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Towards a New Concept of Low Dose

Mothersill, Carmel1; Rusin, Andrej1; Seymour, Colin2

doi: 10.1097/HP.0000000000001074

When people discuss the risks associated with low doses of ionizing radiation, central to the discussion is the definition of a low dose and the nature of harm. Standard answers such as “doses below 0.1 Gy are low” or “cancer is the most sensitive measure of harm” obscure the complexity within these seemingly simple questions. This paper will discuss some of the complex issues involved in determining risks to human and nonhuman species from low-dose exposures. Central to this discussion will be the role of communicable responses to all stressors (often referred to as bystander responses), which include recently discovered epigenetic and nontargeted mechanisms. There is a growing consensus that low-dose exposure to radiation is but one of many stressors to impact populations. Many of these stressors trigger responses that are generic and not unique to radiation. The lack of a unique radiation signature makes absolute definition of radiation risk difficult. This paper examines a possible new way of defining low dose based on the systemic response to the radiation. Many factors will influence this systemic response and, because it is inherently variable, it is difficult to predict and so makes low-dose responses very uncertain. Rather than seeking to reduce uncertainty, it might be valuable to accept the variability in outcomes, which arise from the complexity and multifactorial nature of responses to stressors.

1Department of Biology, McMaster University, Hamilton, Canada

2Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Canada.

The authors declare no conflicts of interest.

For correspondence contact Carmel Mothersill, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, Hamilton, Ontario, Canada, or email at

(Manuscript accepted 9 January 2019)

Online date: April 5, 2019

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THE CONVENTIONAL definition of low dose is <0.1 Gy of acute exposure to low linear energy transfer (LET) radiation. This figure is the dose below which the Life Span Study (LSS) of survivors of the Hiroshima and Nagasaki atomic bombs cannot statistically show an elevated cancer risk (US DOE 2018; Shimizu et al. 1990; Preston et al. 1994; Thompson et al. 1994; Pierce et al. 1996; Heidenreich et al. 1997; Heidenreich and Paretzke 2001; Brenner et al. 2003). It was the dose chosen by the US Department of Energy as the cut-off dose for funding low-dose research. Low dose is therefore defined more as a dose not causing statistically definable harm (usually cancer in humans) rather than a dose that is low in terms of physical effects in matter such as tracks through a cell or energy deposition. So the dose is defined not by physical energy deposition but by a result obtained in humans distant in time. In effect, low dose is defined by the systemic response to that dose. This definition of low dose also obscures the fact that most exposures to ionizing radiation do not involve a single acute exposure, but rather, the exposures are long-term and complicated by chemical speciation of the radionuclide involved, the half-life, the route of exposure, and dispersal (Prise et al. 2002; Morgan and Sowa 2007; Kadhim et al. 2013; Mothersill and Seymour 2014; Omar-Nazir et al. 2018). Within the conventional definition, factors such as lifestyle, other stressors such as pathogen or parasite burden, immune system function, age, and nutritional status are implicitly recognized but explicitly ignored.

Low dose rate is more vaguely defined and definitions come mainly from environmental radiation research based on database (FREDERICA and RESRAD-BIOTA) interrogation (ISCORS 2004; Copplestone and Hingston 2006; Brown et al. 2008; Copplestone et al. 2008; Larsson 2008; Beresford et al. 2010; Ćujić and Dragović 2018). A low dose rate is considered to be <10 μGy h−1 (ISCORS 2004; Copplestone and Hingston 2006; Brown et al. 2008).

To simplify matters for regulation, the concept of linearity is employed; there is an increasing probability of harm with increasing dose extrapolated back to zero harm at zero dose (Averbeck 2009; Cohen 2011). The linear no-threshold (LNT) model causes controversy because of the mechanistic implications often assumed with the model. The debate is very polarized because it is seen as a black or white issue when it is not (Belyakov et al. 2002; Martin 2005; Brenner and Sachs 2006; Tubiana et al. 2007; Cohen 2008; Averbeck 2009; Puskin 2009; Cohen 2011; Calabrese and O’Connor 2014; Mothersill et al. 2017a and b; Mothersill and Seymour 2018). There is confusion regarding whether dose or dose rate is being discussed (Averbeck 2009; Calabrese 2013; Calabrese 2017a and b). Is ambient dose all that matters or is historic dose (i.e., the initial dose that can lead to a genomic instability burden) relevant? This concept is discussed and tested in recent publications by the authors (Omar-Nazir et al. 2018) showing that evidence in Chernobyl and Fukushima populations suggests persistent transgenerational memory effects where harm can be measured many generations after progenitor exposure at a level far higher than would be predicted by the currently used dose-effect models (ICRP 1991).

Evidence in wild populations which could possibly suggest a role of memory effects or other factors not normally included for consideration is the analysis by Garnier-Laplace et al. (2013) showing a 10-fold increase in radiosensitivity in populations from field vs. laboratory studies. Such effects are dismissed as irrelevant for human radiation protection due to the lack of evidence for hereditary effects in the children of atomic bomb survivors (Kodaira et al. 1995, 2004; Satoh et al. 1996; Nakamura 2006), but what transgenerational effects were examined in these studies? Were epigenetic effects and mechanisms considered? Was the statistical power sufficient given the extremely low frequency of gross dominant hereditary effects (Sankaranarayanan 2000; Hall and Giaccia 2006)? This paper will suggest that low doses have completely different underlying mechanisms than high doses and that the two should not be conflated either in terms of predicted outcomes or in terms of the way the dose is viewed in the context of the exposure context and setting.

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“At high doses nothing is more important than dose but at low doses everything is more important than dose.” This statement may seem heretical, but it sums up the conclusion reached by our laboratory after many years of research into low-dose effects. Fig. 1 represents a simple outline of the model suggested as a consequence of this idea. It shows that as radiation dose increases, the relative impact of this dose among all the other stressors becomes greater while the impact of other stressors becomes relatively less important. Most important to note is the fuzziness of the contribution of other stressors such as temperature, mental or emotional distress, and pathogens and other pollutants due to the unpredictable contribution they make to the ultimate outcome. The identification of the dose range within which the crossover shown in Fig. 1 happens may be critical to the relative risk assessment for radiation in a given scenario.

Fig. 1

Fig. 1

Evidence for the critical importance of understanding context of an exposure when the dose is low comes from studies of multiple stressors (Mothersill et al. 2007a and b) where coexposures to radiation and, for example, heavy metals can alter the radiation response (Coen et al. 2001, 2003; Schenck et al. 2001; Ni Shuilleabhain et al. 2004; Glaviano et al. 2006a and b; Mothersill et al. 2007b; Salbu et al. 2008). Some of the changes in dose-effect curves suggest saturable or subadditive responses where the system response does not increase in a linear fashion with increasing total stressor burden (Mothersill et al. 2014; Smith et al. 2015). Other studies show evidence for adaptive response to one stressor, making the second stressor much less effective at causing harm (Zhou et al. 2003; Maguire et al. 2007; Ryan et al. 2008, 2009; Choi et al. 2013). The important point is that the responses are complex and variable in the low-dose region and point to the relative importance and key contributions of costressors, i.e., other nonradioactive stressors that mitigate radiation effect.

The conclusion from this analysis is that the definition of low dose now becomes the intersection band between the two lines shown on Fig. 1 such that a low dose is that range where the direct effect of the radiation is equally important to the systemic response resulting from the micro- and macro-environmental influences discussed above.

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A major factor which has made low-dose effects controversial is the shift away from the DNA-centric paradigm, which has dominated radiobiology and radiation protection since the 1930s (Mothersill et al. 2017a and b). The concept of systemic response involving, for example, hormonal, neural, and immune communication, signaling within and between species, vesicles such as exosomes, and biophotons leading to epigenetic and nontargeted effects, shifts the emphasis from the effect of the radiation to the response to the radiation. This shift means that instead of a simple linear model where increasing dose equates with increasing energy deposition in the target (DNA), the situation now is complicated by the existence of multiple signaling mechanisms, bystander effects, delayed genomic instability, transgenerational fixation of epigenetic effects, and adaptive responses (Seymour and Mothersill 1997; Mothersill and Seymour 2000, 2004a and b, 2006; Ballarini and Ottolenghi 2002; Morgan 2003; Zhou et al. 2003; Kadhim et al. 2004; Mitchell et al. 2004; Koturbash et al. 2006, 2007; Tubiana et al. 2007; Ilnytskyy et al. 2009; Mothersill 2012). In all these mechanisms there is a key role for the macro- and micro-environment of the recipient of the dose in determining the outcome (Barcellos-Hoff and Brooks 2001; Brooks 2004; Mothersill and Seymour 2004a and b).

Very recently, the possibility of physical factors contributing to ionizing radiation response has been shown (Le et al. 2015, 2017, 2018). The discovery of photon emissions from cells treated with ionizing radiation could represent another factor that makes cellular responses to ionizing radiation even more complex due to the presence of ionizing and nonionizing radiations with a range of energies and emission/absorption properties in tissues. Fig. 2 summarizes the key factors and mechanisms that are at play during low-dose exposures that could contribute to the fuzziness alluded to in Fig. 1. The essential point, which underpins the paradigm shift of the last few years, is the recognition that epigenetic and nontargeted effects are key to understanding low-dose effects (Nagar et al. 2003; Koturbash et al. 2007; Kovalchuk and Baulch 2008; Mothersill and Seymour 2012; Desaulniers et al. 2015). However, it is one thing to accept the critical role of these effects, but it is quite another to regulate in a situation where there are no certainties, where a dose can have multiple effects ranging from protective to harmful, and where even in the same individual, the outcome can change over time and circumstance (Mothersill and Seymour 2004a, 2005, 2014).

Fig. 2

Fig. 2

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The arguments presented about the complexity of the response after low-dose exposure suggest that it is futile to try to reduce uncertainty in order more accurately to predict radiation risk. Rather, it is necessary to accept the reality of variability in the low-dose region. This would lead to the concept of protection zones or dose bands rather than rigid dose-response relationships. A corollary of this would be the need to approach radiation protection much in the way personalized medicine is designed—i.e., protection tailored to fit the context of the exposure based on the results of examination of a suite of sensitive biomarkers which inform network and pathway analysis (Fig. 3). The one-size-fits-all approach would be abandoned in favor of a much more flexible approach where “do no harm” is still the paramount aim but within a framework where logical reasoning is applied to assess the context of the exposure. While it may not be necessary to do this for all radiation protection scenarios, it could be useful for worker protection or when developing emergency response or emergency preparedness plans, and it would reduce the fear associated with uncertainty by admitting the reality and dealing with it.

Fig. 3

Fig. 3

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Averbeck D. Does scientific evidence support a change from the LNT model for low-dose radiation risk extrapolation? Health Phys 97:493–504; 2009.
Ballarini F, Ottolenghi A. Low-dose radiation action: possible implications of bystander effects and adaptive response. J Radiol Protect 22:A39–A42; 2002.
Barcellos-Hoff MH, Brooks AL. Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability. Radiat Res 156:618–627; 2001.
Belyakov OV, Folkard M, Mothersill C, Prise KM, Michael BD. Non-targeted effects of radiation: applications for radiation protection and contribution to LNT discussion. In: Proceedings of the European IRPA congress 2002: towards harmonization of radiation protection in Europe [online]. 2002. Available at Accessed 9 March 2019.
Beresford NA, Hosseini A, Brown JE, Cailes C, Beaugelin-Seiller K, Barnett CL, Copplestone D. Assessment of risk to wildlife from ionising radiation: can initial screening tiers be used with a high level of confidence? J Radiol Protect 30:265–281; 2010.
Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, Lubin JH, Preston DL, Preston RJ, Puskin JS. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci 100:13761–13766; 2003.
Brenner DJ, Sachs RK. Estimating radiation-induced cancer risks at very low doses: rationale for using a linear no-threshold approach. Radiat Environ Biophys 44:253–256; 2006.
Brooks AL. Evidence for “bystander effects” in vivo. Hum Exp Toxicol 23:67–70; 2004.
Brown JE, Alfonso B, Avila R, Beresford NA, Copplestone D, Pröhl G, Ulanovsky A. The ERICA tool. J Environ Radioact 99:1371–1383; 2008.
Calabrese EJ. Origin of the linearity no threshold (LNT) dose-response concept. Arch Toxicol 87:1621–1633; 2013.
Calabrese EJ. The threshold vs LNT showdown: dose rate findings exposed flaws in the LNT model part 2. How a mistake led BEIR I to adopt LNT. Environ Res 154:452–458; 2017a.
Calabrese EJ. The threshold vs LNT showdown: dose rate findings exposed flaws in the LNT model part 1. The Russell-Muller debate. Environ Res 154:435–451; 2017b.
Calabrese EJ, O’Connor MK. Estimating risk of low radiation doses—a critical review of the BEIR VII report and its use of the linear no-threshold (LNT) hypothesis. Radiat Res 182:463–474; 2014.
Choi VWY, Ng CYP, Kong MKY, Cheng SH, Yu KN. Adaptive response to ionising radiation induced by cadmium in zebrafish embryos. J Radiol Protect 33:101–112; 2013.
Coen N, Kadhim MA, Wright EG, Case CP, Mothersill CE. Particulate debris from a titanium metal prosthesis induces genomic instability in primary human fibroblast cells. Br J Cancer 88:548–552; 2003. DOI 10.1038/sj.bjc.6600758.
Coen N, Mothersill C, Kadhim M, Wright EG. Heavy metals of relevance to human health induce genomic instability. J Pathol 195:293–299; 2001.
Cohen BL. The linear no-threshold theory of radiation carcinogenesis should be rejected. J Am Physicians Surg 13:70–76; 2008.
Cohen BL. The cancer risk from low level radiation. In: Tack D, Kalra MK, Gevenois PA, eds. Radiation dose from multidetector CT. Heidelberg, Germany: Springer; 2011: 61–79.
Copplestone D, Hingston J, Real A. The development and purpose of the FREDERICA radiation effects database. J Environ Radioact 99:1456–1463; 2008.
Copplestone D, Hingston JL. FREDERICA database manual. Brussels: European Commission; EC contract no. FI6R-CT-2004-508847; 2006.
Ćujić M, Dragović S. Assessment of dose rate to terrestrial biota in the area around coal fired power plant applying ERICA tool and RESRAD BIOTA code. J Environ Radioact 188:108–114; 2018.
Desaulniers D, Al-Mulla F, Al-Temaimi R, Amedei A, Azqueta A, Bisson WH, Brown D, Brunborg G, Charles AK, Chen T, Colacci A, Darroudi F, Forte S, Gonzalez L, Hamid RA, Knudsen LE, Leyns L, Lopez de Cerain Salsamendi A, Memeo L, Mondello C, Mothersill C, Olsen A-K, Pavanello S, Raju J, Rojas E, Roy R, Ryan E, Ostrosky-Wegman P, Salem HK, Scovassi AI, Singh N, Vaccari M, Van Schooten FJ, Valverde M, Woodrick J, Zhang L, van Larebeke N, Kirsch-Volders M, Collins AR. Causes of genome instability: the effect of low dose chemical exposures in modern society. Carcinogenesis 36:S61–S88; 2015. DOI 10.1093/carcin/bgv031.
Garnier-Laplace J, Geras’kin S, Della-Vedova C, Beaugelin-Seiller K, Hinton TG, Real A, Oudalova A. Are radiosensitivity data derived from natural field conditions consistent with data from controlled exposures? A case study of Chernobyl wildlife chronically exposed to low dose rates. J Environ Radioact 121:12–21; 2013.
Glaviano A, Lyng F, Mothersill C, Rubio MA, Case CP. Effects of hTERT on genomic instability caused by either metal or radiation or combined exposure. Mol Biol Cell 17:25–33; 2006a.
Glaviano A, Nayak V, Cabuy E, Baird DM, Yin Z, Newson R, Ladon D, Rubio MA, Slijepcevic P, Lyng F, Mothersill C, Case CP. Effects of hTERT on metal ion-induced genomic instability. Oncogene 25:3424–3435; 2006b. DOI 10.1038/sj.onc.1209399.
Hall EJ, Giaccia AJ. Radiobiology for the radiologist. Baltimore: Lippincott Williams & Wilkins; 2006.
Heidenreich WF, Paretzke HG. City-effects in the atomic bomb survivors data. Math Comput Model 33:1431–1438; 2001.
Heidenreich WF, Paretzke HG, Jacob P. No evidence for increased tumor rates below 200 mSv in the atomic bomb survivors data. Radiat Environ Biophys 36:205–207; 1997.
Ilnytskyy Y, Koturbash I, Kovalchuk O. Radiation-induced bystander effects in vivo are epigenetically regulated in a tissue-specific manner. Environ Mol Mutagen 50:105–113; 2009.
Interagency Steering Committee on Radiation Standards. RESRAD-BIOTA: a tool for implementing a graded approach to biota dose evaluation. Washington, DC: US Department of Energy; DOE/EH-0676; ISCORS Technical Report 2004-02; 2004.
International Commission on Radiological Protection. 1990 recommendations of the International Commission on Radiological Protection. Oxford: Pergamon Press; Publication 60; 1991.
Kadhim M, Salomaa S, Wright E, Hildebrandt G, Belyakov OV, Prise KM, Little MP. Non-targeted effects of ionising radiation—implications for low dose risk. Mutat Res 752:84–98; 2013. DOI 10.1016/j.mrrev.2012.12.001.
Kadhim MA, Moore SR, Goodwin EH. Interrelationships amongst radiation-induced genomic instability, bystander effects, and the adaptive response. Mutat Res Mol Mech Mutagen 568:21–32; 2004.
Kodaira M, Izumi S, Takahashi N, Nakamura N. No evidence of radiation effect on mutation rates at hypervariable minisatellite loci in the germ cells of atomic bomb survivors. Radiat Res 162:350–356; 2004.
Kodaira M, Satoh C, Hiyama K, Toyama K. Lack of effects of atomic bomb radiation on genetic instability of tandem-repetitive elements in human germ cells. Am J Hum Genet 57:1275–1283; 1995.
Koturbash I, Boyko A, Rodriguez-Juarez R, McDonald RJ, Tryndyak VP, Kovalchuk I, Pogribny IP, Kovalchuk O. Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo. Carcinogenesis 28:1831–1838; 2007.
Koturbash I, Rugo RE, Hendricks CA, Loree J, Thibault B, Kutanzi K, Pogribny I, Yanch JC, Engelward BP, Kovalchuk O. Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene 25:4267–4275; 2006.
Kovalchuk O, Baulch JE. Epigenetic changes and nontargeted radiation effects—is there a link? Environ Mol Mutagen 49:16–25; 2008.
Larsson CM. An overview of the ERICA integrated approach to the assessment and management of environmental risks from ionising contaminants. J Environ Radioact 99:1364–1370; 2008.
Le M, Fernandez-Palomo C, McNeill FE, Seymour CB, Rainbow AJ, Mothersill CE. Exosomes are released by bystander cells exposed to radiation-induced biophoton signals: reconciling the mechanisms mediating the bystander effect. PLOS ONE 12:e0173685; 2017. DOI 10.1371/journal.pone.0173685.
Le M, McNeill FE, Seymour CB, Rusin A, Diamond K, Rainbow AJ, Murphy J, Mothersill CE. Modulation of oxidative phosphorylation (OXPHOS) by radiation-induced biophotons. Environ Res 163:80–87; 2018.
Le M, Mothersill CE, Seymour CB, Ahmad SB, Armstrong A, Rainbow AJ, McNeill FE. Factors affecting ultraviolet-A photon emission from beta-irradiated human keratinocyte cells. Phys Med Biol 60:6371–6389; 2015. DOI 10.1088/0031-9155/60/16/6371.
Maguire P, Mothersill C, McClean B, Seymour C, Lyng FM. Modulation of radiation responses by pre-exposure to irradiated cell conditioned medium. Radiat Res 167:485–492; 2007. DOI 10.1667/RR0159.1.
Martin CJ. The LNT model provides the best approach for practical implementation of radiation protection. Br J Radiol 78:14–16; 2005.
Mitchell SA, Marino SA, Brenner DJ, Hall EJ. Bystander effect and adaptive response in C3H 10T½ cells. Int J Radiat Biol 80:465–472; 2004.
Morgan WF. Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation? Oncogene 22:7094–7099; 2003.
Morgan WF, Sowa MB. Non-targeted bystander effects induced by ionizing radiation. Mutat Res Mol Mech Mutagen 616:159–164; 2007.
Mothersill C. Are epigenetic mechanisms involved in radiation-induced bystander effects? Front Genet 3:74; 2012. DOI 10.3389/fgene.2012.00074.
Mothersill C, Mosse I, Seymour C, eds. Multiple stressors: a challenge for the future. New York: Springer; 2007a.
Mothersill C, Rusin A, Seymour C. Low doses and non-targeted effects in environmental radiation protection: where are we now and where should we go? Environ Res 159:484–490; 2017a.
Mothersill C, Salbu B, Heier LS, Teien HC, Denbeigh J, Oughton D, Rosseland BO, Seymour CB. Multiple stressor effects of radiation and metals in salmon (Salmo salar). J Environ Radioact 96:20–31; 2007b. DOI 10.1016/j.jenvrad.2007.01.025.
Mothersill C, Seymour C. Genomic instability, bystander effects and radiation risks: implications for development of protection strategies for man and the environment. Radiatsionnaia Biol Radioecol 40:615–620; 2000.
Mothersill C, Seymour C. Radiation-induced bystander effects and adaptive responses—the yin and yang of low dose radiobiology? Mutat Res Mol Mech Mutagen 568:121–128; 2004a. DOI 10.1016/j.mrfmmm.2004.06.050.
Mothersill C, Seymour C. Radiation-induced bystander effects: are they good, bad or both? Med Confl Surviv 21:101–110; 2005.
Mothersill C, Seymour C. Radiation-induced bystander effects: evidence for an adaptive response to low dose exposures? Dose-Response 4:283–290; 2006. DOI 10.2203/dose-response.06-111.Mothersill.
Mothersill C, Seymour C. Are epigenetic mechanisms involved in radiation-induced bystander effects? Front Genet 3:5–9; 2012. DOI 10.3389/fgene.2012.00074.
Mothersill C, Seymour C. Implications for human and environmental health of low doses of ionising radiation. J Environ Radioact 133:5–9; 2014. DOI 10.1016/j.jenvrad.2013.04.002.
Mothersill C, Seymour C. Old data—new concepts: integrating “indirect effects” into radiation protection. Health Phys 115:170–178; 2018.
Mothersill C, Seymour CB. Radiation-induced bystander effects—implications for cancer. Nat Rev Cancer 4:158–164; 2004b. DOI 10.1038/nrc1277.
Mothersill C, Smith RW, Heier LS, Teien HC, Land OC, Seymour CB, Oughton D, Salbu B. Radiation-induced bystander effects in the Atlantic salmon (Salmo salar L.) following mixed exposure to copper and aluminum combined with low-dose gamma radiation. Radiat Environ Biophys 53:103–114; 2014. DOI 10.1007/s00411-013-0505-6.
Mothersill CE, Rusin A, Fernandez-Palomo C, Seymour CB. History of bystander effects research 1905–present; what’s in a name? Int J Radiat Biol 94:696–707; 2017b.
Nagar S, Smith LE, Morgan WF. Characterization of a novel epigenetic effect of ionizing radiation: the death-inducing effect. Cancer Res 63:324–328; 2003.
Nakamura N. Genetic effects of radiation in atomic-bomb survivors and their children: past, present and future. J Radiat Res 47:B67–B73; 2006.
Ni Shuilleabhain S, Mothersill C, Sheehan D, O’Brien NM, O’Halloran J, Van Pelt F, Davoren M. In vitro cytotoxicity testing of three zinc metal salts using established fish cell lines. Toxicol Vitr 18:365–376; 2004. DOI 10.1016/j.tiv.2003.10.006.
Omar-Nazir L, Shi X, Moller A, Mousseau T, Byun S, Hancock S, Seymour C, Mothersill C. Long-term effects of ionizing radiation after the Chernobyl accident: possible contribution of historic dose. Environ Res 165:55–62; 2018.
Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi K. Studies of the mortality of atomic bomb survivors. Report 12, part I. Cancer: 1950–1990. Radiat Res 146:1–27; 1996.
Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A, Kamada N, Dohy H, Matsui T, Nonaka H. Cancer incidence in atomic bomb survivors. Part III: leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res 137:S68–S97; 1994.
Prise MK, Belyakov VO, Newman CH, Patel S, Schettino G, Folkard M, Michael DB. Non-targeted effects of radiation: bystander responses in cell and tissue models. Radiat Protect Dosim 99:223–226; 2002.
Puskin JS. Perspective on the use of LNT for radiation protection and risk assessment by the US Environmental Protection Agency. Dose-Response 7:284–291; 2009. DOI 10.2203/dose-response.09-005.Puskin.
Ryan LA, Seymour CB, Joiner MC, Mothersill CE. Radiation-induced adaptive response is not seen in cell lines showing a bystander effect but is seen in lines showing HRS/IRR response. Int J Radiat Biol 85:87–95; 2009. DOI 10.1080/09553000802635062.
Ryan LA, Seymour CB, O’Neill-Mehlenbacher A, Mothersill CE. Radiation-induced adaptive response in fish cell lines. J Environ Radioact 99:739–747; 2008. DOI 10.1016/j.jenvrad.2007.10.001.
Salbu B, Denbeigh J, Smith RW, Heier LS, Teien HC, Rosseland BO, Oughton D, Seymour CB, Mothersill C. Environmentally relevant mixed exposures to radiation and heavy metals induce measurable stress responses in Atlantic salmon. Environ Sci Technol 42:3441–3446; 2008. DOI 10.1021/es7O27394.
Sankaranarayanan K. Estimation of genetic risks of exposure to ionizing radiation: status in the year 2000. Radiatsionnaia Biol Radioecol 40:621–626; 2000.
Satoh C, Takahashi N, Asakawa J, Kodaira M, Kuick R, Hanash SM, Neel JV. Genetic analysis of children of atomic bomb survivors. Environ Health Perspect 104:511–519; 1996.
Schenck FJ, Case CP, Mothersill C. Induction of genomic instability by metal wear debris from total hip prostheses. Mol Biol Cell 12:358A; 2001.
Seymour CB, Mothersill C. Delayed expression of lethal mutations and genomic instability in the progeny of human epithelial cells that survived in a bystander-killing environment. Radiat Oncol Investig 5:106–110; 1997.
Shimizu Y, Schull WJ, Kato H. Cancer risk among atomic bomb survivors: the RERF Life Span Study. JAMA 264:601–604; 1990.
Smith RW, Seymour CB, Moccia RD, Mothersill CE. Tissue-specific effects of acute aluminium exposure on the radiation-induced bystander effect in rainbow trout (Oncorhynchus mykiss, Walbaum). Int J Radiat Biol 91:715–723; 2015. DOI 10.3109/09553002.2015.1062573.
Thompson DE, Mabuchi K, Ron E, Soda M, Tokunaga M, Ochikubo S, Sugimoto S, Ikeda T, Terasaki M, Izumi S. Cancer incidence in atomic bomb survivors. Part II: solid tumors, 1958-1987. Radiat Res 137:S17–S67; 1994.
Tubiana M, Arengo A, Averbeck D, Masse R, Tubiana M, Aurengo A, Averbeck D, Bonnin A, Le Guen B, Masse R. Linear-no-threshold is a radiation-protection standard rather than a mechanistic effect model. Radiat Res 167:742–744; 2007.
US Department of Energy, Biological Systems Science Division. Radiobiology: low dose radiation research [online]. 2018. Available at Accessed 5 September 2018.
Zhou H, Randers-Pehrson G, Geard CR, Brenner DJ, Hall EJ, Hei TK. Interaction between radiation-induced adaptive response and bystander mutagenesis in mammalian cells. Radiat Res 160:512–516; 2003.

dose, low; radiation, ionizing; radiation protection; radiobiology

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