Many different types ofchemical exposures can increase the incidence of tumors in animals and humans, but usually a long period of time is required before the carcinogenic risk of an exposure is manisfested. Both of these observations can be explained by a multistep/multigene model of carcinogenesis. In this model, a normal cell evolves into a cancer cell as the result of heritable changes in multiple, independent genes. The two-stage model of initiation and promotion for chemical carcinogenesis has provided a paradigm by which chemicals can act by qualitatively different mechanisms, but the process ofcarcinogenesis is now recognized as more complex than simply initiation and protion. Even a three-stage model of initiation, promotion, and progression, which can be operationally defined, is not adequate to describe the carcinogenic process. The number of genes altered in a cancer cell compared to a normal cell is not known; recent evidence suggests that3-10 genetic events are involvedin common adult magancesin humans.
Carcinogenesis Is a Multistep ProcessCancer remains a major chronic health problem associated with toxicological substances. The long latency period of cancer induction (years in rodents and decades in humans) is a major problem in the evaluation of toxicological hazards and risk assessment. We understand, at least in part, the underlying reasons for the time requirement of cancer formation. It is now clear that for a normal cell to evolve into a cancer cell, multiple heritable changes within the cell are required, i.e., carcinogenesis is a multistep process involving multiple genes. Several lines of evidence support the conclusion that chemical carcinogenesis is a multistep process. These are listed in Table 1 and discussed in detail elsewhere (1).One of the underlying premises of most multistep models of carcinogenesis is that genetic and/or epigenetic alterations of multiple, independent genes are involved. Although the process of chemical carcinogenesis is often separated operationally into three stages, i.e., initiation, promotion, and progression (2), the number of genetic changes involved in each of these operationally defined stages has not yet been determined.Initiation involves the induction ofan irreversibly altered cell and is frequently equated with a mutational event. aSee Barrett (12) for a more complete discussion and references.
This paper considers the opportunities for effective humanitarian collaboration in the Democratic People’s Republic of Korea (DPRK). It brings together perspectives from three individuals with extensive lived experience working in the DPRK. Collectively, these authors have worked in various sectors of international humanitarian aid and other areas of engagement such as emergency response and preparedness, education, social enterprise and tourism. The paper draws from these experiences to present lessons on overcoming obstacles and harnessing opportunities in the DPRK.
Carcinogenic agents can influence the carcinogenic process either by mutating critical target genes or by increasing the number of cells at risk for mutations. Cytogenetic and molecular studies of asbestos-related cancers indicate that inactivation or loss of multiple tumor suppressor genes occurs during lung cancer development. Aneuploidy and other chromosomal changes induced by asbestos fibers may be involved in genetic alterations in asbestos-related cancers. Furthermore, asbestos fibers may influence the carcinogenic process by inducing cell proliferation, free radicals, or other promotional mechanisms. Therefore, asbestos fibers may act at multiple stages of the carcinogenic process by both genetic and epigenetic mechanisms. Biopersistence is undoubtedly important in fiber carcinogenicity. However, the time required for a fiber to remain in the lung to exert a cancer-related effect is difficult to specify.
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