A principal justification for studying cancer cells in vitro, abstracted from the entire organism, is that a neoplasm is usually considered as arising from a single cell that has undergone a critical change. Evidence of that includes the fact that some malignancies can be propagated by a single cell, and many, but not all, tumors have been shown to be monoclonal in origin, in that every cell carries the same biochemical marker (for example, Pathak 1990). It is important to note that many steps are involved from the malignant transformation of a single cell to the development of an overt neoplasm, including tissue response and potential immunological factors (Nagarkatti and others 1996), and care must be taken in directly extrapolating exposure and dose-response relationships for cells exposed to low doses of high-LET particles to risk for the development of cancer.

Cellular and molecular research generally focuses on early changes induced by radon and attempts to understand the mechanisms involved in production and repair of these changes. Such mechanistic understanding is essential to evaluate the response of cells to environmental radon exposure in which only a small fraction of the cell population interacts with the alpha particles. However, the role and progression of these cellular and molecular changes in the development of disease also can be addressed with experimental-animal studies. It should be noted that although many of the studies discussed in this chapter used interactions of bronchial tissue with alpha particles as the experimental model, there is a much greater base of information on interactions of x rays with other target tissues. When appropriate, we draw inferences from these other experimental models, but such conclusions will inevitably be less certain than those derived from experiments with alpha particles and bronchial tissue, the target tissue for radon-induced damage.

As the cells of a cancer grow and divide, progressive stages, or steps, from preneoplasia to malignancy can be identified. Those steps have been described as initiation, promotion, and progression. The progressive nature of carcinogenesis has been known for many years; it was first described in phenomenologic terms for skin cancer in animals. With sputum cytology, it has been possible to use histologic changes in lung cells as a predictive measure of bronchogenic cancer (Saccomanno and others 1988). The progressive cellular changes suggest a multistage process during the development of radon-induced lung-cancer. More-recent evidence of the multistep nature of cancer has come from studies of the clinical progression of colorectal cancer from polyp to metastatic cancer (see, for example, Fearon and others 1990). Those studies have demonstrated an association between the clinical progression of the cancer — from a benign state, through nonmalignant adenomas, to full-blown cancer — and the activation of oncogenes, the loss of antioncogenes, and other chromosomal changes.

Although the multistep nature of radiation carcinogenesis is almost certainly true, it is as yet only a qualitative observation. Our current state of knowledge precludes systematic quantitative understanding of all the various steps from early subcellular lesions to observed malignancy, and of the potential influence

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