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4.1 INTRODUCTION AND HISTORICAL PERSPECTIVE

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Although many factors contribute to cancer causation, this chapter focuses on providing an overview of the mechanisms by which exogenous chemicals may influence the risk of cancer initiation and tumor growth, and how knowledge of these mechanisms might be exploited to improve human health through prevention or intervention. The reader is directed to the bibliography for a list of critical reviews that summarize the past history, current status, and future prospects for the field of chemical carcinogenesis. The relative importance of environmental chemical exposures to the total burden of cancer risk remains highly contentious and it has been estimated that chemical pollution of the environment accounts for no more than 1% to 3% of all human cancers. However, such estimates do not consider chemical exposures in the workplace (5%) or cigarette smoke (30%) to be environmental pollutants, and they tend to have a primary focus on genotoxic chemicals as causative agents. Thus they may underestimate the importance of the interplay between the permanent tumor-initiating effects of low-level carcinogen exposure, the additional effects of nongenotoxic chemicals, and the potentially reversible modulating effects on tumor growth of diet, exercise, and other lifestyle factors.

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Historically, epidemiological studies suggesting that chemicals can cause human cancer date to more than 230 years ago when Percival Pott observed that scrotal cancer was correlated with soot exposure in English chimney sweeps, and Butlin suggested subsequently that the better hygiene practices of European sweeps reduced their cancer risk. In 1895, Rehn reported a high rate of bladder cancer in German factory workers who were exposed to aniline-based azo dyes. The 20th century saw the identification of specific chemicals associated with increased risk of cancer, and provided methods for identifying cellular and molecular targets of the causative agents and for elucidating mechanisms involved in the conversion of normal cells to produce tumors. A seminal breakthrough was Yamagiwa's production of skin tumors in rabbits by the direct application of coal tar in 1915, which led to the isolation, identification, synthesis, and biological testing of polycyclic aromatic hydrocarbons (PAHs) as chemical carcinogens, including dibenz[a,h]anthracene and benzo[a]pyrene (Fig. 4–1). In 1938, Hueper followed up Rehn's observation by demonstrating that the aromatic amine β-naphthylamine (Fig. 4–1), a reagent used in manufacturing azo dyes, caused bladder tumors in dogs.

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FIGURE 4–1

Structures of some direct-acting carcinogens and procarcinogens that require metabolic activation.

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With the establishment of DNA as the mediator of genetic inheritance in 1953, it became clear that carcinogen-induced DNA damage leading to fixed mutations that could be transmitted to progeny cells was a key event in the process by which exposure to carcinogens led to uncontrolled cell division and tumor growth. The concept that many carcinogens require enzymatic bioactivation into electrophilic metabolites that bind covalently with DNA was ...

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