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Targeted and non-targeted effects of ionizing radiation
J o u r n a l o f R a d i a t i o n R e s e a r c h a n d A p p l i e d S c i e n c e s 8 ( 2 0 1 5 ) 2 4 7 e2 5 4
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Journal of Radiation Research and Applied Sciences journal homepage: http://www.elsevier.com/locate/jrras
Targeted and non-targeted effects of ionizing radiation Omar Desouky a,*, Nan Ding b, Guangming Zhou b a
Radiation Physics Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Cairo, Egypt b Department of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
article info
abstract
Article history:
For a long time it was generally accepted that effects of ionizing radiation such as cell
Received 26 February 2015
death, chromosomal aberrations, DNA damage, mutagenesis, and carcinogenesis result
Accepted 6 March 2015
from direct ionization of cell structures, particularly DNA, or from indirect damage through
Available online 19 March 2015
reactive oxygen species produced by radiolysis of water, and these biological effects were attributed to irreparable or misrepaired DNA damage in cells directly hit by radiation. Using
Keywords:
linear non-threshold model (LNT), possible risks from exposure to low dose ionizing ra-
Target theory
diation (below 100 mSv) are estimated by extrapolating from data obtained after exposure
Bystander effect
to higher doses of radiation. This model has been challenged by numerous observations, in
Adaptive response
which cells that were not directly traversed by the ionizing radiation exhibited responses
Radiation protection
similar to those of the directly irradiated cells. Therefore, it is nowadays accepted that the
Linear non-threshold
detrimental effects of ionizing radiation are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects. Copyright © 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
All living organisms are daily exposed to radiation. In addition to diagnostic and therapeutic medical exposures, we are exposed chronically to background radiation from cosmic rays, radioactive waste, radon decay, nuclear tests, and accidents. The contribution to dose from naturally occurring radionuclides is much larger. In recent years, it has become evident that inhalation of the short-lived decay products of 222 Rn is one of the more important sources of natural exposure. The diagnostic applications of ionizing radiation (IR) in medicine include the use of X-rays and radioisotopes in
diagnostic imaging. Natural radiation and radioactivity in the environment, along with diagnostic medical exposure, make up the very largest part of the accumulated annual dose to human beings who are not occupationally exposed to ionizing radiation from other sources during their daily work activity. Despite the vast benefits derived from various medical applications, radiation can be harmful and is well established as a carcinogen to living organisms (Little, 2003). The adverse effects of radiation are grouped into two categories: deterministic effects and stocohahstic effects. Deterministic effects are based on cell killing and characterized by a threshold dose. Below the threshold dose there is no clinical effect. Stochastic effects are associated with long-term, low-level (chronic)
* Corresponding author. E-mail address: [email protected] (O. Desouky). Peer review under responsibility of The Egyptian Society of Radiation Sciences and Applications. http://dx.doi.org/10.1016/j.jrras.2015.03.003 1687-8507/Copyright © 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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exposure to radiation. With exposures above the threshold dose the severity of the injury increases with dose. The probabilities of experiencing detrimental effects from exposure to low-dose radiation are estimated by extrapolating from data obtained after exposure to high-dose radiation, using a linear model without a threshold (the LNT model). Using this model, possible risks from exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to higher doses of radiation (Matsumoto, Tomita, Otsuka &, Hatashita, 2009). The LNT model has been widely used to establish international rules and standards of radiation protection (ICRP). It follows the notion that increases in the physical energy deposition of IR linearly increases the carcinogenic risk with increasing dose. The conventional model, based on direct targeted effects of radiation, has developed in radiobiology and it has been extended to apply to radiation health risks and to guide radiation protection practice. The radiation effects have been explained using target theory. According to this, deleterious effects of IR, such as mutation and carcinogenesis, are attributed to damage to a cellular target, usually identified as nuclear DNA via direct absorption of radiation energy, the consequences of which are expressed in the surviving irradiated cells (UNSCEAR 1993). Although this model is applied carefully and conservatively, there is room for concern about the validity of the low dose exposure risks obtained in this way because a number of findings have accumulated which cannot be explained by the classical “target theory” of radiation biology. Specific cellular responses observed in response to low dose and/or low doserate radiation have been described as the radioadaptive response, the radiation-induced bystander response, lowdose hyper-radiosensitivity, and genomic instability. All of these phenomena are considered to be responses to radiation which involve non-targeted molecules or molecules which have not interacted directly with radiation (Waldren 2004). The propagation of damaging effects from irradiated to nonirradiated bystander cells would, presumably, result in supra-linear doseeresponse relationships. In contrast, the expression of adaptive responses that mitigate the initial damaging effects induced by radiation would suggest an infralinear doseeresponse relationship or the existence of a threshold dose, below which there would be no risk.
2. Conventional interactions of ionizing radiation with biological matter 2.1.
Interaction types
Ionizing radiation is energetic and penetrating. Many of its chemical effects in biological matter are due to the geometry of the initial physical energy deposition events, referred to as the track structure. Ionizing radiation exists in either particulate or electromagnetic types. The particulate radiation interacts with the biological tissue either by ionization or excitation. The ionizations and excitations that it produced tend to be localized, along the tracks of individual charged particles. Whereas the photon can penetrate matter without
interacting, it can be completely absorbed by depositing its energy, or it can be scattered (deflected) from its original direction and deposit part of its energy as follows: 1. Photoelectric interaction: a photon transfers all its energy to an electron located in one of the atomic shells, usually the outer shell. The electron is ejected from the atom and begins to pass through surrounding matter. 2. Compton scattering: only a portion of the photon energy is absorbed and a photon is scattered with reduced energy. The photon that is produced leaves in a different direction than that of the original photon with different energy. 3. Pair production: the photon interacts with the nucleus in such a way that its energy is converted to matter producing a pair of particles, an electron and a positively charged positron. This only occurs with photons with energies in excess of 1.02 MeV. (Hall & Giaccia, 2011)
3.
Direct and indirect effect
Radiation damage to the cell can be caused by the direct or indirect action of radiation on the DNA molecules. In the direct action, the radiation hits the DNA molecule directly, disrupting the molecular structure. Such structural change leads to cell damage or even cell death. Damaged cells that survive may later induce carcinogenesis or other abnormalities. This process becomes predominant with high-LET radiations such as a-particles and neutrons, and high radiation doses. In the indirect action, the radiation hits the water molecules, the major constituent of the cell, and other organic molecules in the cell, whereby free radicals such as hydroxyl (HO) and alkoxy (RO2) are produced. Free radicals are characterized by an unpaired electron in the structure, which is very reactive, and therefore reacts with DNA molecules to cause a molecular structural damage. Hydrogen peroxide, H2O2, is also toxic to the DNA molecule. The result of indirect action of radiation on DNA molecules is the impairment of function or death of the cell. The number of free radicals produced by ionizing radiation depends on the total dose. It has been found that the majority of radiationinduced damage results from the indirect action mechanism because water constitutes nearly 70% of the composition of the cell (Saha, 2013). In addition to the damages caused by water radiolysis products (i.e. the indirect effect), cellular damage may also involve reactive nitrogen species (RNS) and other species (Wardman, 2009), and can occur also as a result of ionization of atoms on constitutive key molecules (e.g. DNA). The ultimate result, of direct and indirect effects, is the development of biological and physiological alterations that may manifest themselves seconds or decades later. Genetic and epigenetic changes may be involved in the evolution of these alterations (Koturbash, 2008).(Fig. 1) X-ray and g-ray photons deposit energy in tissue in a highly dispersed manner, characterized as low “linear energy transfer” (LET). IR can be either low LET (sparsely ionizing) or high LET (densely ionizing). Photons are low LET radiation, displaying a very broad energy distribution in tissue, and the peak dose is located relatively close to the surface. Heavy
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they do to high dose/high dose-rate radiation (Waldren, 2004). These effects have been termed “non-(DNA)-targeted” (Ward, 1999) and include radiation-induced bystander effects (Iyer & Lehnert, 2000), genomic instability (Wright, 1998, 2000), adaptive response (Wolff, 1998), low dose hyperradiosensitivity (HRS) (Joiner, 2001), delayed reproductive death and induction of genes by radiation (Amundson et al., 2001). An essential feature of “non-targeted” effects is that they do not require a direct nuclear exposure by irradiation to be expressed and they are particularly significant at low doses.
5.
Fig. 1 e Direct and indirect actions of radiation (modified from Hall & Giaccia, 2011). charged particles are high LET and interact with matter by depositing energy quite differently from photons. Because of their large mass, compared with electrons, charged particles travel in straight trajectories as they penetrate tissue (Furusawa, 2014; Weber & Kraft, 2009).
4.
Paradigm shift in target theory
The LNT theory assumes a linear relationship between DNA damage in the form of double-strand breaks (DSB), that each DSB will have the same probability of inducing a cell transformation, and that each transformed cell will have the same probability of developing into a cancer (Tubiana, Feinendegen, Yang, & Kaminski, 2009). Thus, cancer is thought to result from mutagenic DNA damage to a single cell caused by a single radiation track (Little et al., 2009). A low LET dose of 1 mGy is delivered to one cell nucleus by one electron track (NCRP, 2001). The LNT assumption is easy to implement utilizing the equivalent dose (biological damage weighted measure) and the effective dose (equivalent dose multiplied by a tissue weighting factor). Expected cancer cases are easily calculated based on the summed effective dose (person-sievert) for an irradiated population (Scott, 2008). The LNT assumption does not consider the role of biological defense mechanisms, but assumes that cancer risk proceeds in a proportionate linear fashion without a threshold to a point of zero dose through the origin. The LNT assumption with a low dose and dose rate effectiveness factor (DDREF) guarantees that any radiation dose, no matter how small, increases the risk of cancer. The validity of using this doseeresponse model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose/low dose-rate radiation than
Radiation induced bystander effects
The ionizing radiation-induced bystander effects (RIBE) is broadly defined as the occurrence of biological effects in unirradiated cells as a result of exposure of other cells in the population to radiation. Bystander effects have been mainly observed in high density cell cultures exposed to low fluences of a particles wherein only a small fraction of cells is irradiated (Nagasawa & Little, 1992). RIBE show non-linear doseeresponse; they are more pronounced at low doses of radiation and tend to disappear, though not always, at high radiation doses, suggesting an onoff mechanism. As a result, they are frequently linked to lowdose radiation effects and thus to radiation protection (Morgan & Bair, 2013). Obviously, such non-targeted effects change the actual radiation target size and give rise to nonlinear responses in cell populations and tissues. Moreover, they put very much into question the overall validity of the LNT hypothesis (Morgan & Sowa, 2007). RIBE have been observed in a variety of endpoints including DNA damage induction (Yang, Assad, & Held, 2005), as well as in the induction of mutations, micronuclei (MN) formation (Azzam, De Toledo, Spitz, & Little, 2002; Huo, Nagasawa, & Little, 2001; Kashino et al., 2004; Zhou, 2000), sister chromatid exchanges (SCE), chromosomal instability (Limoli & Giedzinski, 2003; Lorimore et al., 1998), transformation (Sawant, Randers-Pehrson, Geard, Brenner, & Hall, 2001), cell death or apoptosis (Belyakov, Folkard, Mothersill, Prise, & Michael, 2002), altered gene expression (Iyer & Lehnert, 2000), differentiation (Gerashchenko & Howell, 2003), and alteration in the microRNAs (miRNAs) profile (Koturbash, Zemp, Kolb, & Kovalchuk, 2011; Kovalchuk et al., 2010). All these manifestations of RIBE require DNA damage.
6. Probable mechanisms of the bystander effects Non-targeted effect represents a paradigm shift in our understanding of the mechanism (s) of how radiation might exert its effects. It is likely that multiple pathways are involved in signaling the response from an irradiated cell to a non-irradiated cell, and that different cell types will respond differently to the signaling pathways stimulated. It appears that a bystander signal may be transmitted either by direct cell-to-cell contact or through soluble factors released into the culture medium (Little, 2006).
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Cell-to-cell communications
The ability of cells to communicate with one another plays a crucial role in the radiation induced bystander phenomenon. Cell-to-cell communication is a complicated multistage process. However published literature (Nikjoo & Khvostunov (2004)) identified two main pathways of cell signaling involved in the radiation induced bystander phenomenon short range Gap Junctional Intercellular Communication (GJIC) and long range Distant Cell Signaling Intercellular Communication (DSIC), mediated by soluble transmissible factors and propagated by Brownian active or passive diffusive motion. One of the reported mechanisms of the RIBE is the gapejunction mediated intercellular communication (GJIC) which depends on the intercellular gap junctions' ability to transmit signals from irradiated to unirradiated cells (Azzam, de Toledo, & Little, 2001). GJIC is mainly regulated by the expression and phosphorylation of connexin43 protein (C x 43) which is located in gap junctions (Dowling-Warriner & Trosko, 2000). Evidence for the involvement of GJIC in propagation of bystander effects has been derived from studies with a particle, b particle, g-rays, and HZE radiations. These studies highlight the relevance of bystander responses to radiotherapy, diagnostic radiology, and risk of environmental and occupational exposures (Howell et al., 2006). Participation of GJIC in stress-induced bystander effects is not unique to ionizing radiation; it has also been described in high density cell populations exposed to chemotherapeutic agents. Toxicity of these compounds was enhanced by functional gapejunction communication in target cells (Jensen & Glazer, 2004).
6.2.
ROS & RNS
Direct intercellular communication is not unique in propagating radiation-induced non-targeted effects. A wealth of data has also shown the critical importance of secreted diffusible factors in the expression of radiation-induced nontargeted effects (Mothersill & Seymour, 2004). TGF-b, interleukin-8, serotonin and others have been implicated in propagation of bystander effects (Lehnert & Goodwin, 1997). The other proposed mechanisms of RIBE is known as a medium-mediated bystander effect, and is based on the ability of irradiated cells to excrete intracellularly-generated low-molecular-weight factors in the growth medium (e.g. ROS, cytokines, calcium ions, small RNAs) that are then received by unirradiated cells (Merrifield & Kovalchuk, 2013). There is wealth of evidence that ROS contribute to the bystander effect extracellularly and also intracellularly through a continuous cascade of events (Azzam et al., 2002). ROS are produced directly by the irradiated cells as radiolytic products or indirectly via inflammatory process and pass to neighboring bystander cells through passive diffusion, gap junctions, or active transport (Azzam, de Toledo, & Little, 2003). Although, most ROS have a short half-life and cause damage locally, hydrogen peroxide (H2O2) has relatively longer half-life. It can also migrate freely across plasma membranes and travel long distances causing DNA damage at distant sites (Sokolov, Dickey, Bonner, & Sedelnikova, 2007).
Furthermore, hydroxyl radicals and to a lesser extent the singlet molecular oxygen can react with DNA, as well as with proteins and lipids (Hussain, Hofseth, & Harris, 2003), resulting in the modulation of their functions. With regard to radiation exposure, there are at least two main factors which play an important role in radiationinduced bystander signaling, the quality and the quantity of the radiation. The involvement of the quality of radiation exposure in RIBE signaling pathways has been questioned and some experimental work (Lorimore, Coates, Scobie, Milne, & Wright, 2001) suggested that the gap junction intercellular communication is more likely to be induced by high LET radiation (Should be careful about this point! are there follow-up studies?). Whereas bystander signal propagation, mediated via distant intercellular communication mechanisms, is more likely to be triggered by low LET radiation. Thus, Mothersill and Seymour (Mothersill & Seymour, 1998) demonstrated that the cell to cell contact is not required to induce bystander responses in non-targeted cells after low LET irradiation. Overall, several studies challenge the traditional paradigm that the important biological effects of ionizing radiation are due to DNA damage induced as a result of direct interaction of the radiation track with the cell nucleus. They indicate that irradiated and non-irradiated cells interact, and oxidative metabolism and intercellular communication have an essential role in signaling events leading to radiation-induced bystander effects. However, clear evidence explaining how these events occur is still lacking. Regardless, the occurrence of bystander effects implies that the modeling of dose response relationships based on the number of irradiated cells may not be a valid approach (Little, 2003). However, despite the enormous amount of data on RIBE, until today, their nature remains elusive; some studies have clearly shown that there is no evidence of any bystander effect using various biological endpoints (Terzoudi, DontaBakoyianni, Iliakis, & Pantelias, 2010). The relatively unclear results regarding the mechanisms underlying RIBE as well as the controversial results from various experimental studies and systems indicate that the research on bystander effects will serve as an interesting scientific playground for debate in current and future radiobiology. The experimental evidence on RIBE, indicate that a more analytical and mechanistic in depth approach is needed to secure an answer to one of the most interesting questions in radiobiology (Vasiliki et al., 2015).
7. Radiation-induced adaptive response (RIAR) The “adaptive response” is a phenomenon generally induced by low dose/low LET radiation that protects cells and whole organisms against endogenous damage or damage due to a subsequent dose of radiation (Wolff, 1992). Data generated over the last three decades suggest that exposure of mammalian cells, including human cells, to low doses of low LET radiation (e.g. X-rays, g-rays, b particles) induces molecular processes that are different from those induced by high dose radiation (Feinendegen, Paratzke, & Neumann, 2007). Such processes were found to be protective against stress
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measured by several biological endpoints (de Toledo & Azzam, 2006). Radiation-induced adaptive responses were dependent on the adapting dose, dose rate, expression time, culture conditions and stage of the cell cycle (Shadley, 1994). Chronic exposure of mouse embryo fibroblasts to cobalt-60 g-radiation at doses as low as 10 cGy protected the cells not only against damage from endogenous metabolic processes, but also against neoplastic transformation by a subsequent large acute radiation exposure (Azzam, Raaphorst, & Mitchel, 1994). Peripheral blood lymphocytes isolated from a group of 41 temporary nuclear plant workers receiving doses ranging from 0 to 10 mSv showed no increase in the baseline micronuclei frequencies as compared to the control values before the in vivo dose (Thierens et al., 2002). After an in vitro challenging dose of 3.5 Gy 60Co g-rays, given either at a high-dose rate (1 Gy/min) or a low-dose rate (4 mGy/min), the number of micronuclei was statistically lower for the exposed persons as compared to the non-exposed persons. Interestingly, the level of adaptation was elevated if the challenging dose was given at a low-dose rate. A definitive proof of adaptive response belonging to the group of non-targeted effects came from a study by Iyer and Lehnert, demonstrating that non-irradiated human lung fibroblast cells (HFL-1) were able to adapt if grown in a medium transferred from HFL-1 cells, irradiated with either 0.1 Gy g-rays or 0.1 Gy a-particles (Iyer & Lehnert, 2002). The adaptation was shown as increased clonogenic survival after a challenging dose of 2 or 4 Gy g-rays, or 1.0 or 1.9 Gy a-particles, respectively. Adaptive response was found to be associated with a decreased level of p53 protein, increased level of intracellular ROS as well as increased level of DNA repair protein AP-endonuclease. The study suggested that nontargeted cells are able to adapt after receiving an extracellular signal. There are three major cellular defense systems against ionizing radiation that comprise the radioadaptive response (Tubiana, Arengo, Averbeck, & Masse, 2007): (1) protection against reactive oxygen species (ROS) by antioxidant molecules (such as glutathione) and detoxifying enzymes (such as catalase and superoxide dismutase); (2) DNA repair, particularly for double-strand breaks, that disappears at doses >0.5 Gy; and (3) elimination of genomically damaged cells by immune defenses and apoptosis at doses as low as a few mSv. The hormesis response is associated with increased lifespan, and decreased mutations, chromosome aberrations, neoplastic transformations, cancer, and congenital malformations (Kant, Chauhan, & Sharma, 2003). The adaptive response occurs at dose values ranging from 0.01 to 0.5 Gy and at dose rate values ranging from 0.01 to 1.0 Gy/min (Aurengo, Averbeck, & Bonnin, 2005). The radioadaptive response appears most beneficial at doses <0.1 Gy. The response begins to disappear at doses >0.2 Gy of low-LET radiation and is rarely seen at a dose of >0.5 mGy. However, the probability of apoptosis appears to increase in a linear fashion beyond 0.5 mGy (Feinendegen et al., 2007). The bottom line for most of the studies on the adaptive response is that biological processes are activated by low doses of ionizing radiation that trigger repair and protective processes and decrease the risk for late effects of radiation. These adaptive processes support the possibility that
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intervention that enhances these normal processes is possible and may provide an avenue to modify and decrease the risk for cancer induced by low doses of ionizing radiation (Brooks, 2005).
8.
Radiation protection
Radiological protection is a science-based discipline in which concepts, methods, and procedures are developed to be used for the protection of humans and the environment from the harmful effects of ionizing radiation. More specifically, radiological protection has the objective of reducing the likelihood of radiation-induced stochastic effects, in particular cancer, and preventing deterministic effects, also called ‘tissue reactions’. Recommendations and practical guidance for radiological protection have been developed by the International Commission on Radiological Protection (ICRP) for more than 80 years and in its 2007 Recommendations the Commission has described its latest system of protection with this aim in mind (Menzel, & Harrison, 2012). Almost all regulatory requirements authorizing activities that use ionizing radiation such as in industry, health, agriculture, and basic research, is based on the radiation protection concept that hinges on the acceptance of the linear nonthreshold (LNT) theory. LNT implies that any dose, no matter how low, can pose risks for genetic (hereditary) defects or cause cancer. Cancer risk is assumed to increase linearly with increasing radiation dose, with no threshold. LNT was derived using statistically significant doseeresponse (DR) relationship between radiation dose received by the survivors of the atomic bomb explosions in Hiroshima and Nagasaki and the observed health effects, mainly hereditary disorders and cancer (Decades later, non-cancer risks are also derived from the same population). The DR was based on the observable significant clinical/deterministic effects that were seen on population exposed at high doses, from 0.2 Gy upwards. Below this dose, there were no observable effects seen on the population. Nevertheless, DR is assumed to be linear down to zero dose. The extrapolation to zero of the DR has not been supported by sufficient evidence/data in man to show its linearity at low doses. However, this assumption has been accepted to be the conservative and most careful approach to address the delayed effects of ionizing radiation, and to estimate health risks at low doses (Aleta, 2009). The LNT model is being challenged particularly in relation to the environment because it is now clear that at low doses of concern in radiation protection, cells, tissues and organisms respond to radiation by inducing responses which are not readily predictable by dose. These include adaptive responses, bystander effects; genomic instability and low dose hypersensitivity. The phenomena contribute to observed radiation responses and appear to be influenced by genetic, epigenetic and environmental factors, meaning that dose and response are not simply related and the modeling of dose response relationships based on the number of irradiated cells may not be a valid approach (Little, 2003).
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ICRP in its new review (2007), considered possible challenges to its linear non-threshold model but concluded that for the purposes of radiological protection, it is scientifically reasonable to assume that the incidence of cancer or hereditary disorders will rise in direct proportion to an increase in the equivalent dose in the relevant organs and tissues, below about 100 mSv. ICRP also considered issues such as cellular adaptive responses, genomic instability and bystander signaling but notes that ‘since the estimation of nominal cancer risk coefficients is based upon direct human epidemiological data, any contribution from these biological mechanisms would be included in that estimate’ (Wrixon, 2008). BEIR VII concluded that the available biological and biophysical low dose data support a linear-no-threshold (LNT) risk model. According to this model, even the smallest dose of radiation has the potential to cause a small increase in health risk to humans. The reports from UNSCEAR and the ICRP concluded that the LNT hypothesis remains a prudent basis for radiation protection at low doses and low dose rates, but may not reflect biological differences and risks in the low dose region (Morgan & Bair, 2013)
9.
Conclusion
This paper has reviewed new information that demonstrates that bystander effects and adaptive responses which important parts of the response of molecules, cells and tissues to ionizing radiation. It is important to recognize that these new observations make it possible to shift from the assumption that radiation has to interact with a cell directly only.
Acknowledgments This work was supported by TWAS-UNISCO, Chinese academy of science and institute of modern physics.
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Koturbash, I., Kutanzi, K., Hendrickson, K., Rodriguez-Juarez, R., Kogosov, D., & Kovalchuk, O. (2008). Radiation-induced bystander effects in vivo are sex specifi c. Mutation Research, 642(1e2), 28e36. Koturbash, I., Zemp, F., Kolb, B., & Kovalchuk, O. (2011). Sexspecific radiation-induced microRNAome responses in the hippocampus, cerebellum and frontal cortex in a mouse model. Mutation Research: Fundamental and Molecular Mechanisms of Mutagenesis, 722, 114e118. Kovalchuk, O., Zemp, F. J., Filkowski, J. N., Altamirano, A. M., Dickey, J. S., Jenkins-Baker, G., et al. (2010). MicroRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways. Carcinogenesis, 31, 1882e1888. Lehnert, B. E., & Goodwin, E. H. (1997). Extracellular factor(s) following exposure to alpha particles can cause sister chromatid exchanges in normal human cells. Cancer Research, 57, 2164e2171. Limoli, C. L., & Giedzinski, E. (2003). Induction of chromosomal instability by chronic oxidative stress. Neoplasia, 5, 339e346. Little, J. B. (2003). Genomic instability and bystander effects: a historical perspective. Oncogene, 22, 6978e6987. Little, J. B. (2006). Cellular radiation effects and the bystander response. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 597, 113e118. Little, M. P., Wakeford, R., Janet Tawn, E., Bouffler, Simon D., de Gonzalez, A. Berrington, et al. (2009). Risks associated with low doses and low dose rates of ionizing radiation: why linearity may be (almost) the best we can do. Radiology, 251, 6e12. Lorimore, S. A., Coates, P. J., Scobie, G. E., Milne, G., & Wright, E. G. (2001). Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Oncogene, 20(48), 7085e7095. Lorimore, S. A., Kadhim, M., Pocock, D. A., Papworth, D., Stevens, D. L., Goodhead, D. T., et al. (1998). Chromosomal instability in the descendants of unirradiated surviving cells after a-particle irradiation. Proceedings of the National Academy Sciences USA, 95, 5730e5733. Menzel, H.-G., & Harrison, J. (2012). Effective dose: a radiation protection quantity. Annals of the ICRP, 41, 117e123. Merrifield, M., & Kovalchuk, O. (2013). Epigenetics in radiation biology: a new research frontier. Frontiers in Genetics, 4, 1e5. Morgan, W. F., & Bair, W. J. (2013). Issues in low dose radiation biology: the controversy continues. A perspective. Radiation Research, 179, 501e510. Morgan, W. F., & Sowa, M. B. (2007). Non-targeted bystander effects induced by ionizing radiation. Mutation Research, 616, 159e164. Mothersill, C., & Seymour, C. B. (1998). Cellecell contact during gamma irradiation is not required to induce a bystander effect in normal human keratinocytes: evidence for release during irradiation of a signal controlling survival into the medium. Radiation Research, 149, 256e262. Mothersill, C., & Seymour, C. B. (2004). Radiation-induced bystander effectseimplications for cancer. Nature Reviews Cancer, 4, 158e164. Nagasawa, H., & Little, J. B. (1992). Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Research, 52, 6394e6396. NCRP (National Council on Radiation Protection and Measurements). (2001). Evaluation of the linear-non-threshold dose-response model for ionizing radiation. NCRP Report No. 136, Bethesda, MD. Nikjoo, H., & Khvostunov, I. K. (2004). A theoretical approach to the role and critical issues associated with bystander effect in risk estimation. Human & Experimental Toxicology, 23, 81e86.
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Journal of Radiation Research and Applied Sciences journal homepage: http://www.elsevier.com/locate/jrras
Targeted and non-targeted effects of ionizing radiation Omar Desouky a,*, Nan Ding b, Guangming Zhou b a
Radiation Physics Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Nasr City, Cairo, Egypt b Department of Space Radiobiology, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
article info
abstract
Article history:
For a long time it was generally accepted that effects of ionizing radiation such as cell
Received 26 February 2015
death, chromosomal aberrations, DNA damage, mutagenesis, and carcinogenesis result
Accepted 6 March 2015
from direct ionization of cell structures, particularly DNA, or from indirect damage through
Available online 19 March 2015
reactive oxygen species produced by radiolysis of water, and these biological effects were attributed to irreparable or misrepaired DNA damage in cells directly hit by radiation. Using
Keywords:
linear non-threshold model (LNT), possible risks from exposure to low dose ionizing ra-
Target theory
diation (below 100 mSv) are estimated by extrapolating from data obtained after exposure
Bystander effect
to higher doses of radiation. This model has been challenged by numerous observations, in
Adaptive response
which cells that were not directly traversed by the ionizing radiation exhibited responses
Radiation protection
similar to those of the directly irradiated cells. Therefore, it is nowadays accepted that the
Linear non-threshold
detrimental effects of ionizing radiation are not restricted only in the irradiated cells, but also to non-irradiated bystander or even distant cells manifesting various biological effects. Copyright © 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
All living organisms are daily exposed to radiation. In addition to diagnostic and therapeutic medical exposures, we are exposed chronically to background radiation from cosmic rays, radioactive waste, radon decay, nuclear tests, and accidents. The contribution to dose from naturally occurring radionuclides is much larger. In recent years, it has become evident that inhalation of the short-lived decay products of 222 Rn is one of the more important sources of natural exposure. The diagnostic applications of ionizing radiation (IR) in medicine include the use of X-rays and radioisotopes in
diagnostic imaging. Natural radiation and radioactivity in the environment, along with diagnostic medical exposure, make up the very largest part of the accumulated annual dose to human beings who are not occupationally exposed to ionizing radiation from other sources during their daily work activity. Despite the vast benefits derived from various medical applications, radiation can be harmful and is well established as a carcinogen to living organisms (Little, 2003). The adverse effects of radiation are grouped into two categories: deterministic effects and stocohahstic effects. Deterministic effects are based on cell killing and characterized by a threshold dose. Below the threshold dose there is no clinical effect. Stochastic effects are associated with long-term, low-level (chronic)
* Corresponding author. E-mail address: [email protected] (O. Desouky). Peer review under responsibility of The Egyptian Society of Radiation Sciences and Applications. http://dx.doi.org/10.1016/j.jrras.2015.03.003 1687-8507/Copyright © 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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exposure to radiation. With exposures above the threshold dose the severity of the injury increases with dose. The probabilities of experiencing detrimental effects from exposure to low-dose radiation are estimated by extrapolating from data obtained after exposure to high-dose radiation, using a linear model without a threshold (the LNT model). Using this model, possible risks from exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to higher doses of radiation (Matsumoto, Tomita, Otsuka &, Hatashita, 2009). The LNT model has been widely used to establish international rules and standards of radiation protection (ICRP). It follows the notion that increases in the physical energy deposition of IR linearly increases the carcinogenic risk with increasing dose. The conventional model, based on direct targeted effects of radiation, has developed in radiobiology and it has been extended to apply to radiation health risks and to guide radiation protection practice. The radiation effects have been explained using target theory. According to this, deleterious effects of IR, such as mutation and carcinogenesis, are attributed to damage to a cellular target, usually identified as nuclear DNA via direct absorption of radiation energy, the consequences of which are expressed in the surviving irradiated cells (UNSCEAR 1993). Although this model is applied carefully and conservatively, there is room for concern about the validity of the low dose exposure risks obtained in this way because a number of findings have accumulated which cannot be explained by the classical “target theory” of radiation biology. Specific cellular responses observed in response to low dose and/or low doserate radiation have been described as the radioadaptive response, the radiation-induced bystander response, lowdose hyper-radiosensitivity, and genomic instability. All of these phenomena are considered to be responses to radiation which involve non-targeted molecules or molecules which have not interacted directly with radiation (Waldren 2004). The propagation of damaging effects from irradiated to nonirradiated bystander cells would, presumably, result in supra-linear doseeresponse relationships. In contrast, the expression of adaptive responses that mitigate the initial damaging effects induced by radiation would suggest an infralinear doseeresponse relationship or the existence of a threshold dose, below which there would be no risk.
2. Conventional interactions of ionizing radiation with biological matter 2.1.
Interaction types
Ionizing radiation is energetic and penetrating. Many of its chemical effects in biological matter are due to the geometry of the initial physical energy deposition events, referred to as the track structure. Ionizing radiation exists in either particulate or electromagnetic types. The particulate radiation interacts with the biological tissue either by ionization or excitation. The ionizations and excitations that it produced tend to be localized, along the tracks of individual charged particles. Whereas the photon can penetrate matter without
interacting, it can be completely absorbed by depositing its energy, or it can be scattered (deflected) from its original direction and deposit part of its energy as follows: 1. Photoelectric interaction: a photon transfers all its energy to an electron located in one of the atomic shells, usually the outer shell. The electron is ejected from the atom and begins to pass through surrounding matter. 2. Compton scattering: only a portion of the photon energy is absorbed and a photon is scattered with reduced energy. The photon that is produced leaves in a different direction than that of the original photon with different energy. 3. Pair production: the photon interacts with the nucleus in such a way that its energy is converted to matter producing a pair of particles, an electron and a positively charged positron. This only occurs with photons with energies in excess of 1.02 MeV. (Hall & Giaccia, 2011)
3.
Direct and indirect effect
Radiation damage to the cell can be caused by the direct or indirect action of radiation on the DNA molecules. In the direct action, the radiation hits the DNA molecule directly, disrupting the molecular structure. Such structural change leads to cell damage or even cell death. Damaged cells that survive may later induce carcinogenesis or other abnormalities. This process becomes predominant with high-LET radiations such as a-particles and neutrons, and high radiation doses. In the indirect action, the radiation hits the water molecules, the major constituent of the cell, and other organic molecules in the cell, whereby free radicals such as hydroxyl (HO) and alkoxy (RO2) are produced. Free radicals are characterized by an unpaired electron in the structure, which is very reactive, and therefore reacts with DNA molecules to cause a molecular structural damage. Hydrogen peroxide, H2O2, is also toxic to the DNA molecule. The result of indirect action of radiation on DNA molecules is the impairment of function or death of the cell. The number of free radicals produced by ionizing radiation depends on the total dose. It has been found that the majority of radiationinduced damage results from the indirect action mechanism because water constitutes nearly 70% of the composition of the cell (Saha, 2013). In addition to the damages caused by water radiolysis products (i.e. the indirect effect), cellular damage may also involve reactive nitrogen species (RNS) and other species (Wardman, 2009), and can occur also as a result of ionization of atoms on constitutive key molecules (e.g. DNA). The ultimate result, of direct and indirect effects, is the development of biological and physiological alterations that may manifest themselves seconds or decades later. Genetic and epigenetic changes may be involved in the evolution of these alterations (Koturbash, 2008).(Fig. 1) X-ray and g-ray photons deposit energy in tissue in a highly dispersed manner, characterized as low “linear energy transfer” (LET). IR can be either low LET (sparsely ionizing) or high LET (densely ionizing). Photons are low LET radiation, displaying a very broad energy distribution in tissue, and the peak dose is located relatively close to the surface. Heavy
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they do to high dose/high dose-rate radiation (Waldren, 2004). These effects have been termed “non-(DNA)-targeted” (Ward, 1999) and include radiation-induced bystander effects (Iyer & Lehnert, 2000), genomic instability (Wright, 1998, 2000), adaptive response (Wolff, 1998), low dose hyperradiosensitivity (HRS) (Joiner, 2001), delayed reproductive death and induction of genes by radiation (Amundson et al., 2001). An essential feature of “non-targeted” effects is that they do not require a direct nuclear exposure by irradiation to be expressed and they are particularly significant at low doses.
5.
Fig. 1 e Direct and indirect actions of radiation (modified from Hall & Giaccia, 2011). charged particles are high LET and interact with matter by depositing energy quite differently from photons. Because of their large mass, compared with electrons, charged particles travel in straight trajectories as they penetrate tissue (Furusawa, 2014; Weber & Kraft, 2009).
4.
Paradigm shift in target theory
The LNT theory assumes a linear relationship between DNA damage in the form of double-strand breaks (DSB), that each DSB will have the same probability of inducing a cell transformation, and that each transformed cell will have the same probability of developing into a cancer (Tubiana, Feinendegen, Yang, & Kaminski, 2009). Thus, cancer is thought to result from mutagenic DNA damage to a single cell caused by a single radiation track (Little et al., 2009). A low LET dose of 1 mGy is delivered to one cell nucleus by one electron track (NCRP, 2001). The LNT assumption is easy to implement utilizing the equivalent dose (biological damage weighted measure) and the effective dose (equivalent dose multiplied by a tissue weighting factor). Expected cancer cases are easily calculated based on the summed effective dose (person-sievert) for an irradiated population (Scott, 2008). The LNT assumption does not consider the role of biological defense mechanisms, but assumes that cancer risk proceeds in a proportionate linear fashion without a threshold to a point of zero dose through the origin. The LNT assumption with a low dose and dose rate effectiveness factor (DDREF) guarantees that any radiation dose, no matter how small, increases the risk of cancer. The validity of using this doseeresponse model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose/low dose-rate radiation than
Radiation induced bystander effects
The ionizing radiation-induced bystander effects (RIBE) is broadly defined as the occurrence of biological effects in unirradiated cells as a result of exposure of other cells in the population to radiation. Bystander effects have been mainly observed in high density cell cultures exposed to low fluences of a particles wherein only a small fraction of cells is irradiated (Nagasawa & Little, 1992). RIBE show non-linear doseeresponse; they are more pronounced at low doses of radiation and tend to disappear, though not always, at high radiation doses, suggesting an onoff mechanism. As a result, they are frequently linked to lowdose radiation effects and thus to radiation protection (Morgan & Bair, 2013). Obviously, such non-targeted effects change the actual radiation target size and give rise to nonlinear responses in cell populations and tissues. Moreover, they put very much into question the overall validity of the LNT hypothesis (Morgan & Sowa, 2007). RIBE have been observed in a variety of endpoints including DNA damage induction (Yang, Assad, & Held, 2005), as well as in the induction of mutations, micronuclei (MN) formation (Azzam, De Toledo, Spitz, & Little, 2002; Huo, Nagasawa, & Little, 2001; Kashino et al., 2004; Zhou, 2000), sister chromatid exchanges (SCE), chromosomal instability (Limoli & Giedzinski, 2003; Lorimore et al., 1998), transformation (Sawant, Randers-Pehrson, Geard, Brenner, & Hall, 2001), cell death or apoptosis (Belyakov, Folkard, Mothersill, Prise, & Michael, 2002), altered gene expression (Iyer & Lehnert, 2000), differentiation (Gerashchenko & Howell, 2003), and alteration in the microRNAs (miRNAs) profile (Koturbash, Zemp, Kolb, & Kovalchuk, 2011; Kovalchuk et al., 2010). All these manifestations of RIBE require DNA damage.
6. Probable mechanisms of the bystander effects Non-targeted effect represents a paradigm shift in our understanding of the mechanism (s) of how radiation might exert its effects. It is likely that multiple pathways are involved in signaling the response from an irradiated cell to a non-irradiated cell, and that different cell types will respond differently to the signaling pathways stimulated. It appears that a bystander signal may be transmitted either by direct cell-to-cell contact or through soluble factors released into the culture medium (Little, 2006).
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Cell-to-cell communications
The ability of cells to communicate with one another plays a crucial role in the radiation induced bystander phenomenon. Cell-to-cell communication is a complicated multistage process. However published literature (Nikjoo & Khvostunov (2004)) identified two main pathways of cell signaling involved in the radiation induced bystander phenomenon short range Gap Junctional Intercellular Communication (GJIC) and long range Distant Cell Signaling Intercellular Communication (DSIC), mediated by soluble transmissible factors and propagated by Brownian active or passive diffusive motion. One of the reported mechanisms of the RIBE is the gapejunction mediated intercellular communication (GJIC) which depends on the intercellular gap junctions' ability to transmit signals from irradiated to unirradiated cells (Azzam, de Toledo, & Little, 2001). GJIC is mainly regulated by the expression and phosphorylation of connexin43 protein (C x 43) which is located in gap junctions (Dowling-Warriner & Trosko, 2000). Evidence for the involvement of GJIC in propagation of bystander effects has been derived from studies with a particle, b particle, g-rays, and HZE radiations. These studies highlight the relevance of bystander responses to radiotherapy, diagnostic radiology, and risk of environmental and occupational exposures (Howell et al., 2006). Participation of GJIC in stress-induced bystander effects is not unique to ionizing radiation; it has also been described in high density cell populations exposed to chemotherapeutic agents. Toxicity of these compounds was enhanced by functional gapejunction communication in target cells (Jensen & Glazer, 2004).
6.2.
ROS & RNS
Direct intercellular communication is not unique in propagating radiation-induced non-targeted effects. A wealth of data has also shown the critical importance of secreted diffusible factors in the expression of radiation-induced nontargeted effects (Mothersill & Seymour, 2004). TGF-b, interleukin-8, serotonin and others have been implicated in propagation of bystander effects (Lehnert & Goodwin, 1997). The other proposed mechanisms of RIBE is known as a medium-mediated bystander effect, and is based on the ability of irradiated cells to excrete intracellularly-generated low-molecular-weight factors in the growth medium (e.g. ROS, cytokines, calcium ions, small RNAs) that are then received by unirradiated cells (Merrifield & Kovalchuk, 2013). There is wealth of evidence that ROS contribute to the bystander effect extracellularly and also intracellularly through a continuous cascade of events (Azzam et al., 2002). ROS are produced directly by the irradiated cells as radiolytic products or indirectly via inflammatory process and pass to neighboring bystander cells through passive diffusion, gap junctions, or active transport (Azzam, de Toledo, & Little, 2003). Although, most ROS have a short half-life and cause damage locally, hydrogen peroxide (H2O2) has relatively longer half-life. It can also migrate freely across plasma membranes and travel long distances causing DNA damage at distant sites (Sokolov, Dickey, Bonner, & Sedelnikova, 2007).
Furthermore, hydroxyl radicals and to a lesser extent the singlet molecular oxygen can react with DNA, as well as with proteins and lipids (Hussain, Hofseth, & Harris, 2003), resulting in the modulation of their functions. With regard to radiation exposure, there are at least two main factors which play an important role in radiationinduced bystander signaling, the quality and the quantity of the radiation. The involvement of the quality of radiation exposure in RIBE signaling pathways has been questioned and some experimental work (Lorimore, Coates, Scobie, Milne, & Wright, 2001) suggested that the gap junction intercellular communication is more likely to be induced by high LET radiation (Should be careful about this point! are there follow-up studies?). Whereas bystander signal propagation, mediated via distant intercellular communication mechanisms, is more likely to be triggered by low LET radiation. Thus, Mothersill and Seymour (Mothersill & Seymour, 1998) demonstrated that the cell to cell contact is not required to induce bystander responses in non-targeted cells after low LET irradiation. Overall, several studies challenge the traditional paradigm that the important biological effects of ionizing radiation are due to DNA damage induced as a result of direct interaction of the radiation track with the cell nucleus. They indicate that irradiated and non-irradiated cells interact, and oxidative metabolism and intercellular communication have an essential role in signaling events leading to radiation-induced bystander effects. However, clear evidence explaining how these events occur is still lacking. Regardless, the occurrence of bystander effects implies that the modeling of dose response relationships based on the number of irradiated cells may not be a valid approach (Little, 2003). However, despite the enormous amount of data on RIBE, until today, their nature remains elusive; some studies have clearly shown that there is no evidence of any bystander effect using various biological endpoints (Terzoudi, DontaBakoyianni, Iliakis, & Pantelias, 2010). The relatively unclear results regarding the mechanisms underlying RIBE as well as the controversial results from various experimental studies and systems indicate that the research on bystander effects will serve as an interesting scientific playground for debate in current and future radiobiology. The experimental evidence on RIBE, indicate that a more analytical and mechanistic in depth approach is needed to secure an answer to one of the most interesting questions in radiobiology (Vasiliki et al., 2015).
7. Radiation-induced adaptive response (RIAR) The “adaptive response” is a phenomenon generally induced by low dose/low LET radiation that protects cells and whole organisms against endogenous damage or damage due to a subsequent dose of radiation (Wolff, 1992). Data generated over the last three decades suggest that exposure of mammalian cells, including human cells, to low doses of low LET radiation (e.g. X-rays, g-rays, b particles) induces molecular processes that are different from those induced by high dose radiation (Feinendegen, Paratzke, & Neumann, 2007). Such processes were found to be protective against stress
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measured by several biological endpoints (de Toledo & Azzam, 2006). Radiation-induced adaptive responses were dependent on the adapting dose, dose rate, expression time, culture conditions and stage of the cell cycle (Shadley, 1994). Chronic exposure of mouse embryo fibroblasts to cobalt-60 g-radiation at doses as low as 10 cGy protected the cells not only against damage from endogenous metabolic processes, but also against neoplastic transformation by a subsequent large acute radiation exposure (Azzam, Raaphorst, & Mitchel, 1994). Peripheral blood lymphocytes isolated from a group of 41 temporary nuclear plant workers receiving doses ranging from 0 to 10 mSv showed no increase in the baseline micronuclei frequencies as compared to the control values before the in vivo dose (Thierens et al., 2002). After an in vitro challenging dose of 3.5 Gy 60Co g-rays, given either at a high-dose rate (1 Gy/min) or a low-dose rate (4 mGy/min), the number of micronuclei was statistically lower for the exposed persons as compared to the non-exposed persons. Interestingly, the level of adaptation was elevated if the challenging dose was given at a low-dose rate. A definitive proof of adaptive response belonging to the group of non-targeted effects came from a study by Iyer and Lehnert, demonstrating that non-irradiated human lung fibroblast cells (HFL-1) were able to adapt if grown in a medium transferred from HFL-1 cells, irradiated with either 0.1 Gy g-rays or 0.1 Gy a-particles (Iyer & Lehnert, 2002). The adaptation was shown as increased clonogenic survival after a challenging dose of 2 or 4 Gy g-rays, or 1.0 or 1.9 Gy a-particles, respectively. Adaptive response was found to be associated with a decreased level of p53 protein, increased level of intracellular ROS as well as increased level of DNA repair protein AP-endonuclease. The study suggested that nontargeted cells are able to adapt after receiving an extracellular signal. There are three major cellular defense systems against ionizing radiation that comprise the radioadaptive response (Tubiana, Arengo, Averbeck, & Masse, 2007): (1) protection against reactive oxygen species (ROS) by antioxidant molecules (such as glutathione) and detoxifying enzymes (such as catalase and superoxide dismutase); (2) DNA repair, particularly for double-strand breaks, that disappears at doses >0.5 Gy; and (3) elimination of genomically damaged cells by immune defenses and apoptosis at doses as low as a few mSv. The hormesis response is associated with increased lifespan, and decreased mutations, chromosome aberrations, neoplastic transformations, cancer, and congenital malformations (Kant, Chauhan, & Sharma, 2003). The adaptive response occurs at dose values ranging from 0.01 to 0.5 Gy and at dose rate values ranging from 0.01 to 1.0 Gy/min (Aurengo, Averbeck, & Bonnin, 2005). The radioadaptive response appears most beneficial at doses <0.1 Gy. The response begins to disappear at doses >0.2 Gy of low-LET radiation and is rarely seen at a dose of >0.5 mGy. However, the probability of apoptosis appears to increase in a linear fashion beyond 0.5 mGy (Feinendegen et al., 2007). The bottom line for most of the studies on the adaptive response is that biological processes are activated by low doses of ionizing radiation that trigger repair and protective processes and decrease the risk for late effects of radiation. These adaptive processes support the possibility that
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intervention that enhances these normal processes is possible and may provide an avenue to modify and decrease the risk for cancer induced by low doses of ionizing radiation (Brooks, 2005).
8.
Radiation protection
Radiological protection is a science-based discipline in which concepts, methods, and procedures are developed to be used for the protection of humans and the environment from the harmful effects of ionizing radiation. More specifically, radiological protection has the objective of reducing the likelihood of radiation-induced stochastic effects, in particular cancer, and preventing deterministic effects, also called ‘tissue reactions’. Recommendations and practical guidance for radiological protection have been developed by the International Commission on Radiological Protection (ICRP) for more than 80 years and in its 2007 Recommendations the Commission has described its latest system of protection with this aim in mind (Menzel, & Harrison, 2012). Almost all regulatory requirements authorizing activities that use ionizing radiation such as in industry, health, agriculture, and basic research, is based on the radiation protection concept that hinges on the acceptance of the linear nonthreshold (LNT) theory. LNT implies that any dose, no matter how low, can pose risks for genetic (hereditary) defects or cause cancer. Cancer risk is assumed to increase linearly with increasing radiation dose, with no threshold. LNT was derived using statistically significant doseeresponse (DR) relationship between radiation dose received by the survivors of the atomic bomb explosions in Hiroshima and Nagasaki and the observed health effects, mainly hereditary disorders and cancer (Decades later, non-cancer risks are also derived from the same population). The DR was based on the observable significant clinical/deterministic effects that were seen on population exposed at high doses, from 0.2 Gy upwards. Below this dose, there were no observable effects seen on the population. Nevertheless, DR is assumed to be linear down to zero dose. The extrapolation to zero of the DR has not been supported by sufficient evidence/data in man to show its linearity at low doses. However, this assumption has been accepted to be the conservative and most careful approach to address the delayed effects of ionizing radiation, and to estimate health risks at low doses (Aleta, 2009). The LNT model is being challenged particularly in relation to the environment because it is now clear that at low doses of concern in radiation protection, cells, tissues and organisms respond to radiation by inducing responses which are not readily predictable by dose. These include adaptive responses, bystander effects; genomic instability and low dose hypersensitivity. The phenomena contribute to observed radiation responses and appear to be influenced by genetic, epigenetic and environmental factors, meaning that dose and response are not simply related and the modeling of dose response relationships based on the number of irradiated cells may not be a valid approach (Little, 2003).
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ICRP in its new review (2007), considered possible challenges to its linear non-threshold model but concluded that for the purposes of radiological protection, it is scientifically reasonable to assume that the incidence of cancer or hereditary disorders will rise in direct proportion to an increase in the equivalent dose in the relevant organs and tissues, below about 100 mSv. ICRP also considered issues such as cellular adaptive responses, genomic instability and bystander signaling but notes that ‘since the estimation of nominal cancer risk coefficients is based upon direct human epidemiological data, any contribution from these biological mechanisms would be included in that estimate’ (Wrixon, 2008). BEIR VII concluded that the available biological and biophysical low dose data support a linear-no-threshold (LNT) risk model. According to this model, even the smallest dose of radiation has the potential to cause a small increase in health risk to humans. The reports from UNSCEAR and the ICRP concluded that the LNT hypothesis remains a prudent basis for radiation protection at low doses and low dose rates, but may not reflect biological differences and risks in the low dose region (Morgan & Bair, 2013)
9.
Conclusion
This paper has reviewed new information that demonstrates that bystander effects and adaptive responses which important parts of the response of molecules, cells and tissues to ionizing radiation. It is important to recognize that these new observations make it possible to shift from the assumption that radiation has to interact with a cell directly only.
Acknowledgments This work was supported by TWAS-UNISCO, Chinese academy of science and institute of modern physics.
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