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PNAS 102 (40): 14203-14208

Copyright © 2005 by the National Academy of Sciences.

From The Cover


Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away

Oleg V. Belyakov *, {dagger}, Stephen A. Mitchell *, Deep Parikh {ddagger}, Gerhard Randers-Pehrson *, Stephen A. Marino *, Sally A. Amundson *, Charles R. Geard *, and David J. Brenner *, §

*Center for Radiological Research, Columbia University, New York, NY 10032; {dagger}Radiation Biology Laboratory, Research and Environmental Surveillance, Radiation and Nuclear Safety Authority, P.O. Box 14, FIN-00881, Helsinki, Finland; and {ddagger}Stuyvesant High School, New York, NY 10282

Edited by Richard B. Setlow, Brookhaven National Laboratory, Upton, NY

Accepted for publication August 3, 2005.

Received for publication June 16, 2005.

Abstract: A central tenet in understanding the biological effects of ionizing radiation has been that the initially affected cells were directly damaged by the radiation. By contrast, evidence has emerged concerning "bystander" responses involving damage to nearby cells that were not themselves directly traversed by the radiation. These long-range effects are of interest both mechanistically and for assessing risks from low-dose exposures, where only a small proportion of cells are directly hit. Bystander effects have been observed largely by using single-cell in vitro systems that do not have realistic multicellular morphology; no studies have as yet been reported in three-dimensional, normal human tissue. Given that the bystander phenomenon must involve cell-to-cell interactions, the relevance of such single-cell in vitro studies is questionable, and thus the significance of bystander responses for human health has remained unclear. Here, we describe bystander responses in a three-dimensional, normal human-tissue system. Endpoints were induction of micronucleated and apoptotic cells. A charged-particle microbeam was used, allowing irradiation of cells in defined locations in the tissue yet guaranteeing that no cells located more than a few micrometers away receive any radiation exposure. Unirradiated cells up to 1 mm distant from irradiated cells showed a significant enhancement in effect over background, with an average increase in effect of 1.7-fold for micronuclei and 2.8-fold for apoptosis. The surprisingly long range of bystander signals in human tissue suggests that bystander responses may be important in extrapolating radiation risk estimates from epidemiologically accessible doses down to very low doses where nonhit bystander cells will predominate.

Key Words: bystander • normal human tissue • radiological risk

Author contributions: O.V.B., G.R.-P., S.A.A., C.R.G., and D.J.B. designed research; O.V.B., S. A. Mitchell, D.P., and S. A. Marino performed research; G.R.-P. contributed new reagents/analytic tools; O.V.B., S.A.A., and D.J.B. analyzed data; and O.V.B., S.A.A., C.R.G., and D.J.B. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Freely available online through the PNAS open access option.

See Commentary on page 14127.

§ To whom correspondence should be addressed at: Center for Radiological Research, Columbia University, 630 West 168th Street, New York, NY 10032. E-mail: djb3{at}

© 2005 by The National Academy of Sciences of the USA

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