Are Bystander Effects Important at Low Radiation Doses?
D. J. Brenner,* C. R. Geard,* E. J. Hall,* and R. K. Sachs†
*Center for Radiological Research, Columbia University,
New York
†Department of Mathematics,
University of California, Berkeley, California
At low doses of high-LET radiation and at very low doses of low-LET radiation, some cells are directly hit by the radiation, but a significant number of cells are not - at least in an appropriate time frame for oncogenic damage development. This inhomogeneous energy deposition is of potential public-health relevance because there is convincing evidence, at least in vitro, that irradiated cells can send out signals that can lead to damage to nearby "bystander" cells. The evidence for bystander effects is particularly strong for high-LET radiation, for a broad variety of in-vitro endpoints.
Relevant low-dose high-LET exposure scenarios include home-dwellers exposed to domestic levels of radon, radiation workers or airflight personnel exposed to neutrons, and astronauts in deep space exposed to galactic cosmic rays; of these, the dominant public health concern is domestic exposure to radon. Direct epidemiological assessment of the risks from domestic radon exposure is difficult, resulting in risk estimates with wide confidence intervals. Consequently domestic radon risk estimates are currently based on extrapolation of data from miner studies, largely at considerably higher exposures (1). There are very different proportions of non-hit bystander cells in individuals exposed domestically to radon, compared to miners exposed to higher levels of radon (1). Given that risk estimates from miner data are used as the basis of a linear extrapolation of risk down to domestic radon exposure levels, it is of importance to understand whether the different proportions of bystander cells in these two situations might result in misleading conclusions from such a linear extrapolation.
We have used the Columbia University single-particle / single-cell microbeam (2) in a series of studies (3, 4) to probe bystander effects induced by alpha particles. Broad conclusions (5) were that
Whilst such results suggest that bystander effects for endpoints relevant to cancer can be important, it is also clear that there must also be a component of radiobiological damage which is "direct", in the sense that it involves damage in a cell by a radiation track which directly deposits energy in that cell nucleus. We have discussed (5, 6) possible high-LET dose-risk relationships using an approach (denoted BaD) which incorporates radiobiological damage both from a Bystander response to signals emitted by irradiated cells, and also from Direct traversal of high-LET radiations through cell nuclei. The approach produces predictions consistent with the series of studies (3, 4) of the bystander phenomenon using the Columbia University microbeam, with the endpoint of in-vitro oncogenic transformation.
Within the BaD framework, the addition of a saturating bystander response to a linear direct response results in an overall risk varying non-linearly with dose. Different assumptions about the prerequisites for emission of a bystander signal by hit cells, and about whether directly-hit cells can also show a bystander response, can produce predictions consistent with in-vitro data, but result in significantly different extrapolations of radon risks from high to low exposures (6).
Comparisons of such models with epidemiological data (miner data at high doses, domestic case control studies at low doses) are, however, hindered by our limited knowledge of the appropriate cellular targets in the bronchial epithelium (e.g. basal cells vs. secretory cells, nucleus vs. whole cell), as well as uncertainties in the appropriate time scales in which to consider numbers of a particles traversing those targets. However, when the most likely scenarios are considered, the most likely outcomes appear to be either a) the same (linear) dose-risk relation would apply both for domestic radon exposure and for high radon exposures in mines, implying the validity of a linear risk extrapolation from high to low exposures, or b) linear extrapolation to low doses of radon risks based on high-exposure miner data could overestimate domestic radon risks, by (misleadingly) including a bystander component which could be present at high but not low radon exposures (6).
Both these scenarios are consistent with current epidemiological data for radon. Further laboratory-based studies on the patterns of the bystander effect at low doses and, particularly, about its temporal aspects, should yield more insights as to appropriate extrapolation of radiation risks from intermediate to low doses, both for high- and low-LET radiations.
This work was supported by DOE grants DE-FG03-98ER62686 and DE-FG03-00ER62909.
1. Committee on the Health Risks of Exposure to Radon (BEIR VI). Health Effects of Exposure to Radon, National Academy Press, Washington DC, 1999.
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6. D. J. Brenner and R. K. Sachs, Are bystander effects relevant for domestic radon exposure risk estimation? Int. J. Radiat. Biol. (2001).