Ionizing radiation is also an effective method for treating tumors because it can be localized to the tumor and is a potent inducer of DNA double-strand breaks, a highly toxic form of DNA damage. While much has been learned about x-ray and gamma-ray effects on cells and whole organisms, less is known about the biological effects of neutrons. Neutrons are highly energetic uncharged particles that induce more severe DNA damage than photons and are therefore more effective than photons in controlling radioresistant tumors. The relative biological effectiveness of neutrons has been reported to be as low as 1 and perhaps higher than 10 depending on the tissue type, neutron energy and the biological endpoint being measured. Neutrons were listed as a carcinogen for the first time in the Eleventh Report on Carcinogens. High levels of neutron irradiation occur in patients receiving neutron therapy, while low levels of neutron exposure occur in patients treated with high energy photons and protons. Other sources of low level neutron irradiation may include occupational exposure to workers at nuclear power plants and accelerator facilities, astronauts, airline crews and passengers on high altitude flights, as well as radiation incidents such as the Hiroshima-Nagasaki atomic bomb explosions and the tsunami-induced radiation leak at the Fukushima Daiichi site in Japan. One of the major paradigm shifts in the field of radiation biology was the discovery of non-targeted effects such as the bystander effect in which cells in the vicinity of radiation-damaged cells behave as though they were also irradiated. In addition, late effects such as chromosomal instability may increase susceptibility to cancer. Thus, cells that are directly damaged are not the sole targets of radiation exposure. Cells that do not absorb radiation directly may nevertheless be damaged or altered in ways that do not become apparent for many cell generations. Such non-targeted effects may have serious implications for human health and may cause cancer. Therefore, the risks of ionizing radiation need to be analyzed in terms of both direct and non-targeted effects. The bystander effect has been observed repeatedly in mammalian cell lines, including human skin fibroblasts, epithelial cells and leukemic cells in response to ionizing photons. Depending upon the cell and tissue type, bystander signals can be transmitted either through the culture medium or by cellto-cell contact including gap junctional communication. Some of the candidate intercellular signaling molecules that have been implicated in bystander effects are reactive oxygen species, reactive nitrogen species, nitric oxide, cytokines such as TGFb and interleukin 8, and small molecules such as amino acids. The involvement of intracellular signaling molecules including mitogen-activated protein kinases and their downstream proteins, protein kinase C isoforms.