that yield unequivocal results. However, such experiments might well be good models only for the initiation part of the carcinogenic process. Although the data are hard to interpret in animal experiments, alpha particles and tobacco smoke often appear to produce effects that are larger than additive; this observation can be understood in that tobacco smoke, as well as being a carcinogen, contains irritants that stimulate cell proliferation which is a known factor in oncogenesis. The experimental data are consistent with the supra-additive model which appears to be most useful in the human data (see chapter 3).

Biologic Signatures of Alpha-Particle Cancers

Early attempts (Vahakangas and others 1992; Taylor and others 1994) to identify a molecular ''signature" of prior alpha-particle damage through the identification of unusual point mutations have not yet proved useful (Rossi 1991; Hei and others 1994a; McDonald and others 1995; Bartsch and others 1995; Hollstein and others 1997). More mechanistic approaches based on larger-scale genomic alterations (for example, Brenner and Sachs 1994; Griffin and others 1995; Savage 1996) are more promising. The newer techniques currently require further experimental validation but offer hope for future molecular epidemiologic approaches to the radon problem.

Individual Susceptibility

Animal experiments show significant but unexplained differences among species in susceptibility to lung-cancer from radon progeny. For example, rats are susceptible to radon-induced lung-cancer, but Syrian hamsters are extremely resistant. In addition, within a given species, different inbred strains show variations in susceptibility to ionizing radiation or chemical carcinogens. Cell lines or animals with specific repair deficiencies also show increased susceptibility to radiation-induced malignant or premalignant changes, although there have been few experiments specifically with alpha particles from radon progeny.

The sum of available evidence leads to the conclusions that for an outbred human population a broad spectrum of susceptibility to alpha-particle-induced carcinogenesis would be expected and that there could be a marked increase in susceptibility in people suffering from a genetic deficiency. Evidence of genes related to susceptibility for many forms of cancer is emerging, although there is as yet no convincing evidence of a gene that confers sensitivity to radiation-induced cancer on a heterozygotic population.

Much research is being focused on the possibility of subpopulations that might have a genetically based increased susceptibility to radiation-induced cancer. The existence of subpopulations that are highly sensitive to alpha-particle-induced lung-cancer could substantially affect individual risk estimates but may have only minor impact on population risk estimates.



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