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The introduction to discrete irreversible processes in Chapter 13 noted that there are two important examples of groups of diseases that follow this pattern: immune sensitization and carcinogenesis. Unfortunately, much less is known about the intermediate steps in sensitization, and few examples of biologically based models have been applied to studies of immune diseases in humans, as was noted. This chapter discusses carcinogenesis, which has been more extensively studied.

Malignant cells differ from normal tissues in a number of fundamental properties. The malignancy in cells is a result of the changes in the genetic make-up of the cells. Changes in the sequences of the DNA due to amplification of protein production are associated with the development and maintenance of malignant growth. Furthermore, changes in cell regulation and tissue growth also lead to malignancy. This chapter focuses on the biological issues of cancer to equip readers with a comprehensive background on the processes by which a malignant growth can cause symptoms from both the local and metastatic sides and by which malignancy can cause death. Discussions in it include the aetiology of cancer, the different stages of carcinogenesis, the high incidence of cancer due to genetic factors and gene abnormality, and the history and progression of malignant disease.

Mathematical models of cancer evolution can provide helpful insights. This chapter describes a way to model cancer in which carcinogenesis is a microevolutionary process inside an organ. It uses both stochastic methods and methods of evolutionary population dynamics and focuses on two particular problems: (a) the role of genetic instability in cancer initiation and progression; and (b) the problem of resistance in cancer treatment with small molecule inhibitors. The dynamics are generated by cell reproduction and mutation, and by the selection pressures that act on the different cell variants. These dynamics can be captured in equations which yield insights into the outcome of these complex processes that would otherwise not be possible. The general message of this review is that population dynamics and evolutionary thinking can provide a new dimension to cancer research, which complements the molecular and cell-focused approach that is primarily used.

This chapter discusses the link between therapeutic drugs and cancer. Topics covered include chemical carcinogenesis, drug safety, pharmacoepidemiologic studies, methodologic issues in studies of drugs and cancer, methodologic issues in studies of drugs and cancer, and magnitude of the problem of carcinogenesis due to drugs.

Clarifying the complex etiologic role of environmental and genetic factors in carcinogenesis will be challenging but necessary to understand fully the causes of cancer and how it can be prevented. The decoding of the human genome sequence, and the availability of information on the common genetic variation in populations has led to the conduct of genome-wide association studies (GWAS), that have identified loci for dozens of new cancer susceptibility genes. Observational epidemiology studies (case-control and cohort studies) have become the main design used for the association of low penetrance alleles with cancer risk. Studies that identify genetic markers of risk may identify new biological mechanisms and aid in personal assessment of cancer risk. Such studies may also potentially provide clues for cancer therapy, and facilitate early detection and screening efforts in genetically susceptible subgroups of the population.

Mercury is an element with unique physical and chemical properties whose deleterious effects on various organ systems have been known for centuries. The metal (Hg°) mercury is the only element liquid at ambient temperatures and has an extremely high vapor pressure. Natural degassing of the earth’s crust by volcanoes and emissions from soils and waters are estimated to contribute on the order of 2700 to 30,000 tons per year (Nriagu 1989, Lindqvist 1991). A second source of mercury is anthropogenic from burning of coal or petroleum. The total input into the atmosphere may be up to 150,000 tons per year, with natural emissions accounting for the major input (Berlin 1986). However, estimations of contributions from different sources vary. Aristotle wrote about mercury as liquid silver (hydrargyrum) with the metallic mercury extracted in ancient times, as today, from the sulphide mineral cinnabar (HgS). Although technical developments have brought about more sophisticated methods of distilling mercury, all processes create mercury vapor, which is a potential hazard. Mercury mines pose environmental concern, due to mine tailings and waste rock contributing mercury-enriched sediment to watersheds (Rytuba 2000) such as in the California Coast Ranges (Rytuba 2000), the Idria mine in Slovenia (Hines et al. 2000), in Slovakia (Svoboda et al. 2000), and, perhaps most conspicuously, the mine tailings in Aznacollar, Spain, that caused a recent accident (Grimalt et al. 1999). Any industrial sites that utilize mercury during production may also produce contamination of the environment (Sunderland and Chmura 2000). The possible sources of mercury exposure are presented in Table 10.1. Amalgamation with mercury has been used as a method for beneficiation of gold and silver since Roman times. The total global release of mercury into the environment from these activities before 1930 was estimated as over 260,000 tons. Thereafter, with the introduction of cyanidation processing technology, the emissions declined (Lacerda and Solomons 1998). However, small-scale artisanal gold mining continues and is a serious hazard to largely unskilled persons in rural areas over the world.

Chapter 10 explains how molecular approaches to cancer survived a period of political and cultural disillusionment in the late 1970s. Environmental and social approaches to the cancer problem reemerged in national policy discussions. The revival of molecular approaches by the mid-1980s depended not on the demonstrated therapeutic returns of the “oncogene paradigm” but on the promise of breakthroughs at an accelerating pace in oncogene and oncoprotein research. This sense of potential depended on recycling the infrastructure of virus studies built during the War on Cancer by figures such as Robert Weinberg while administrators such as Vincent DeVita recast the history of virus studies to create a new alignment between the biomedical research emphasis of the National Cancer Institute and the disciplinary interests of molecular biology.

Hormones are highly biologically active endogenous compounds that control the growth, development, physiology, and homeostasis of numerous organ systems. Because of this, they have long been thought likely to play key roles in both normal and abnormal (malignant) growth. They are also noteworthy for being produced away from the tissues that they control, and are thus secreted into circulating blood to reach their target organs. This combination of potent, targeted agents of growth and development that can be measured in available biologic fluids has made steroidal and peptide hormonesparticularly susceptible and relevant to epidemiologic investigation. In addition, medications containing hormones and hormone antagonists have come into widespread use, providing further opportunities for epidemiologic insights into hormonal carcinogenesis. The development of increasingly more accurate assays to measure sex hormones and their metabolites has resulted in major advances in understanding the hormonal etiology of breast and gynecologic malignancies.