary DNA strand. Of course, this does not occur if the repair of the damage precedes replication. Consequently, the relationship in time of the repair and replication of DNA may be a major determinant of the potential for the occurrence of mutations and also, presumably, of carcinogenesis.

Chemical carcinogens have been shown to produce a variety of types of DNA damage that can lead to genetic effects on cells (table 2) (Sarma et al. 1975; Drake and Baltz 1976; Singer and Grunberger 1983). Point mutations and frameshift mutations can alter the regulatory or coding regions of genes. On a larger scale, carcinogens can directly affect chromatids and chromosomes (Evans 1983). By still unknown mechanisms, carcinogen damage can cause the exchange of DNA segments between sister chromatids, and chromosomal breakage that leads to large deletions or transposition of chromosomal segments to other chromosomes. Presumably, such damage may lead to failures of mitotic division with unequal distribution of chromosomes between daughter cells, resulting in abnormal DNA content. DNA damage is also thought to be one mechanism for the amplification of segments of DNA.

Fragile sites are locations in chromosomes that are particularly prone to breakage. When cell growth conditions are altered, such as through deprivation of thymidine and folic acid, chromosomes have been found to break consistently at the same sites. These sites are closely related to sites where chromosomal rearrangements occur in human cancers (Yunis and Soreng 1984), suggesting that structural peculiarities that make these sites prone to breakage may be important factors in the development of cancers. Another notable point is the chromosomal location of these fragile sites relative to several of the known protooncogenes. Although the power of the scientific methods used to compare the locations of these sites is not great, the apparent statistical relationship within the experimental error of the methods suggests that some very important feature of cancer development is related to the structure of DNA at these sites.

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