The linear no-threshold model does not hold for low-dose ionizing radiation

Almost all of the data on the biological effects of ionizing radiation come from studies of high doses. However, the human population is unlikely to be exposed to such doses. Regulatory limits for radiation exposure are based on the linear no-threshold model, which predicts that the relationship between biological effects and radiation dose is linear, and that any dose has some effect. Chromosomal changes are an important effect of ionizing radiation because of their role in carcinogenesis. Here we exposed pKZ1 mice to single whole-body X-radiation doses as low as 1 microGy. We observed three different phases of response: (1) an induction of inversions at ultra-low doses, (2) a reduction below endogenous inversion frequency at low doses, and (3) an induction of inversions again at higher doses. These results do not fit a linear no-threshold model, and they may have implications for the way in which regulatory standards are presently set and for understanding radiation effects.     

Why the concept of hormesis has not been incorporated into mainstream radiation health theory: Radiation perspective

Although adaptive and reparative responses to radiation were recognized in the early decades of this century, mutations and chromosome aberrations were subsequently observed to increase as linear‐nondireshold functions of the dose at low‐to‐intermediate levels of exposure. For certain cancers, likewise, although the dose‐response relationships in humans and laboratory animals have been observed to vary, depending on the type of neoplasm, the dose, dose rate, and LET of the radiation, the age, sex, and genetic background of the exposed population, and other variables, the existing data have been interpreted to suggest that the risks may not depart significantly from linearity at low doses and low dose rates. Hence, although the available data do not exclude alternative dose‐response relationships, the linear‐nonthreshold model has generally come to be used as a basis for assessing the risks of low‐level irradiation for purposes of radiation protection. While the use of this model has generally been considered to be prudent on the basis of the precautionary principle, the possibility that the model may grossly overestimate the risks of low‐level irradiation remains to be excluded. Therefore, especially in the light of the growing evidence that adaptive responses may protect against the effects of small doses of radiation, further research to clarify the relevant dose‐response relationships is strongly indicated.     

Low-dose ionizing radiation: induction of differential intracellular signalling possibly affecting intercellular communication

Given the complexity of the carcinogenic process and the lack of any mechanistic understanding of how ionizing radiation at low-level exposures affects the multistage, multimechanism processes of carcinogenesis, it is imperative that concepts and paradigms be reexamined when extrapolating from high dose to low dose. Any health effect directly linked to low-dose radiation exposure must have molecular/biochemical and biological bases. On the other hand, demonstrating some molecular/biochemical or cellular effect, using surrogate systems for the human being, does not necessarily imply a corresponding health effect. Given the general acceptance of an extrapolated LNT model, our current understanding of carcinogenesis cries out for a resolution of a real problem. How can a low-level acute, or even a chronic, exposure of ionizing radiation bring about all the different mechanisms (mutagenic, cytotoxic, and epigenetic) and genotypic/phenotypic changes needed to convert normal cells to an invasive, malignant cell, given all the protective, repair, and suppressive systems known to exist in the human body? Until recently, the prevailing paradigm that ionizing radiation brings about cancer primarily by DNA damage and its conversion to gene and chromosomal mutations, drove our interpretation of radiation carcinogenesis. Today, our knowledge includes the facts both that epigenetic events play a major role in carcinogenesis and that low-dose radiation can also induce epigenetic events in and between cells in tissues. This challenges any simple extrapolation of the LNT model. Although a recent delineation of “hallmarks” of the cancer process has helped to focus on how ionizing radiation might contribute to the induction of cancers, several other hallmarks, previously ignored—namely, the stem cells in tissues as targets for carcinogenesis and the role of cell–cell communication processes in modulating the radiation effects on the target cell—must be considered, particularly for the adaptive response, bystander effects, and genomic instability phenomena.     

Cancer incidence and mortality after low-dosage radiation exposure: Epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, bears some cancer risk. In this review, epidemiological evidence is discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that show that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than estimates based on the LNT model. The discovery of low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dosage region. Further studies in this field will provide new insights into the mechanisms of radiation carcinogenesis.     

Cancer incidence and mortality after low-dose radiation exposure: epidemiological aspects

Current recommendations for limiting exposure to ionizing radiation are based on the linear-no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, carries with it some cancer risk. In this review, epidemiological evidences are discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that showed that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than projections based on the LNT model. The discovery of the low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dose region. The further studies in this field will provide new insights about the mechanisms of radiation carcinogenesis.     

Hypersensitivity to very-low single radiation doses: Its relationship to the adaptive response and induced radioresistance

There is now little doubt of the existence of radioprotective mechanisms, or stress responses, that are upregulated in response to exposure to small doses of ionizing radiation and other DNA-damaging agents. Phenomenologically, there are two ways in which these induced mechanisms operate. First, a small conditioning dose (generally below 30 cGy) may protect against a subsequent, separate, exposure to radiation that may be substantially larger than the initial dose. This has been termed the adaptive response. Second, the response to single doses may itself be dose-dependent so that small acute radiation exposures, or exposures at very low dose rates, are more effective per unit dose than larger exposures above the threshold where the induced radioprotection is triggered. This combination has been termed low-dose hypersensitivity (HRS) and induced radioresistance (IRR) as the dose increases. Both the adaptive response and HRS/IRR have been well documented in studies with yeast, bacteria, protozoa, algae, higher plant cells, insect cells, mammalian and human cells in vitro, and in studies on animal models in vivo. There is indirect evidence that the HRS/IRR phenomenon in response to single doses is a manifestation of the same underlying mechanism that determines the adaptive response in the two-dose case and that it can be triggered by high and low LET radiations as well as a variety of other stress-inducing agents such as hydrogen peroxide and chemotherapeutic agents although exact homology remains to be tested. Little is currently known about the precise nature of this underlying mechanism, but there is evidence that it operates by increasing the amount and rate of DNA repair, rather than by indirect mechanisms such as modulation of cell-cycle progression or apoptosis. Changed expression of some genes, only in response to low and not high doses, may occur within a few hours of irradiation and this would be rapid enough to explain the phenomenon of induced radioresistance although its specific molecular components have yet to be identified.     

Cancer as an emergent phenomenon in systems radiation biology

Radiation-induced DNA damage elicits dramatic cell signaling transitions, some of which are directed towards deciding the fate of that particular cell, while others lead to signaling to other cells. Each irradiated cell type and tissue has a characteristic pattern of radiation-induced gene expression, distinct from that of the unirradiated tissue and different from that of other irradiated tissues. It is the sum of such events, highly modulated by genotype that sometimes leads to cancer. The challenge is to determine as to which of these phenomena have persistent effect that should be incorporated into models of how radiation increases the risk of developing cancer. The application of systems biology to radiation effects may help to identify which biological responses are significant players in radiation carcinogenesis. In contrast to the radiation biology paradigm that focuses on genomic changes, systems biology seeks to integrate responses at multiple scales (e.g. molecular, cellular, organ, and organism). A key property of a system is that some phenomenon emerges as a property of the system rather than of the parts. Here, the idea that cancer in an organism can be considered as an emergent phenomenon of a perturbed system is discussed. Given the current research goal to determine the consequences of high and low radiation exposures, broadening the scope of radiation studies to include systems biology concepts should benefit risk modeling of radiation carcinogenesis. Presented at the First International Workshop on Systems Radiation Biology, February 14–16 2007, GSF-Research Centre, Neuherberg, Germany.     

A microdosimetric understanding of low-dose radiation effects

This paper presents a microdosimetric approach to the problem of radiation response by which effects produced at low doses and dose rates can be understood as the consequences of radiation absorption events in the nucleus of a single relevant cell and in its DNA. Radiation absorption at the cellular level, i.e. in the cell nucleus as a whole, is believed to act through radicals. This kind of action is called 'non-specific' and leads to the definition of an 'elemental dose' and the 'integral response probability' of a cell population. Radiation absorption at the molecular level, i.e. in sensitive parts of the DNA, is thought to act through double-strand breaks. This kind of action is called 'specific' and leads to a 'relative local efficiency'. In general, both mechanisms occur for all types of radiation; however, it is the dose contribution of both specific and non-specific effects that determines the radiation quality of a given radiation. The implications of this approach for the specification of low-dose and low dose-rate regions are discussed.     

Chronic low‐dose radiation inhibits cisplatin‐induced formation of tumorous clones in Drosophila melanogaster wts/ + heterozygotes

Ionizing radiation is one of the most extensively studied carcinogens. In contrast to the detrimental effects of high‐dose radiation in carcinogenesis, the biological effects of low‐dose radiation remains poorly understood. In this study, we introduced adult wts/ + heterozygotes of Drosophila melanogaster as transgenic model organisms to determine the tumorigenic activity of low‐dose radiation. The warts (wts) gene is a tumor suppressor gene in mice and humans that is directly involved in cell cycle regulation. Fruit flies at the first larval stage were subjected to ionizing radiation, and then tumorigenic activity was evaluated as the frequency of observed warts tumorous mosaic clones in adult flies. Low‐dose irradiation alone did not cause tumorigenesis in our system. In combined treatment with a chemical carcinogen, chronic irradiation at 0.2 Gy decreased the frequency of tumorous clones induced by cisplatin. These results suggest that low‐dose radiation alone is not deleterious but beneficial in tumorigenesis induced by a chemical carcinogen.     

Failla memorial lecture. Risk, research, and radiation protection

Radiation protection concerns the risk of stochastic late effects, especially cancer, and limits on radiation exposure both occupationally and for the public tend to be based on these risks. The risks are determined, mainly by expert committees, from the steadily growing information on exposed human populations, especially the survivors of the atomic bombs dropped in Japan in 1945. Risks of cancer estimated up to the early 1980s were in the range 1 to 5 X 10(-2)/Sv, but recent revisions in the dosimetry of the Japanese survivors and additional cycles of epidemiological information suggest values now probably at the high end of this range. These are likely to require an increase in the values used for radiation protection. A major problem with risk estimation is that data are available only for substantial doses and must be extrapolated down to the low-dose region of interest in radiation protection. Thus the shape of the dose-response curve is important, and here we must turn to laboratory research. Of importance are studies involving (1) dose rate, which affects the response to low-LET radiation and often to high-LET radiation as well; (2) radiation quality, since the shapes of the dose-response curves for high- and low-LET radiation differ and thus the RBE, the ratio between them, varies, reaching a maximum value RBEM at low doses; and (3) modifiers of the carcinogenic response, which either enhance or reduce the effect of a given dose. Radiation protection depends both on risk information, and especially also on comparisons with other occupational and public risks, and on research, not only for extrapolations of risk to low doses but also in areas where human information is lacking such as in the effects of radiation quality and in modifications of response.     

Radiobiological models in prediction of radiation cardiotoxicity

Coronary disease induced by previous radiotherapy is the most common cause of death among patients treated with radiotherapy for cancer. Risk factors that may affect the frequency and intensity of radiotherapy’s cardiac toxicity are primarily the radiation dose and the volume of the heart exposed to radiation. The prolonged survival time of patients after radiotherapy, but also the intensive development of modern radiotherapy techniques results in the necessity of precise estimation of both tumor control probability, and the risk of normal tissue damage, thus the models describing the probability of complications in normal tissues have also been developed. The response from the cardiovascular system to high-dose radiation is known and associated with a pro-inflammatory response. However, the effect of low doses may be completely different because it induces an anti-inflammatory response. Also, there is no unambiguous answer to the question of whether RICD is a deterministic effect. Moreover, there is a lack of literature data on the use of known radiobiological models to assess the risk of cardiovascular complications. The models described are general and concerns any healthy tissue. Therefore, when planning treatment for patients, particular attention should be paid to the dose and area of ​​the heart to be irradiated.     

Effect of low-dose radiation on repair of DNA and chromosome damage

In this report results of studies on the effect of different doses of low LET (linear energy transfer) radiations on the unscheduled DNA synthesis (UDS) and DNA polymerase activity as well as the induction of adaptive response in bone marrow cells (BMC) by low dose radiation were presented. It was found that whole-body irradiation (WBI) with X-ray doses above 0.5 Gy caused a dose-dependent depression of both UD5 and DNA polymerase activity, while low dose radiation below 250 mGy could stimulate the DNA repair synthesis and the enzyme activity. WBI of mice with low doses of X-rays in the range of 2-100 mGy at a dose rate of 57.3 mGy per minute induced an adaptive response in the BMC expressed as a reduction of chromosome aberrations following a second exposure to a larger dose (0.65 mGy). It was demonstrated that the magnitude of the adaptive response seemed to be inversely related to the induction dose. The possibility of induction of adaptive response in GO phase of the cell cycle and the possibility of a second induction of the adaptive response were discussed.     

DNA damage responses at low radiation doses

Increased cell killing after exposure to low acute doses of X rays (0-0.5 Gy) has been demonstrated in cells of a number of human tumor cell lines. The mechanisms underlying this effect have been assumed to be related to a threshold dose above which DNA repair efficiency or fidelity increases. We have used cells of two radioresistant human tumor cell lines, one that shows increased sensitivity to low radiation doses (T98G) and one that does not (U373), to investigate the DNA damage response at low doses in detail and to establish whether there is a discontinuous dose response or threshold in activation of any important mediators of this response. In the two cell lines studied, we found a sensitive, linear dose response in early signaling and transduction pathways between doses of 0.1 and 2 Gy with no evidence of a threshold dose. We demonstrate that ATM-dependent signaling events to downstream targets including TP53, CHK1 and CHK2 occur after doses as low as 0.2 Gy and that these events promote an effective damage response. Using chemical inhibition of specific DNA repair enzymes, we show that inhibition of DNA-PK-dependent end joining has relatively little effect at low (<1 Gy) doses in hyper-radiosensitive cells and that at these doses the influence of RAD51-mediated repair events may increase, based on high levels of RAD51/BRCA2 repair foci. These data do not support a threshold model for activation of DNA repair in hyper-radiosensitive cells but do suggest that the balance of repair enzyme activity may change at low doses.     

Adaptive response for chromosomal inversions in pKZ1 mouse prostate induced by low doses of X radiation delivered after a high dose

Adaptive responses are induced by stress such as X radiation and result in a lower than expected biological response. Two-dose adaptive response experiments typically involve a low priming dose followed by a subsequent high radiation dose. Here, we used a sensitive in vivo chromosomal inversion assay to demonstrate for the first time an adaptive response when a low dose (0.01-1 mGy) was given several hours after a high 1000-mGy radiation dose. The adaptive responses in this study were of similar magnitude to the two-dose adaptive responses previously observed in this test system when the low dose was given first. A chromosomal inversion adaptive response was also induced by two 1000-mGy doses and when a 1-mGy dose was preceded or followed by a dose of 0.01 mGy, but not by two 4000-mGy doses. This is also the first example of an adaptive response when both doses are low. Our data agree with previous reports of an on-off mechanism of adaptive response. The induction of an adaptive response by a low dose after a high damaging dose provides evidence that the mechanisms underlying radiation adaptive responses are not due to prevention of damage induced by the high dose but to modulation of the cellular response to this damage.     

Estimation and reduction of the radiation dose to the fetus from external-beam radiotherapy

The appearance of a malignant disease during pregnancy is relatively rare. The use of external-beam radiation therapy is limited to non-pelvic tumors which are usually located above the diaphragm. However, supradiaphragmatic radiotherapy unavoidably exposes the fetus to secondary radiation due to head leakage, scatter from the machine and scatter produced inside the patient. This fetal exposure may be associated with an elevated risk for the development of deterministic harmful effects and/or carcinogenesis. The decision about the administration of radiotherapy in a pregnant patient is influenced by the fetal dose which must always be estimated before the patient’s treatment course. The methods employed for fetal dosimetry in external-beam radiotherapy are described in this review study. Direct dose measurements using thermoluminescent dosemeters or large ionization chambers placed on physical phantoms may be used. Monte Carlo simulations on computational phantoms may also provide accurate fetal dose calculations. The physical and/or computational phantoms need to simulate the full-scatter geometry of the pregnant patient. Typical fetal dose values attributable to radiation therapy for brain tumors, head and neck cancer, breast carcinoma and Hodgkin lymphoma at the first, second and third trimesters of gestation are presented. The effectiveness of different shielding devices for fetal dose reduction in radiotherapy is discussed. The effect of the dimensions and setup of the shielding material on the radiation dose received by the fetus is described. Moreover, practical methods for reducing the fetal dose by selecting the appropriate irradiation parameters are presented.     

Distinct response of adult neural stem cells to low versus high dose ionising radiation

Radiosusceptibility is the sensitivity of a biological organism to ionising radiation (IR)-induced carcinogenesis, an outcome of IR exposure relevant following low doses. The tissue response is strongly influenced by the DNA damage response (DDR) activated in stem and progenitor cells. We previously reported that in vivo exposure to 2 Gy X-rays activates apoptosis, proliferation arrest and premature differentiation in neural progenitor cells (transit amplifying cells and neuroblasts) but not in neural stem cells (NSCs) of the largest neurogenic region of the adult brain, the subventricular zone (SVZ). These responses promote adult quiescent NSC (qNSC) activation after 2 Gy. In contrast, neonatal (P5) SVZ neural progenitors continue proliferating and do not activate qNSCs. Significantly, the human and mouse neonatal brain is radiosusceptible.Here, we examine the response of stem and progenitor cells in the SVZ to low IR doses (50–500 mGy). We observe a linear dose-response for apoptosis but, in contrast, proliferation arrest and neuroblast differentiation require a threshold dose of 200 or 500 mGy, respectively. Importantly, qNSCs were not activated at doses below 500 mGy. Thus, full DDR activation in the neural stem cell compartment in vivo necessitates a threshold dose, which can be considered of significance when evaluating IR-induced cancer risk and dose extrapolation.     

Cellular transformation by radiation: Induction,promotion, and inhibition

Mammalian cell cultures offer powerful tools for evaluating qualitatively and quantitatively the oncogenic potential of radiation over a wide range of doses with particular importance at the low dose range that is relevant to human exposure and risk. Our studies have shown that early events in the process of radiation induced transformation in both rodent and human cells requires initial replication for fixation of transformation as a hereditary property of the cells and further clonal expansion for full expression. Early events (fixation) are inhibited by cell–cell contact and high cell density but can be modified at low temperature where repair processes are slowed. Cell–cell contact and communication in tissue organization may be in part responsible for our findings that radiation oncogenesis induced in utero in hamsters is expressed at a lower frequency than that induced in vitro. Quantitative studies carried out on hamster embryo cells indicate that neutrons are more effective in their carcinogenic potential than x-rays but also more toxic, that splitting the dose of x-rays at low doses leads to enhanced transformation, but that at high doses protracted radiation has a sparing effect. At all dose ranges survival was increased by protracting the radiation dose, thus suggesting that different repair processes must be involved for survival and transformation. Similar observations were seen when the protease inhibitor Antipain was found to enhance transformation in rodent and human cells when present at the time of radiation, but was protective when added after radiation. Survival was not modified under any of those conditions, and Antipain did not affect DNA replication and repair. In our qualitative studies, once cells are transformed by radiation, they exhibit a wide range of structural and functional phenotypic changes, some of which are membrane-associated and are expressed within days after induction. Our current studies on nutritional and hormonal influences on radiation transformation indicate the following: Pyrolysate products from broiled protein foods act in synergism with radiation to produce transformation, whereas vitamin A analogs are powerful, preventive agents. Retinoids inhibit both x-ray-induced transformation and its promotion by TPA: these modifications (enhancement by TPA, inhibition by retinoids) are not reflected in sister chromatid exchanges, but are reflected in the level of membrane associated enzymes Na/K ATPase. Whereas retinoids modify late events (expression, promotion), we find that thyroid hormone plays a crucial role in the early phases of radiation and chemically induced transformation. Under hypothyroid conditions no transformation is observed. The addition of triiodothyronine at physiological levels results in a transformation rate that is dose-related. Our recent success in transforming human skin fibroblasts will enable quantitative and qualitative studies of radiation carcinogenesis in a system relevant to man.     

Altitude, radiation, and mortality from cancer and heart disease

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.