WHAT IS A LOW DOSE?
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.
RELATIVE UNIMPORTANCE OF DOSE IN THE LOW-DOSE REGION
“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.
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.
EPIGENETICS AND NONTARGETED EFFECTS
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).
INSTEAD OF REDUCING UNCERTAINTY WE NEED TO ACCEPT VARIABILITY
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.
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