The Dose Window for Radiation-Induced Protective Adaptive Responses

Mitchel, R. E. J.

doi:10.2203/dose-response.09-039.mitchel

Cited by 58 publications

(52 citation statements)

References 63 publications

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“…Since the direct biological consequences of low-dose irradiation are relatively subtle and difficult to measure, 7,8 we opted to study the radioadaptive response model to investigate the effects of low-dose radiation because animal studies have demonstrated such adaptive response. 6 We define doses at or below 0.1 Gy as low-dose radiation, 7 equivalent to the upper limit dose from a full-body spiral CT scan 8 and 2-4 Gy as high-dose radiation that causes substantial DNA damage to cells, 9,23 4 Gy is close to the LD50 for human whole-body exposure. 24 Using gH2AX as a surrogate marker of DNA damage, 23 we examined whether 0.1 Gy pretreatment of human fibroblasts could modulate cell sensitivity to a subsequent 4 Gy irradiation.…”

Section: Resultsmentioning

confidence: 99%

“…11 Of note is the observation that low-dose IR-induced resistance seems not limited to irradiation, implicating an induction of a general cellular stress tolerance. 6 Under physiological conditions, the majority of differentiated cells use primarily mitochondrial oxidative phosphorylation to fully catabolize glucose for energy production. 20 Using a combined genetic, biochemical and metabolomics approaches, we demonstrate that low-dose radiation induces a metabolic switch from oxidative phosphorylation to aerobic glycolysis.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 This adaptive response is in fact part of a general cellular response to stress that is evolutionally conserved. 6 Hence, many have argued that the use of the LNT model has led to unfounded levels of public fear regarding low levels of radiation exposure, and misunderstandings about the safety of diagnostic imaging for medical use. 1 However, the controversy remains unresolved due to a lack of understanding of the molecular mechanisms underlying the adaptive stress response, 7,8 and there is insufficient scientific evidence to warrant a change from the LNT model.…”

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Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

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Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1a, which is induced specifically by lowdose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to lowdose radiation has important implications in understanding and assessing the health risks of radiation exposure.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

et al. 2014

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“…Accordingly, the dose-effect curve would deviate from linearity with the dose and dose rate decreasing down to the background levels; the relationship can even become inverse in accordance with hormesis. A corresponding graph plotted on the basis of experimental data is presented in [73] with a comment that the window for maximum adaptive response protection occurs at doses between 1 and 100 mGy, where risk is reduced below the spontaneous level of cancer risk [73]. It means that a large part of experimental data is at variance with results of epidemiological studies discussed in [2,43].…”

Section: On the Dose-response Relationshipmentioning

confidence: 99%

Biological Effectiveness of Ionizing Radiation: Acute vs. Protracted Exposures

2016

J Environ Stud

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This letter refers to the current discussion around re-evaluation of the dose and dose rate effectiveness factor (DDREF) equal to 2, presently recommended by the International Commission on Radiological Protection. The topics of the threshold, hormesis and DDREF are interrelated with the linear no-threshold theory (LNT). The LNT does not take into account that DNA damage and repair are permanent processes in dynamic equilibrium. Given the evolutionary prerequisite of best fitness, it would be reasonable to assume that living organisms have been adapted by the natural selection to the background levels of ionizing radiation. Accordingly, there must be an optimal exposure level, as it is for many environmental factors. Several studies cited in the literature in support of the LNT and lowering of the DDREF down to 1 are discussed here. In the author's opinion, the dose-effect relationships with non-neoplastic diseases found in certain exposed populations call in question dose-effect relationships with cancer. Self-selection and other biases in epidemiological studies are discussed. The dose-response relationships should be clarified in largescale experiments involving different animal species. In conclusion, the LNT and under-estimation of DDREF tend to exaggerate radiationrelated health risks at low radiation doses and dose rates. Arguments against Linear No-Threshold Theory (LNT)Radiation-related cancer risk estimates have been primarily based on the data from atomic bomb survivors. To adjust the risk estimates at acute exposures to low dose and continuous (low dose rate) exposures, a dose and dose rate effectiveness factor (DDREF) is used [1]. This letter refers to the discussion around re-evaluation of the DDREF value equal to 2, currently recommended by the International Commission on Radiological Protection (ICRP) [2]. The topics of the threshold, hormesis and DDREF are interrelated with the linear no-threshold theory (LNT). Hormesis and LNT are considered controversial by many scientists; discussion is in [3][4][5][6][7][8]. The LNT is corroborated by the following arguments: the more tracks go through a cell nucleus, the more DNA damage would result and the higher the risk of malignant transformation would be. "Decreasing the number of damaged cells by a factor of 10 would be expected to decrease the biological response by the same factor of 10" [9]. This concept does not take into account that DNA damage and repair are permanent processes in dynamic equilibrium. Given the evolutionary prerequisite of best fitness, it would be reasonable to assume that living organisms have been adapted by the natural selection to background levels of ionizing radiation [10]. Accordingly, there must be an optimal exposure level, as it is for many environmental factors: visible and ultraviolet light, different chemical elements and compounds [11], as well as the products from radiolysis of water [12]. Evolutionary adaptation to a changing environmental factor would lag behind its current value and correspond to some ...

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“…The paper by Vaiserman (2010) reviews some of the abundant epidemiological and other data on radiation hormesis as it relates to cancer suppression. Mitchel (2010) points out in his paper that radiation adaptive responses occur in all organisms and describes a dose window (which corresponds to the hormetic zone) over which cancer suppression via stimulated adaptive protection occurs. The hormetic zone is thought to depend on the type of radiation (Scott 2005;Elmore et al 2009) and how the radiation is delivered (e.g., brief high rate vs. protracted low rate exposure [Elmore et al 2006;Feinendegen et al 2010]).…”

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confidence: 99%

Special Issue Introduction

Scott¹

2010

Dose-Response

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Ionizing radiation protection regulations for humans are based on the presumption that any amount or radiation, no matter how small, will cause cancer in a very large population. The regulations impact on the use of ionizing radiation in routine diagnostic procedures (e.g., computed tomography), on allowable radiation levels in the environment (e.g., residential radon levels), and on allowable radiation exposures in the workplace (e.g., nuclear facilities). Cancer risks evaluations are based on the linear-no-threshold (LNT) paradigm for which risk is assumed to increase linearly as the radiation dose increases (Puskin 2009 Justification for the continued use of the LNT risk model is based largely on results from epidemiological studies that employ inappropriate methods (Scott et al. 2008) such as the following: (1) giving considerable weight to high-dose, high-dose-rate data where excess cancers clearly occur while ignoring the absence of excess cancers after low doses and dose rates; (2) dose lagging (i.e., discarding some of the dose thereby shifting the dose-response curve to the left, making smaller doses appear more harmful than they actually are); (3) attributing observed low-doseassociated reductions in the cancer incidence among radiation workers to a presumed healthy worker effect; (4) not allowing for the possibility that a threshold or a reduction in risk at low doses may occur because of radiation-stimulated adaptive protection; and (5) averaging over wide dose intervals so that nonlinearity is removed.This issue provides additional support for the rapidly growing view that the LNT risk model should not be used for low-dose cancer risk assessment. The paper by Fornalski and Dobrzyński (2010) discusses the inappropriate use of the healthy worker effect assumption in attempts to

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The Dose Window for Radiation-Induced Protective Adaptive Responses

Cited by 58 publications

References 63 publications

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

Biological Effectiveness of Ionizing Radiation: Acute vs. Protracted Exposures

Special Issue Introduction

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