Interpretation of risk projections for the general population is further clouded by synergism between smoking and radon progeny: some lung-cancer cases reflect the joint effect of the two agents and are in principle preventable by removing either agent.

Susceptibility

The development of lung-cancer is considered to be a multistep process involving a sequence of genetic changes that ultimately results in malignant transformation. A rapidly growing body of literature describes some of these changes, for example, in tumor-suppressor genes and oncogenes (Economou and others 1994). There are many points in this sequence, from carcinogen metabolism to DNA repair, at which genetic susceptibility might influence lung-cancer risk. In fact, there is descriptive evidence from epidemiologic studies that a family history of lung-cancer is associated with increased risk (Economou and others 1994). The evidence has not addressed radon progeny specifically, but it was deemed sufficiently compelling by the BEIR VI committee to warrant its being considered as one of the critical issues. In particular, the committee considered the implications of identifying population groups at risk for lung-cancer generally or for lung-cancer caused by radon progeny specifically.

Links Between Biologic Evidence and Risk Models

The BEIR VI phase 1 committee recognized that key sources of uncertainty listed above as the first 4 critical issues would be best addressed by risk models that directly reflect current biologic understanding directly and are not simply empiric and based on analysis of observational data. The assumptions to be made with regard to the relationship between exposure and risk and with regard to the inverse exposure-rate effect were judged to be particularly critical. Consequently, the phase 2 committee was constituted to include the full range of scientific disciplines concerned with radon carcinogenesis, and a subcommittee, the Molecular and Cellular Working Group, synthesized the evidence with a goal of providing guidance to a second subcommittee, the Risk Modeling Working Group.

Signatures of Radon Effects

Lung-cancer constitutes a clinically and histologically heterogeneous group of malignancies. There are 4 principal histologic types: squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and large cell carcinoma. Each has somewhat different clinical characteristics. In addition, substantial heterogeneity at the molecular level has been demonstrated with markers of genetic change. This heterogeneity, initially at the light-microscopy level and now at the genetic



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