Introduction

The carcinogenic risk associated with exposure to ionizing radiation has been evaluated previously in the IARC Monographs: radon in Volume 43 (IARC, 1988), X-rays, γ-rays, and neutrons in Volume 75 (IARC, 2000), and some internally deposited radionuclides in Volume 78 (IARC, 2001). An updated review on all carcinogenic types of radiation, also including solar and ultraviolet radiation, was published as Volume 100D (IARC, 2012).

For certain types of ionizing radiation, the evidence of carcinogenicity in humans is clear, but in other cases the data are few or non-existent. However, the overall conclusion reached in Volume 100D of the IARC Monographs was that all types of ionizing radiation should be considered as carcinogenic to humans (Group 1). The rationale for this was that all types of ionizing radiation transfer their energy to biological material in clusters of ionization and excitation events, primarily through a mechanism mediated by free electrons. In addition, DNA damage is a common biological outcome of exposure to all ionizing radiation; energy deposition results in a wide variety of molecular damage, such as base damage and single- and double-strand breaks, some of which may be clustered to form complex lesions. Subsequent processing of these lesions may lead to chromosomal aberrations and mutations. The generality of induction of and response to radiation damage is discussed for all types of ionizing radiation in greater depth later in this chapter.

In addition to the above-mentioned reviews in the IARC Monographs, there have been many major national and international reviews of the literature on radiation, as well as radiation risk estimates. These include the publications of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR, 2000, 2008, 2010) and the reports from the United States National Research Council (NRC, 1999, 2006), the United States National Council on Radiation Protection and Measurements (NCRP, 1993, 1999, 2001, 2005), and the International Commission on Radiological Protection (ICRP, 2003, 2007; Valentin, 2005).

Two major issues faced when studying radiation carcinogenesis is that radiation-induced cancers are indistinguishable from those that occur naturally, and that risk estimates rely on epidemiological data for which statistical significance is reached only at high doses. The existing data are not powerful enough to enable comment on the shape of the dose–response curve and the associated risks at doses associated with typical human exposures. Many of the in vitro and in vivo studies investigating the mechanisms underlying cancer risk from exposure to ionizing radiation have concentrated on low-dose exposures, typically of 0.1 Gy (= 0.1 J/kg) and below.

The nature of ionizing radiation

Ionizing radiation is a term used for any radiation that is capable of ionizing (i.e. removing electrons from) atoms or molecules of the medium being traversed. Ionizing radiations are usually classified as either electromagnetic or particulate.

X-rays and γ-rays are both electromagnetic radiations. They do not differ in nature, but their designation reflects their origin; X-rays are produced by extranuclear processes and γ-rays by intranuclear processes. These types of radiation are often classified as indirectly ionizing, because the chemical and biological damage is dominated by the charged particles (mainly electrons) produced as a result of interactions within the medium. Neutrons are also classified as indirectly ionizing. They deposit energy and cause damage through recoil protons, α-particles, and nuclear fragments that result from neutron interactions.

Particulate radiations include electrons, positrons, protons, neutrons, α-particles, and other ions. With the exception of neutrons, all of these particles are charged and are classified as directly ionizing (if they have sufficient energy) because they directly ionize the medium they are traversing, producing chemical and biological damage.

The human body can be irradiated either from external sources or through internal exposure as a result of ingestion, inhalation, dermal absorption, or injection of radionuclides. The effects of radiation are directly related to the dose received by individual cells or organs, and by the radiation quality. Therefore, these effects can vary significantly, depending on the resulting dose distribution or distribution of radionuclides throughout the body. The dose distribution may vary from being essentially uniform after whole-body exposure to being highly heterogeneous in the case of non-uniform distribution of internal radionuclides that emit short-range α-particles or β-particles. Medium- to high-energy X-rays, γ-rays, and neutrons are typically highly penetrating and will traverse the body, whereas α-particles and β-particles typically have a short range (for α-particles, less than 100 μm, and for β-particles, from less than 1 μm to several millimetres). In general, the penetration range of charged particles can vary significantly depending on their energy and the type of particle.

Genotoxicity and the importance of radiation track structure

Ionizing radiation interacts within cells and tissues by depositing energy in highly structured tracks of ionization and excitation events that are stochastic in nature. On average, these events are relatively sparsely distributed for high-energy X-rays and γ-rays, which deposit energy via electrons with relatively low linear energy transfer (LET), where LET corresponds to the energy loss per unit track length. For example, cobalt-60 γ-rays have an LET of about 0.25 keV/μm (where 1 eV = 1.602 × 10⁻¹⁹ J). The ionization and excitation events are much closer together for low-energy charged particles, which are considered to be high-LET radiation. For example, an α-particle with an energy of 2 MeV has an LET of about 180 keV/μm.

All types of ionizing radiation induce a wide range of damage and effects, including DNA damage, chromosomal aberrations, mutations, cell transformation, and cell killing (NRC, 1999, 2006; UNSCEAR, 2000; ICRP, 2003, 2007). The efficiency in causing damage and subsequent biological effects is related not only to the amount of energy transferred per unit mass (the absorbed dose, expressed in units of gray, where 1 Gy = 1 J/kg) and the rate of energy transfer (the dose rate) but also to the microdistribution of energy, which is determined by the type of radiation and the associated track structure.

The relative biological effectiveness is defined as the inverse ratio of the dose required to produce a given biological effect to the dose required by a reference radiation to produce the same effect. The relative biological effectiveness typically increases with the LET value of the radiation, and it reaches a peak at about 100–200 keV/μm for a range of biological end-points. Whereas the absorbed dose unadjusted for attenuation by the body is expressed in units of gray (Gy), the weighted organ dose (the equivalent or effective dose) is expressed in sieverts (Sv) or millisieverts (mSv), which are also the units in which radiation exposure limits are given.

For many biological effects, nuclear DNA is a critical target of ionizing radiation (UNSCEAR, 1993). Ionizing radiation can cause DNA damage either by direct ionization of the constituent atoms in the DNA or indirectly by reactions with free radicals produced by interactions with water molecules (most notably the hydroxyl radical, which can induce DNA strand breakage or base damage), or by a combination of direct and indirect effects. In the cell, hydroxyl radicals will typically only diffuse a few nanometres (< 6 nm), thus preserving the spatial structure of the radiation tracks.

Ionizing radiation can thus induce a range of different types of molecular damage in DNA, such as base damage (including apurinic/apyrimidinic sites), strand breaks, DNA–protein cross-links, and combinations of these within a few base pairs of each other. Examples are double-strand breaks (DSBs) and non-DSB clusters (two or more base damages and/or strand breaks within about 10 base pairs, but not resulting in a DSB). The pattern and frequency of these lesions are determined by the clustering of ionization and excitation events on the nanometre scale, which ultimately produces clustering of damage over the dimensions of the DNA helix and larger.

Theoretical analyses show that clustered DNA damage that is more complex than a single-strand break can occur at biologically relevant frequencies with all types of ionizing radiation (Goodhead 1987, 1994; Brenner and Ward, 1992). Such clustered damage in DNA is produced mainly within a single track, with a probability that increases with increasing ionization density (LET). Calculations show that a dose of greater than 10 000 Gy is required for a second track to have a reasonable chance of contributing to the local complexity of DNA damage (Nikjoo and Goodhead, 1991). These more complex forms of damage are essentially unique to ionizing radiation and are not seen spontaneously or with other DNA-damaging agents.

The number of DSBs induced in DNA is approximately 20–40 per cell per gray for low-LET X-rays and γ-rays, and a similar number is observed for α-particles in standard assays. However, the percentage of complex DSBs (with extra strand breaks and/or associated base damage within 10 base pairs) is about 30–50% for electrons (similar to the percentage produced by X-rays and γ-rays) based on Monte Carlo calculations, and this percentage increases with increasing ionization density (LET) of the radiation, to about 90% for 0.3 MeV protons and about 96% for high-LET 2 MeV α-particles (Nikjoo et al., 1991; Goodhead, 2006). In addition to this increase in the frequency of complex DSBs with increasing LET, there is also an increase in the overall complexity of the damage spectrum produced. Clustering of damage is not confined to DNA but can occur in all biomolecules.

Complex non-DSB damage has been shown to be a significant component of the lesions induced by radiation, occurring 4–8 times as frequently as direct DSB formation. Whereas isolated lesions (e.g. base damage or single-strand breaks) are repaired quickly and generally with high fidelity, for non-DSB clusters the rate of repair is typically impaired by the presence of additional lesions within the cluster. The delay and the ultimate consequence depend on the types of lesion and their relative positions. The longer lifetime of these clusters also results in an increased probability that the damage will be present during DNA replication, which ultimately leads to stalled replication forks that may give rise to DSBs or mutations. Therefore, non-DSB clusters are potentially highly mutagenic and are likely to play a more important role at low doses of low-LET radiation; because non-DSB damage is produced at a higher frequency than DSBs at these lower doses, more cells will contain non-DSB clustered damage compared with DSBs (reviewed by Eccles et al., 2011).

DNA is wrapped around histone proteins to form nucleosomes, which are organized into 30 nm chromatin fibres that are typically arranged in loops. As a result of the sequence of ionization events along individual radiation tracks, especially in the case of densely ionizing high-LET particles such as α-particles, these tracks can lead to multiple correlated DSBs over short sections of DNA arranged in these structures. Conventional DSB assays (e.g. pulsed-field gel electrophoresis and γH2AX assays) are not able to resolve these additional DSBs and therefore typically underestimate the absolute yields (Friedland et al., 2008). However, experimental and theoretical data have demonstrated the existence of these short fragments for these particles, showing a significant deviation from a random distribution (Rydberg et al., 1998; Friedland et al., 2008). Whereas viable radiation-induced mutations are rarely associated with visible chromosomal exchanges observed by use of fluorescence in situ hybridization (FISH), molecular analysis of these sites shows that high-LET particles can induce gene mutations of greater complexity than simple deletions or point mutations, consistent with the correlation of damage along the radiation track (Singleton et al., 2002).

The pattern of energy deposition is also important on the cellular or nuclear scale (over distances in the micrometre range). When an α-particle traverses a cell, the dose distribution of the energy deposited is highly heterogeneous across the cell, with a greater probability of correlated damage and DSBs within a single chromosome or adjacent chromosomes. Studies with multiplex FISH (mFISH) have shown that commonly four and up to a maximum of eight different chromosomes may be involved in rearrangements after the nuclear traversal of a human peripheral blood lymphocyte by an α-particle (Anderson et al., 2002, 2006); a similar response was seen in human CD34-positive haematopoietic stem cells (Anderson et al., 2007). This is in contrast to the production of mainly simple rearrangements between two chromosomes observed for low doses of low-LET X-rays. Complex rearrangements have been observed in radiation workers with a large body burden of α-particle-emitting plutonium (Anderson et al., 2005). Stable intrachromosomal rearrangements were also found in lymphocytes of former nuclear weapons workers who were exposed to plutonium (Hande et al., 2003), although not consistently for all cases of in vivo high-LET exposures (reviewed by Hada et al., 2011).

Other potential mechanisms for modifying cancer risk from radiation exposure

Ionizing radiation also produces a whole range of effects with potential implications for carcinogenesis (UNSCEAR, 2012). For example, the patterns of gene and protein expression are critical in determining cellular function and response. Ionizing radiation has been shown to modulate protein phosphorylation (Yang et al., 2006) and gene expression in a dose- and dose rate-dependent manner (Ding et al., 2005; Fachin et al., 2009). Epigenetic changes can also result in modifications in gene expression, and ionizing radiation produces DNA methylation (Kovalchuk et al., 2004), histone methylation (Pogribny et al., 2005), and chromatin modification (Kim et al., 2009; Luijsterburg et al., 2009; Nagarajan et al., 2009; Pandita and Richardson, 2009), along with modulation of microRNA expression (Templin et al., 2011).

The importance of dose distribution with respect to tumour sites

The passage of ionizing radiation through the body results in the deposition of energy within the irradiated tissue volume. External irradiation with photons is typically highly penetrating and will often result in all cells and tissues in the radiation field being irradiated. In contrast, emission from internalized radionuclides typically occurs from specified locations occupied by the emitting nuclide source. This will often lead to a non-uniform dose distribution in the body, especially if the emitted radiation has only a short range (e.g. for α-particles and β-particles).

The biological effects of deposited radionuclides in the body depend on the amount and activity of the radionuclide deposited, the type of radiation emitted, the physical half-life of the isotope, the mode of entry, the organs and tissues in which the radionuclide is retained, the duration of retention, and the rate of excretion from the body. The chemical characteristics of the radionuclide (or the compound in which it is incorporated) along with its physical properties (such as size and shape) determine its behaviour, including absorption and transport within the body, elimination route and rate, and uptake and retention in organs. In some cases, for example for radioactive heavy metals, the health effects and carcinogenic potential may also be related to, and potentially dominated by, the chemical properties rather than the radiation emitted.

In some cases, a radionuclide may spread throughout the whole body; in other cases, it will concentrate in specific organs or locations within the body. If the emitted radiation has a short range (e.g. for α-particles and β-particles), this can lead to significant heterogeneity in the resulting dose distribution, with certain organs receiving a significant dose while for others the radiation dose is minimal. Biokinetic models (ICRP, 1989, 1993, 1994, 1995a, b, c, 2001) are used to estimate the spatial and temporal uptake of radionuclides as well as their subsequent distribution and ultimate excretion. Dosimetry models (Eckerman, 1994) are then used to calculate the resulting dose distribution over the body and organs, based on the physical characteristics of the radionuclides.

The ability of internal radionuclides to produce a biological response and ultimately cancer in various organs is related to the biodistribution of these emitters within the body (which will depend on the chemical and physical properties of the particles and the route of entry). Examples are iodine-131, which concentrates largely in the thyroid, and strontium-90 and plutonium-239, which are deposited mainly in the bone. The same radionuclide may result in a different range of tumours if it is delivered in such a way as to produce a different biodistribution pattern. In addition, there may be confounding factors, such as chemical toxicity, that may contribute to or even dominate the cancer response.

Human exposures to ionizing radiation typically occur at low dose and low dose rate

The effects of radiation are most notable at the high doses (above a few gray) that are usually associated with significant radiation accidents and radiotherapy treatments, and that are observed in atomic bomb survivors. These effects include erythema, oedema, ulceration, necrosis, fibrosis, telangiectasia, inflammation, immunosuppression (through bone marrow depletion), and pneumonitis (HPA, 2007; Stewart et al., 2012). Although there is clear evidence from epidemiological data for significant cancer risks associated with high-dose exposures, the existing data for the low-dose range are limited, such that below approximately 0.1 Gy – doses associated with typical human exposures – the data are not powerful enough to enable comment on the shape of the dose–response curve and the associated risks.

For an average annual environmental background exposure of approximately 0.001 Gy for low-LET radiation, individual cells may receive no track at all or only single tracks, well isolated in time. The nucleus of each cell in a tissue will experience on average one electron track per year from background radiation, assuming a spherical nucleus of 8 μm diameter. Exposure from diagnostic procedures can vary from 0.005 Gy for dental exposures to approximately 0.01 Gy for typical exposures from computed tomography (CT), or occasionally up to 0.1 Gy for some procedures over a short period (Brenner and Hall, 2007, 2012). Individuals are also exposed to high-LET α-particles as a result of naturally occurring radon gas. With typical residential levels of radon gas, the cell nuclei in the bronchial epithelium of the inhabitants are estimated to receive on average between 0.15 and 0.6 α-particle traversals per year (NRC, 1999). However, for those cell nuclei that are occasionally traversed, the dose to the traversed nucleus is significant (on the order of 0.1–0.5 Gy).

For the high doses associated with radiotherapy or significant accidental exposures, it is expected that classical direct effects of radiation are likely to dominate the response, as a result of radiation-induced DNA damage. However, at the very low doses associated with typical human exposures, where only a small fraction of cells have a DNA DSB, it is possible that other mechanisms for cancer induction or modulation of cancer incidence (such as radiation-induced genomic instability or effects associated with perturbation of intercellular signalling) may play a more important role.

Generality of response after exposure to different types of ionizing radiation

All types of ionizing radiation ultimately lead to clusters of ionization and excitation events, along with the production of electrons, through which energy is deposited. Interaction of X-rays and γ-rays with tissues generates fast electrons that interact with atoms or nuclei, producing additional electrons as they slow down and deposit energy. Charged particles such as α-particles and protons also interact with tissue, producing primary ionization and excitation events, and also a trail of secondary electrons along the path of the primary particle. Uncharged neutrons also interact with tissue and deposit energy via lower-energy charged particles such as protons, deuterons, α-particles, and heavy-ion recoils, ultimately leading to energy deposition via secondary electrons.

Therefore, energy deposition by way of electrons is common to all ionizing radiation. Indeed, isolated track ends of low-energy electrons (produced by all ionizing radiations) have been shown not only to be capable of affecting a wide range of genotoxic end-points but to do so with a high efficiency per unit dose (Goodhead and Nikjoo, 1990; Hill et al., 2001; Hill, 2004; HPA, 2007). Because of their increased local ionization density, these track ends of low-energy (0.1–5.0 keV) electrons have been proposed as the biologically critical component of low-LET radiation, rather than the isolated ionization and excitation events along the path of fast electrons (Goodhead and Nikjoo, 1990; Botchway et al., 1997).

In addition, α-particles emitted by radionuclides, irrespective of their source, produce the same pattern of secondary ionizations and the same pattern of localized damage to biological molecules, including DNA, and ultimately the same biological effects. Therefore, due to the communality in their interactions within the body and in the biological responses induced, all types of ionizing radiation have been classified by IARC as carcinogenic to humans (Group 1), even though in some cases direct evidence is weak or non-existent, with the risk of cancer depending on dose and radiation quality. Although internal radionuclides can vary significantly in the range of cancers and cancer sites observed, the cancer response is ultimately dominated by the biodistribution of these emitters within the body.

References

• Anderson RM, Papworth DG, Stevens DL, Sumption ND, Goodhead DT (2006). Increased complexity of radiation-induced chromosome aberrations consistent with a mechanism of sequential formation. Cytogenet Genome Res. 112(1–2):35–44. 10.1159/000087511 [PubMed: 16276088] [CrossRef]
• Anderson RM, Stevens DL, Goodhead DT (2002). M-FISH analysis shows that complex chromosome aberrations induced by alpha-particle tracks are cumulative products of localized rearrangements. Proc Natl Acad Sci U S A. 99(19):12167–72. 10.1073/pnas.182426799 [PMC free article: PMC129416] [PubMed: 12205292] [CrossRef]
• Anderson RM, Stevens DL, Sumption ND, Townsend KMS, Goodhead DT, Hill MA (2007). Effect of linear energy transfer (LET) on the complexity of alpha-particle-induced chromosome aberrations in human CD34+ cells. Radiat Res. 167(5):541–50. 10.1667/RR0813.1 [PubMed: 17474795] [CrossRef]
• Anderson RM, Tsepenko VV, Gasteva GN, Molokanov AA, Sevan’kaev AV, Goodhead DT (2005). mFISH analysis reveals complexity of chromosome aberrations in individuals occupationally exposed to internal plutonium: a pilot study to assess the relevance of complex aberrations as biomarkers of exposure to high-LET alpha particles. Radiat Res. 163(1):26–35. 10.1667/RR3286 [PubMed: 15606304] [CrossRef]
• Barber RC, Hardwick RJ, Shanks ME, Glen CD, Mughal SK, Voutounou M, et al. (2009). The effects of in utero irradiation on mutation induction and transgenerational instability in mice. Mutat Res. 664(1–2):6–12. 10.1016/j.mrfmmm.2009.01.011 [PubMed: 19428375] [CrossRef]
• Barcellos-Hoff MH, Park C, Wright EG (2005). Radiation and the microenvironment – tumorigenesis and therapy. Nat Rev Cancer. 5(11):867–75. 10.1038/nrc1735 [PubMed: 16327765] [CrossRef]
• Bielas JH, Loeb KR, Rubin BP, True LD, Loeb LA (2006). Human cancers express a mutator phenotype. Proc Natl Acad Sci U S A. 103(48):18238–42. 10.1073/pnas.0607057103 [PMC free article: PMC1636340] [PubMed: 17108085] [CrossRef]
• Botchway SW, Stevens DL, Hill MA, Jenner TJ, O’Neill P (1997). Induction and rejoining of DNA double-strand breaks in Chinese hamster V79-4 cells irradiated with characteristic aluminum K and copper L ultrasoft X rays. Radiat Res. 148(4):317–24. 10.2307/3579516 [PubMed: 9339947] [CrossRef]
• Brenner DJ, Hall EJ (2007). Computed tomography – an increasing source of radiation exposure. N Engl J Med. 357(22):2277–84. 10.1056/NEJMra072149 [PubMed: 18046031] [CrossRef]
• Brenner DJ, Hall EJ (2012). Cancer risks from CT scans: now we have data, what next? Radiology. 265(2):330–1. 10.1148/radiol.12121248 [PubMed: 22915598] [CrossRef]
• Brenner DJ, Ward JF (1992). Constraints on energy deposition and target size of multiply damaged sites associated with DNA double-strand breaks. Int J Radiat Biol. 61(6):737–48. 10.1080/09553009214551591 [PubMed: 1351522] [CrossRef]
• Burdak-Rothkamm S, Short SC, Folkard M, Rothkamm K, Prise KM (2007). ATR-dependent radiation-induced γH2AX foci in bystander primary human astrocytes and glioma cells. Oncogene. 26(7):993–1002. 10.1038/sj.onc.1209863 [PubMed: 16909103] [CrossRef]
• Coates PJ, Rundle JK, Lorimore SA, Wright EG (2008). Indirect macrophage responses to ionizing radiation: implications for genotype-dependent bystander signaling. Cancer Res. 68(2):450–6. 10.1158/0008-5472.CAN-07-3050 [PubMed: 18199539] [CrossRef]
• Ding LH, Shingyoji M, Chen F, Hwang J-J, Burma S, Lee C, et al. (2005). Gene expression profiles of normal human fibroblasts after exposure to ionizing radiation: a comparative study of low and high doses. Radiat Res. 164(1):17–26. 10.1667/RR3354 [PubMed: 15966761] [CrossRef]
• Eccles LJ, O’Neill P, Lomax ME (2011). Delayed repair of radiation induced clustered DNA damage: friend or foe? Mutat Res. 711(1–2):134–41. 10.1016/j.mrfmmm.2010.11.003 [PMC free article: PMC3112496] [PubMed: 21130102] [CrossRef]
• Eckerman KF (1994). Dosimetric methodology of the ICRP. In: Raabe OG, editor. Internal radiation dosimetry. Madison, (WI), USA: Medical Physics Publishing; pp. 239–70.
• Fachin AL, Mello SS, Sandrin-Garcia P, Junta CM, Ghilardi-Netto T, Donadi EA, et al. (2009). Gene expression profiles in radiation workers occupationally exposed to ionizing radiation. J Radiat Res. 50(1):61–71. 10.1269/jrr.08034 [PubMed: 19218781] [CrossRef]
• Filkowski JN, Ilnytskyy Y, Tamminga J, Koturbash I, Golubov A, Bagnyukova T, et al. (2010). Hypomethylation and genome instability in the germline of exposed parents and their progeny is associated with altered miRNA expression. Carcinogenesis. 31(6):1110–5. 10.1093/carcin/bgp300 [PubMed: 19959559] [CrossRef]
• Friedland W, Paretzke HG, Ballarini F, Ottolenghi A, Kreth G, Cremer C (2008). First steps towards systems radiation biology studies concerned with DNA and chromosome structure within living cells. Radiat Environ Biophys. 47(1):49–61. 10.1007/s00411-007-0152-x [PubMed: 18193257] [CrossRef]
• Goodhead DT (1987). Relationship of microdosimetric techniques to applications in biological systems. In: Kase KR, Bjarngard BE, Attix FH, editors. The dosimetry of ionizing radiation. Orlando (FL), USA: Academic Press. 10.1016/B978-0-12-400402-3.50004-9 [CrossRef]
• Goodhead DT (1994). Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol. 65(1):7–17. 10.1080/09553009414550021 [PubMed: 7905912] [CrossRef]
• Goodhead DT (2006). Energy deposition stochastics and track structure: what about the target? Radiat Prot Dosimetry. 122(1-4):3–15. [PubMed: 17276998]
• Goodhead DT, Nikjoo H (1990). Current status of ultrasoft X-rays and track structure-analysis as tools for testing and developing biophysical models of radiation action. Radiat Prot Dosimetry. 31(1–4):343–50.
• Goytisolo FA, Samper E, Martín-Caballero J, Finnon P, Herrera E, Flores JM, et al. (2000). Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J Exp Med. 192(11):1625–36. 10.1084/jem.192.11.1625 [PMC free article: PMC2193093] [PubMed: 11104804] [CrossRef]
• Hada M, Wu H, Cucinotta FA (2011). mBAND analysis for high- and low-LET radiation-induced chromosome aberrations: a review. Mutat Res. 711(1–2):187–92. 10.1016/j.mrfmmm.2010.12.018 [PubMed: 21232544] [CrossRef]
• Han W, Wu L, Chen S, Bao L, Zhang L, Jiang E, et al. (2007). Constitutive nitric oxide acting as a possible intercellular signaling molecule in the initiation of radiation-induced DNA double strand breaks in non-irradiated bystander cells. Oncogene. 26(16):2330–9. 10.1038/sj.onc.1210024 [PubMed: 17016433] [CrossRef]
• Hande MP, Azizova TV, Geard CR, Burak LE, Mitchell CR, Khokhryakov VF, et al. (2003). Past exposure to densely ionizing radiation leaves a unique permanent signature in the genome. Am J Hum Genet. 72(5):1162–70. 10.1086/375041 [PMC free article: PMC1180269] [PubMed: 12679897] [CrossRef]
• Hill MA (2004). The variation in biological effectiveness of X-rays and gamma rays with energy. Radiat Prot Dosimetry. 112(4):471–81. 10.1093/rpd/nch091 [PubMed: 15623881] [CrossRef]
• Hill MA, Stevens DL, Stuart Townsend KM, Goodhead DT (2001). Comments on the recently reported low biological effectiveness of ultrasoft X rays. Radiat Res. 155(3):503–10. 10.1667/0033-7587(2001)155[0503:COTRRL]2.0.CO;2 [PubMed: 11245168] [CrossRef]
• HPA (2007). Review of risks from tritium: report of the Independent Advisory Group on Ionising Radiation. Chilton, United Kingdom: Health Protection Agency. Available from: https://www​.gov.uk/government​/publications​/tritium-review-of-risks.
• IARC (1988). Man-made mineral fibres and radon. IARC Monogr Eval Carcinog Risks Hum, 43:1–300. Available from: http://publications​.iarc.fr/61
• IARC (2000). Ionizing radiation, Part 1: X- and gamma (γ)-radiation and neutrons. IARC Monogr Eval Carcinog Risks Hum, 75:1–491. Available from: http://publications​.iarc.fr/93 [PMC free article: PMC7681265] [PubMed: 11203346]
• IARC (2001). Ionizing radiation, Part 2: some internally deposited radionuclides. IARC Monogr Eval Carcinog Risks Hum, 78:1–595. Available from: http://publications​.iarc.fr/96 [PMC free article: PMC5220265] [PubMed: 11421248]
• IARC (2012). Radiation. IARC Monogr Eval Carcinog Risks Hum, 100D:1–341. Available from: http://publications​.iarc.fr/121
• ICRP (1989). Age-dependent doses to members of the public from intake of radionuclides: part 1. ICRP Publication 56. Ann ICRP. 20(2):1–122. [PubMed: 2633670]
• ICRP (1993). Age-dependent doses to members of the public from intake of radionuclides: part 2. Ingestion dose coefficients. ICRP Publication 67. Ann ICRP. 23(3–4):1–167. [PubMed: 7978694]
• ICRP (1994). Human respiratory tract model for radiological protection. ICRP Publication 66. Ann ICRP. 24(1–3):1–482. [PubMed: 7726471]
• ICRP (1995a). Age-dependent doses to members of the public from intake of radionuclides: part 3. Ingestion dose coefficients. ICRP Publication 69. Ann ICRP. 25(1):1–74. [PubMed: 7486461]
• ICRP (1995b). Age-dependent doses to members of the public from intake of radionuclides: part 4. Inhalation dose coefficients. ICRP Publication 71. Ann ICRP. 25(3–4):1–405. [PubMed: 8735008]
• ICRP (1995c). Age-dependent doses to the members of the public from intake of radionuclides: part 5. Compilation of ingestion and inhalation coefficients. ICRP Publication 72. Ann ICRP. 26(1):1–91. [PubMed: 8886253]
• ICRP (2001). Doses to the embryo and fetus from intakes of radionuclides by the mother. ICRP Publication 88. Ann ICRP. 31(1–3):19–515. [PubMed: 11730884]
• ICRP (2003). Relative biological effectiveness (RBE), quality factor (Q), and radiation weighting factor (w_R). ICRP Publication 92. Ann ICRP. 33(4):1–117. [PubMed: 14614921]
• ICRP (2007). The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann ICRP. 37(2–4):1–332. [PubMed: 18082557]
• Kadhim MA, Lorimore SA, Hepburn MD, Goodhead DT, Buckle VJ, Wright EG (1994). Alpha-particle-induced chromosomal instability in human bone marrow cells. Lancet. 344(8928):987–8. 10.1016/S0140-6736(94)91643-8 [PubMed: 7934432] [CrossRef]
• Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG (1992). Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature. 355(6362):738–40. 10.1038/355738a0 [PubMed: 1741061] [CrossRef]
• Kadhim MA, Moore SR, Goodwin EH (2004). Interrelationships amongst radiation-induced genomic instability, bystander effects, and the adaptive response. Mutat Res. 568(1):21–32. 10.1016/j.mrfmmm.2004.06.043 [PubMed: 15530536] [CrossRef]
• Kim YC, Gerlitz G, Furusawa T, Catez F, Nussenzweig A, Oh K-S, et al. (2009). Activation of ATM depends on chromatin interactions occurring before induction of DNA damage. Nat Cell Biol. 11(1):92–6. 10.1038/ncb1817 [PMC free article: PMC2717731] [PubMed: 19079244] [CrossRef]
• Kovalchuk O, Burke P, Besplug J, Slovack M, Filkowski J, Pogribny I (2004). Methylation changes in muscle and liver tissues of male and female mice exposed to acute and chronic low-dose X-ray-irradiation. Mutat Res. 548(1–2):75–84. 10.1016/j.mrfmmm.2003.12.016 [PubMed: 15063138] [CrossRef]
• Little JB (2000). Radiation carcinogenesis. Carcinogenesis. 21(3):397–404. 10.1093/carcin/21.3.397 [PubMed: 10688860] [CrossRef]
• Lorimore SA, Chrystal JA, Robinson JI, Coates PJ, Wright EG (2008). Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation. Cancer Res. 68(19):8122–6. 10.1158/0008-5472.CAN-08-0698 [PubMed: 18829571] [CrossRef]
• Lorimore SA, Kadhim MA, Pocock DA, Papworth D, Stevens DL, Goodhead DT, et al. (1998). Chromosomal instability in the descendants of unirradiated surviving cells after alpha-particle irradiation. Proc Natl Acad Sci U S A. 95(10):5730–3. 10.1073/pnas.95.10.5730 [PMC free article: PMC20447] [PubMed: 9576952] [CrossRef]
• Luijsterburg MS, Dinant C, Lans H, Stap J, Wiernasz E, Lagerwerf S, et al. (2009). Heterochromatin protein 1 is recruited to various types of DNA damage. J Cell Biol. 185(4):577–86. 10.1083/jcb.200810035 [PMC free article: PMC2711568] [PubMed: 19451271] [CrossRef]
• Mantovani A, Allavena P, Sica A, Balkwill F (2008). Cancer-related inflammation. Nature. 454(7203):436–44. 10.1038/nature07205 [PubMed: 18650914] [CrossRef]
• Maxwell CA, Fleisch MC, Costes SV, Erickson AC, Boissière A, Gupta R, et al. (2008). Targeted and nontargeted effects of ionizing radiation that impact genomic instability. Cancer Res. 68(20):8304–11. 10.1158/0008-5472.CAN-08-1212 [PubMed: 18922902] [CrossRef]
• McIlrath J, Bouffler SD, Samper E, Cuthbert A, Wojcik A, Szumiel I, et al. (2001). Telomere length abnormalities in mammalian radiosensitive cells. Cancer Res. 61(3):912–5. [PubMed: 11221881]
• Morgan WF (2003a). Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro. Radiat Res. 159(5):567–80. 10.1667/0033-7587(2003)159[0567:NADEOE]2.0.CO;2 [PubMed: 12710868] [CrossRef]
• Morgan WF (2003b). Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res. 159(5):581–96. 10.1667/0033-7587(2003)159[0581:NADEOE]2.0.CO;2 [PubMed: 12710869] [CrossRef]
• Nagarajan P, Onami TM, Rajagopalan S, Kania S, Donnell R, Venkatachalam S (2009). Role of chromodomain helicase DNA-binding protein 2 in DNA damage response signaling and tumorigenesis. Oncogene. 28(8):1053–62. 10.1038/onc.2008.440 [PMC free article: PMC2648865] [PubMed: 19137022] [CrossRef]
• Natarajan M, Gibbons CF, Mohan S, Moore S, Kadhim MA (2007). Oxidative stress signalling: a potential mediator of tumour necrosis factor alpha-induced genomic instability in primary vascular endothelial cells. Br J Radiol. 80(Spec No 1):S13–22. 10.1259/bjr/15316848 [PubMed: 17704321] [CrossRef]
• NCRP (1993). Risk estimates for radiation protection. NCRP Report No. 115. Bethesda (MD), USA: National Council on Radiation Protection and Measurements.
• NCRP (1999). Biological effects and exposure limits for “hot particles”. NCRP Report No. 130. Bethesda (MD), USA: National Council on Radiation Protection and Measurements.
• NCRP (2001). Evaluation of the linear-nonthreshold dose-response model for ionizing radiation. NCRP Report No. 136. Bethesda (MD), USA: National Council on Radiation Protection and Measurements.
• NCRP (2005). Extrapolation of radiation-induced cancer risks from nonhuman experimental systems to humans. NCRP Report No. 150. Bethesda (MD), USA: National Council on Radiation Protection and Measurements.
• Nikjoo H, Goodhead DT (1991). Track structure analysis illustrating the prominent role of low-energy electrons in radiobiological effects of low-LET radiations. Phys Med Biol. 36(2):229–38. 10.1088/0031-9155/36/2/007 [PubMed: 2008448] [CrossRef]
• Nikjoo H, Goodhead DT, Charlton DE, Paretzke HG (1991). Energy deposition in small cylindrical targets by monoenergetic electrons. Int J Radiat Biol. 60(5):739–56. 10.1080/09553009114552561 [PubMed: 1680946] [CrossRef]
• NRC (1999). Health effects of exposure to radon: BEIR VI. Washington (DC), USA: National Academies Press. [PubMed: 25121310]
• NRC (2006). Health risks from exposure to low levels of ionizing radiation: BEIR VII, Phase 2. Washington (DC), USA: National Academies Press.
• Pandita TK, Richardson C (2009). Chromatin remodeling finds its place in the DNA double-strand break response. Nucleic Acids Res. 37(5):1363–77. 10.1093/nar/gkn1071 [PMC free article: PMC2655678] [PubMed: 19139074] [CrossRef]
• Park CC, Henshall-Powell RL, Erickson AC, Talhouk R, Parvin B, Bissell MJ, et al. (2003). Ionizing radiation induces heritable disruption of epithelial cell interactions. Proc Natl Acad Sci U S A. 100(19):10728–33. 10.1073/pnas.1832185100 [PMC free article: PMC196872] [PubMed: 12960393] [CrossRef]
• Pogribny I, Koturbash I, Tryndyak V, Hudson D, Stevenson SM, Sedelnikova O, et al. (2005). Fractionated low-dose radiation exposure leads to accumulation of DNA damage and profound alterations in DNA and histone methylation in the murine thymus. Mol Cancer Res. 3(10):553–61. 10.1158/1541-7786.MCR-05-0074 [PubMed: 16254189] [CrossRef]
• Portess DI, Bauer G, Hill MA, O’Neill P (2007). Low-dose irradiation of nontransformed cells stimulates the selective removal of precancerous cells via intercellular induction of apoptosis. Cancer Res. 67(3):1246–53. 10.1158/0008-5472.CAN-06-2985 [PubMed: 17283161] [CrossRef]
• Rugo RE, Mutamba JT, Mohan KN, Yee T, Chaillet JR, Greenberger JS, et al. (2011). Methyltransferases mediate cell memory of a genotoxic insult. Oncogene. 30(6):751–6. 10.1038/onc.2010.480 [PMC free article: PMC3044496] [PubMed: 21057543] [CrossRef]
• Rydberg B, Holley WR, Mian IS, Chatterjee A (1998). Chromatin conformation in living cells: support for a zig-zag model of the 30 nm chromatin fiber. J Mol Biol. 284(1):71–84. 10.1006/jmbi.1998.2150 [PubMed: 9811543] [CrossRef]
• Singleton BK, Griffin CS, Thacker J (2002). Clustered DNA damage leads to complex genetic changes in irradiated human cells. Cancer Res. 62(21):6263–9. [PubMed: 12414656]
• Snyder AR, Morgan WF (2005). Lack of consensus gene expression changes associated with radiation-induced chromosomal instability. DNA Repair (Amst). 4(9):958–70. 10.1016/j.dnarep.2005.04.003 [PubMed: 15996903] [CrossRef]
• Stewart FA, Akleyev AV, Hauer-Jensen M, Hendry JH, Kleiman NJ, Macvittie TJ, et al.; on behalf of ICRP (2012). ICRP Publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs – threshold doses for tissue reactions in a radiation protection context. Ann ICRP. 41(1–2):1–322 [PubMed: 22925378]
• Templin T, Amundson SA, Brenner DJ, Smilenov LB (2011). Whole mouse blood microRNA as biomarkers for exposure to γ-rays and ⁵⁶Fe ions. Int J Radiat Biol. 87(7):653–62. 10.3109/09553002.2010.549537 [PMC free article: PMC3586327] [PubMed: 21271940] [CrossRef]
• Toyokuni H, Maruo A, Suzuki K, Watanabe M (2009). The contribution of radiation-induced large deletion of the genome to chromosomal instability. Radiat Res. 171(2):198–203. 10.1667/RR1464.1 [PubMed: 19267545] [CrossRef]
• UNSCEAR (1993). Sources and effects of ionizing radiation. UNSCEAR 1993 Report. New York, USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: http://www​.unscear.org​/docs/publications​/1993/UNSCEAR_1993_Report.pdf.
• UNSCEAR (2000). Sources and effects of ionizing radiation. UNSCEAR 2000 Report. Volume II: effects. New York, USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: http://www​.unscear.org​/unscear/en/publications/2000_2.html.
• UNSCEAR (2008). Effects of ionizing radiation. UNSCEAR 2006 Report. Volume I: report to the General Assembly, with Scientific Annexes A and B. New York, USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: http://www​.unscear.org​/docs/publications​/2006/UNSCEAR_2006_Report_Vol.I.pdf.
• UNSCEAR (2010). Sources and effects of ionizing radiation. UNSCEAR 2008 Report. Volume II: effects. Scientific Annexes C, D and E. New York, USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: http://www​.unscear.org​/docs/publications​/2008/UNSCEAR_2008_Report_Vol.II.pdf.
• UNSCEAR (2012). Biological mechanisms of radiation actions at low doses. New York, USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: http://www​.unscear.org​/docs/reports/Biological​_mechanisms_WP_12-57831.pdf.
• Valentin J (2005). Low-dose extrapolation of radiation-related cancer risk. ICRP Publication 99. Ann ICRP. 35(4):1–140. 10.1016/j.icrp.2005.11.002 [PubMed: 16782497] [CrossRef]
• Williams ES, Klingler R, Ponnaiya B, Hardt T, Schrock E, Lees-Miller SP, et al. (2009). Telomere dysfunction and DNA-PKcs deficiency: characterization and consequence. Cancer Res. 69(5):2100–7. 10.1158/0008-5472.CAN-08-2854 [PMC free article: PMC3595006] [PubMed: 19244120] [CrossRef]
• Yang F, Stenoien DL, Strittmatter EF, Wang J, Ding L, Lipton MS, et al. (2006). Phosphoproteome profiling of human skin fibroblast cells in response to low- and high-dose irradiation. J Proteome Res. 5(5):1252–60. 10.1021/pr060028v [PubMed: 16674116] [CrossRef]