of alpha particles have passed through the cell. The dish is then moved so that the next cell is under the collimated beam. True single-particle irradiation should allow measurement of the effects of exactly 1 alpha-particle traversal relative to multiple traversals. These techniques should also allow evaluation of the effects of cytoplasmic traversals and traversals through nearby cells—the potential "bystander" effect discussed earlier.
In the last few years, it has become increasingly clear that densely ionizing radiation such as alpha particles can exhibit an inverse dose-rate effect for carcinogenesis (for example, Miller and others 1993); that is, for a given dose or cumulative exposure, as the dose rate is lowered, the probability of carcinogenesis increases. The phenomenon has come to be known as the inverse dose-rate effect because it is in marked contrast to the situation for sparsely ionizing radiation, which with protraction in delivery of a given dose, either by fractionation or by low dose rate, usually results in a decreased biologic effect.
The extent and consistency of published reports on the in vitro and in vivo inverse dose-rate effects, leave little doubt that such effects are real (Charles and others 1990; Brenner and Hall 1992). Of interest here is that the inverse dose-rate effect has been clearly demonstrated in miners exposed to radon-progeny alpha particles at different exposure rates. From comparisons of epidemiologic studies involving different average radon-progeny exposure rates, Darby and Doll (1990) inferred the existence of an inverse dose-rate effect. On the basis of epidemiologic studies, an inverse dose-rate effect was reported by Hornung and Meinhardt (1987) in Colorado uranium miners, by Sevc and colleagues (1988) and Tomásek and colleagues (1994a) in Czech uranium miners, and by Xuan and colleagues (1993) in Chinese tin miners. In a recent joint analysis of 11 cohorts of miners exposed to radon progeny, Lubin and colleagues (1995a) clearly demonstrated the existence of a significant inverse dose-rate effect.
Irrespective of the detailed mechanisms involved, and provided that they are confined to single independent cells, basic biophysical arguments imply that if a target cell or its progeny is hit by 1 or 0 alpha particles, it cannot show a dose-rate effect of any kind. Mechanistically (see, for example, Barendsen 1985; Goodhead 1988; Curtis 1989; Brenner 1994), a cell traversed only once by an alpha-particle cannot "know" or respond to any changes in dose rate. Thus, no inverse dose-rate effect would be expected at very low exposures, but such effects would be possible as the cumulative exposure increased to a point where multiple traversals of the targets become significant. The resulting overall effect therefore will be the result of an interplay between cumulative exposure and exposure rate (Brenner 1994). These considerations are summarized in Figure 2-2, which depicts a protraction effect that increases with increasing exposure and decreases with