Carcinogenic Effects

In 2005, 22% of deaths in the United States were from cancer. Along with heart attacks and strokes, it is one of the three leading causes of death. Although life-style choices such as the use of tobacco products, alcohol consumption, and diet are thought to be responsible for a majority of cancers, it is also known that cancer can result from exposure to ionizing radiation and to some chemicals in the environment. In fact, cancer is often the primary stochastic effect analyzed in risk assessments. Cancer is of particular concern because it can be induced at doses far below the level required to induce an observable systemic effect (and possibly, at any nonzero dose). Thus, controlling exposures to prevent systemic effects may be ineffective in providing an acceptable level of protection against cancer.

Of the many chemicals present in the environment, only a few have been determined conclusively to cause cancer. Table 3.1 includes several environmental contaminants that are known or probable carcinogens. Cancer is a class of diseases, all characterized by an uncontrolled growth of cells. Carcinogenesis is the process whereby a normal somatic cell is modified so that it begins to divide abnormally, leading to an abnormal cellular mass in the body. The cancerous cells consume most of the body's energy and starve healthy cells, they secrete digestive enzymes that destroy healthy cells, and they suppress the immune system, making the person susceptible to secondary infection. Consequently, if the growth of cancerous cells is not checked by some combination of radiation therapy, chemical therapy, and surgery, the person affected is likely to die.

Although the mechanisms for the induction of cancer are not known precisely, there is evidence to suggest a multistage process consisting of several distinct phases: initiation, promotion, and progression. Initiation is the mutation of DNA in a single cell by chemicals or radiation (which can be either of natural origin or products of human activities). This mutation proliferates through succeeding cell generations. Except for the presence of the mutated gene, these cells are normal in that they remain differentiated and their growth is regulated. In the promotion phase, which is not well understood, the cells begin to grow and divide abnormally, creating a tumor (also termed a neoplasm). In some tumors, the cells retain most of the characteristics of their differentiated ancestor cells and are contained by the surrounding tissues. These tumors are termed benign (although the abnormal growth of a benign tumor can sometimes lead to significant health effects). Some tumors enter a third phase known as progression. If the internal controls on genetic expression are disrupted, cells can regress or become less differentiated. Whereas mature, differentiated cells are destroyed by the immune system if they are found outside their normal tissue, immature cells are not. They can migrate away from the site of the primary tumor through the blood and lymphatic circulatory systems and start new tumors in distant tissues and organs. The process is known as metastasis, and tumors that have the capability to metastasize are known as malignant.

Carcinogens are often divided into two classes: mutagenic (genotoxic) carcinogens, which can initiate a cancer by transforming the DNA of the target cell, and epigenetic carcinogens, which exert their carcinogenic effects without interacting with genetic material. There is considerable evidence for the key role of mutagenicity in cancer, including the monoclonal nature of most cancers and the fact that most carcinogens are capable of damaging DNA. Although all of the factors that cause a chemical to be mutagenic are not clear, it appears that most mutagenic carcinogens are either highly electrophilic compounds or those that have electrophilic metabolites. If these compounds enter the cell, their chemical characteristics allow them to form a covalent bond with DNA. The resulting bonded molecule is known as an adduct. A number of human carcinogens have been identified as having significant reactivity with DNA. These can either be mutagenic in their parent form, or they may require metabolic activation to produce their mutagenic effects. Activation independent mutagens include alkylat-ing agents and certain metals, such as nickel and cadmium. Activation-dependent mutagens include such compounds as arylamine, nitrosamine, and polycyclic aromatic hydrocarbons.

Epigenetic carcinogens do not affect DNA directly but instead act to promote the growth of a tumor or suppress natural defenses against cancer. These include hormone-modifying compounds, cytotoxic compounds, and immunosuppressive agents. Often, these compounds induce DNA synthesis and cellular proliferation. Unlike genotoxic carcinogens, most epigenetic carcinogens require relatively high and prolonged exposure to manifest their carcinogenic effect. Chemically induced promotion is a major mechanism of epigenetic carcinogenicity and is the mechanism of action of such compounds as organochlorine pesticides, poly-chlorinated/polybrominated biphenyls, and saccharin. Hormone modification by such agents as diethylstilbestrol, estrogens, amitrole, and androgens is another mechanism of action. Chemicals that act through other mechanisms include diethylhexylphthalate, nitrotriacetic acid, cyclosporine A, asbestos, and some plastics.

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