Inverse Dose-rate Effect Research Articles

Canadian National Dose Registry of Radiation Workers: Overview of Research from 1951 Through 2007

The National Dose Registry (NDR) of Canada is a unique resource for a direct estimation of the potential health risks associated with low doses of ionizing radiation. This is the largest national occupational radiation exposure database, comprising records for about 600,000 nuclear, industrial, medical and dental workers. An analysis of the NDR data based on a cohort of about 200,000 workers first exposed before 1984 and followed through 1987 and 1988 for mortality and cancer incidence, respectively, revealed that the mortality from most causes of death considered was lower than that in the general population, which is typical of occupational cohorts. Although the same was also observed for cancer incidence, there was a significant increase in the incidence of thyroid cancer and melanoma which, however, was not clearly related to radiation exposure. A significant dose-response was found for mortality from all causes, all cancers, lung cancer, cardiovascular diseases, accidents, for incidence of all cancers, cancers of the rectum and lung, leukaemia, all cancers except lung, and all cancers except leukaemia. In addition, in male workers, a significant dose-response was found for the incidence of colon, pancreatic, and testicular cancers. The estimates of cancer risks (mortality and incidence) were higher than those in most other occupational cohorts and in the studies on atomic bomb survivors. The biologically based dose-response models used to describe lung cancer incidence in the NDR showed that for a protracted exposure to low radiation doses there was a significant radiation effect on the promotion and malignant conversion, but not on the initiation stage of carcinogenesis. This stands in contrast to the findings for high-dose acute exposures in A-bomb survivors, where the initiation and possibly promotion were found to be affected by radiation exposure. Evidence of an inverse dose-rate effect (i.e. an increase in the risk with a protraction of a given cumulative dose) was found in the NDR cohort.

EXAMINATION OF UNDERGROUND MINER DATA FOR RADON PROGENY SIZE REDUCTION AS CAUSE OF HIGH RADON “INVERSE” DOSE RATE EFFECT

Radon progeny measurements of particle size distributions show that at high radon levels the distributions decrease in arithmetic mean diameters (AMD)--apparently due to increased neutralization rates affected by high radon concentrations. The radon concentration threshold for this diameter decrease effect (enhanced deposition effect, EDE), decreases with increased humidity. From graded screen array measurements, in a test chamber the AMD's are known vs. radon concentration. Knowing all the necessary parameters and using the ICRP 66 human respiratory tract model, the reduction in human lung dose rate per unit radon concentration was computed to be a factor of 2.5 in the test chamber. Supported by other work, this implies that the underground miners must experience a similar lung dose reduction. A prior estimate of a factor of 4 was obtained for the miners, but with only an estimate of the crucially important mine humidity distributions. Here a re-evaluation, using more realistic values for a representative mine work area surface to volume ratio and using in-mine measured humidity data at 108 mine work locations in 15 different mines, the re-computed estimate for the EDE miner lung dose rate reduction was 4.3. Analyzing separately in-mine data in unventilated locations finds a greater transition rate of the EDE lung dose reduction. These results are affirmed by measured mine progeny to radon concentration ratios, mine deposition rates and miners' individual work shift exposures at the North Alice, Utah mine. In comparing our data with other radon "inverse" dose rate effect (IDRE) data, a significant portion of the IDRE must be from reduction in lung dose from this EDE and not from decreased lung cancer incidence per progeny lung dose. We offer the only currently plausible answer for IDRE. This does not negate any bystander effects at the very low radon concentrations where other data are least accurate.

RADON AND LUNG CANCER RISK: AN EXTENSION OF THE MORTALITY FOLLOW-UP OF THE NEWFOUNDLAND FLUORSPAR COHORT

Radon is a well-recognized cause of lung cancer, and studies of underground miners have provided invaluable insights on the mechanisms of radon carcinogenesis. Given the dramatic decreases in occupational exposures and the latent interval between the time of exposure and the development of lung cancer, continued follow-up of these cohorts is needed to address uncertainties in risk estimates. Here, we report on the relationship between radon and lung cancer mortality in a cohort of 1,742 Newfoundland fluorspar miners between 1950 and 2001; follow-up has been extended 11 y from previous analyses. The standardized mortality ratio (SMR) was used to compare the mortality experience of the cohort to similarly aged Newfoundland males. Poisson regression methods were used to characterize the radon-lung cancer relationship with respect to: age at first exposure, attained age, time since last exposure, interactions with cigarette smoking, and exposure rate. In total, 191 lung cancers were observed among underground miners (SMR = 3.09; 95% CI = 2.66, 3.56). ERR/WLMs decreased with attained age and time since last exposure. An inverse dose-rate effect was observed, while age at first exposure was not associated with lung cancer risk. An important strength of this study is that the effects of gamma radiation, thoron, and radioactive dust, common exposures in other miner studies, can be ruled out because the source of radon was from water running through the mine. However, the results should be interpreted cautiously due to uncertainties associated with the estimation of radon exposure levels before ventilation was introduced into the mine, and the relatively small number of lung cancer deaths that precluded joint modeling of multiple risk factors.

Thresholds and transitions for activation of cellular radioprotective mechanisms – correlations between HRS/IRR and the ‘inverse’ dose-rate effect

Purpose: In biophysical modeling for several instances of radiation-induced radioprotection, i.e., adaptive response (AR), hyper-radiosensitivity and induced radioresistance (HRS/IRR), and the inverse dose-rate effect (IDRE), empirical fits are premised for the thresholds and transitions of the radioprotection. We provide realistic model formulations for the observed behaviors, which we apply to both HRS/IRR and IDRE.Materials and methods: We use homeostatic balance equations, including cell biophysical endogenic adjustments (originating from within the cell), providing a radiation-induced ‘trigger’ or continuous thresholds and transitions.Results: A ‘trigger’ threshold requires an instantaneous, step function. Current HRS/IRR transition model does not provide ‘triggered’ threshold but continuous progression from high sensitivity to reduced radiosensitivity, although the investigators premise ‘trigger’ behavior. IDRE data suggest ‘triggered’ thresholds at discrete dose rates. It appears that HRS/IRR and IDRE at low dose and dose rate intentionally provide protection against potentially carcinogenic mutations.Conclusions: The homeostatic formulation shows, when applied to the IRR using a dose and dose rate dependent Linear-Quadratic model (LQ2), that the IRR protection is ‘triggered’ at a discrete low dose and induced by a transitory increase in the damage repair rate constant in the LQ2 model of the single event, linear response, radiation damage. Since both IDRE and IRR have ‘triggered’ thresholds and as a result of increased endogenic damage recognition, increased mobilization of repair resources, activation of cell cycle arrest and/or increased repair rate, we premise that both may be from the same endogenic radioprotection biochemical mechanisms.

Automatic system for single ion/single cell irradiation based on Cracow microprobe

Recently, the Cracow ion microprobe has found its new application as a single ion hit facility (SIHF), allowing precise irradiations of living cells by a controlled number of ions. The instrument enables a broad field of research, such as survival studies, adaptive response investigations, bystander effect, inverse dose-rate effect, low-dose hypersensitivity, etc. This work presents principles of construction and operation of the SIHF based on the Cracow microprobe. We discuss some crucial features of optical, positioning, and blanking systems, including self-developed software responsible for semiautomatic cell recognition, for precise positioning of cells, and for controlling the irradiation process. We also show some tests carried out to determine the efficiency of the whole system and of its segments. In addition, we present results of the first irradiation measurements performed with living cells.

The inverse dose-rate effect for radon induced lung cancer: a modified approach for risk modelling

One of the features of high LET alpha-ray exposure due to radon inhalation is the well-known inverse dose-rate effect. The longer a given dose is delivered to the lung, the higher is its carcinogenic effect. This introduces the problem of risk extrapolation from high levels of radon exposure typical for uranium miners, down to low levels of radon exposure typical for the general population. An analytical model is presented that accounts for dose-rate effects over the entire exposure range. In accordance with radiobiological considerations and microdosimetric implications, the model provides an adequate description of the inverse dose-rate effect in the higher dose range. At the same time, a linear slope at low exposures that is independent of the dose-rate of exposure is attained.

LUNG CANCER RISK AMONG FORMER URANIUM MINERS OF THE WISMUT COMPANY IN GERMANY

After 1946, the WISMUT Company developed the third-largest uranium-mining province in the world in the German Democratic Republic. A case-control study among former WISMUT miners was conducted to investigate the lung cancer risk in relation to attained age, time since exposure, exposure duration, and exposure rate. It consisted of 505 patients with lung cancer and 1,073 controls matched to cases according to the year of birth. The cumulative exposure to radon and radon decay products was calculated as the sum of yearly exposures and expressed in Working Level Months (WLM). Cases had a mean cumulative exposure of 552 WLM compared to 420 WLM in controls. There was a statistically significant increase in lung cancer risk for cumulative exposures above 800 WLM. Under the assumption of a linear risk model, there was a significant increase in the relative risk of 0.10 per 100 WLM after adjusting for smoking and asbestos exposure. For current smokers the increase in relative risk was lower (0.05 per 100 WLM), whereas it was higher (0.20 per 100 WLM) among nonsmokers and longtime ex-smokers. After correcting in a sensitivity analysis for the fact that the controls of this study had a higher average exposure than the population of WISMUT workers they were recruited from, the adjusted ERR increased to 0.24 per 100 WLM. Lung cancer risk declined with time since exposure, except for exposures received 45 or more years ago. No inverse dose rate effect was observed.

The radon inverse dose rate effect and high-LET galactic hazards

The lung dose rate per unit 222Rn concentration in enclosed spaces is shown to experience transitions at high radon concentrations. This has implications on the radon inverse dose rate effect. At an air change rate (ACH) of 0.194 h(-1) and relative humidity (RH) of 52.3% in a 0.283 m3 test chamber, the total human lung dose for an adult male in a residential setting (breathing rate 0.78 m3 h(-1)) would undergo a reduction of 2.5 using the ICRP 66 human respiratory tract model and the BEIR VI methodology. Using the same methodology of both Cross (Pacific Northwest Laboratory rat exposures) and Lubin et al. (miners dose rates), adjustments are necessary for effects of RH and ACHs. These adjustments, however, do not affect the reduction behaviour. It is thus shown that the enhanced deposition effect (EDE) must influence the magnitude of the purported inverse dose rate effect (IDRE). In the analysis of animal data, Cross rat exposures in a 2.0 m3 chamber, a reduction in lung dose is estimated to be over a factor of 3 the transition between the 50 and 500 WLM week(-1) dose rate range. For an estimation of the EDE, using a hypothetical 30 m3 enclosure for underground miners, we obtain a factor of approximately 4 in human lung dose reduction. Although the extensive analyses required make these results qualitative, the EDE behaviour is sufficiently conclusive that these estimates show that the radon IDRE for lung cancer must be an EDE dosimetric issue as well as a radiological lung cell dose response issue. The consequence of analysis of other animal data would achieve the same conclusion.

RADIATION EFFECTIVENESS FACTORS FOR USE IN CALCULATING PROBABILITY OF CAUSATION OF RADIOGENIC CANCERS

This paper presents so-called radiation effectiveness factors that are intended to represent the biological effectiveness of different radiation types, relative to high-energy Co gamma rays, for the purpose of estimating cancer risks and probability of causation of radiogenic cancers in identified individuals. Radiation effectiveness factors are expressed as subjective probability distributions to represent uncertainty that arises from uncertainties in estimates of relative biological effectiveness obtained from radiobiological studies of stochastic endpoints, limited data on biological effectiveness obtained from human epidemiological studies, and other judgments involved in evaluating the applicability of available information to induction of cancers in humans. Primarily on the basis of reviews and evaluations of available data by experts, probability distributions of radiation effectiveness factors are developed for the following radiation types: neutrons of energy less than 10 keV, 10-100 keV, 0.1-2 MeV (including fission neutrons), 2-20 MeV, and greater than 20 MeV; alpha particles of any energy emitted by radionuclides; photons of energy 30-250 keV and less than 30 keV; and electrons of energy less than 15 keV. Photons of energy greater than 250 keV and electrons of energy greater than 15 keV are assumed to have the same biological effectiveness as reference Co gamma rays and are assigned a radiation effectiveness factor of unity, without uncertainty. For neutrons and alpha particles, separate probability distributions of radiation effectiveness factors are developed for solid tumors and leukemias, and small corrections to represent an inverse dose-rate effect are applied to those distributions in cases of chronic exposure. A radiation effectiveness factor different from unity for 15-60 keV electrons is discussed but is not adopted due to a lack of relevant radiobiological data. Radiation effectiveness factors presented in this paper are incorporated in the Interactive RadioEpidemiological Program and were developed for use by The National Institute for Occupational Safety and Health and U.S. Department of Labor in evaluating claims for compensation for radiogenic cancers by workers at U.S. Department of Energy facilities.

Study of the effect of dose-rate on radiation-induced damage to human erythrocytes

Human erythrocytes suspended in an isotonic Na-phosphate buffer, pH 7.4 (hematocrit of 2%) were irradiated with γ-rays at three dose-rates of 66.7, 36.7, 25 Gy min −1 in order to investigate the influence of the dose-rate on radiation-induced membrane damage, hemoglobin oxidation and loss of reduced glutathione. The obtained results showed that such processes as erythrocyte hemolysis, lipid and protein destruction depend on the radiation dose-rate. The parameter values describing these processes showed an inverse dose-rate effect.

Relative Biological Effectiveness of103Pd and125I Photons for Continuous Low-Dose-Rate Irradiation of Chinese Hamster Cells

Monolayers of Chinese hamster lung cells (CCL-16) in a polystyrene phantom were irradiated in vitro by 103Pd and 125I sources at dose rates of 6 to 72 cGy/h. Cell survival curves for acute high-dose-rate irradiation (over 30 Gy/h) were also measured using nearly monoenergetic X-ray beams which were designed to simulate the mean energies of photons emitted by 125I and 103Pd and also using a clinical 250 kVp X-ray beam. A profound dose-rate effect is observed over the dose-rate range of 6 to 20 cGy/h. An inverse dose-rate effect was observed for both radionuclides, with its onset occurring at a dose rate of about 20-30 cGy/h. The average RBE of 103Pd relative to 125I was determined to be 1.45 +/- 0.07, 1.41 +/- 0.07, 0.70 +/- 0.07 and 1.49 +/- 0.07 at dose rates of 6.9, 12.6, 19.0 and 26.7 cGy/h, respectively. Because 103Pd implants are generally prescribed at a higher initial dose rate (21 cGy/h) than the corresponding 125I implants (7 cGy/h), the effects of both dose rate and photon energy on biological response must be considered together. For the CCL-16 cells, the RBE of 103Pd at 19.0 cGy/h relative to that of 125I at 6.9 cGy/h was estimated to be 2.3 +/- 0.5.

Evasion of Early Cellular Response Mechanisms following Low Level Radiation-induced DNA Damage

DNA damage that is not repaired with high fidelity can lead to chromosomal aberrations or mitotic cell death. To date, it is unclear what factors control the ultimate fate of a cell receiving low levels of DNA damage (i.e. survival at the risk of increased mutation or cell death). We investigated whether DNA damage could be introduced into human cells at a level and frequency that could evade detection by cellular sensors of DNA damage. To achieve this, we exposed cells to equivalent doses of ionizing radiation delivered at either a high dose rate (HDR) or a continuous low dose rate (LDR). We observed reduced activation of the DNA damage sensor ataxia-telangiectasia mutated (ATM) and its downstream target histone H2A variant (H2AX) following LDR compared with HDR exposures in both cancerous and normal human cells. This lack of DNA damage signaling was associated with increased amounts of cell killing following LDR exposures. Increased killing by LDR radiation has been previously termed the "inverse dose rate effect," an effect for which no clear molecular processes have been described. These LDR effects could be abrogated by the preactivation of ATM or simulated in HDR-treated cells by inhibiting ATM function. These data are the first to demonstrate that DNA damage introduced at a reduced rate does not activate the DNA damage sensor ATM and that failure to activate ATM-associated repair pathways contributes to the increased lethality of continuous LDR radiation exposures. This inactivation may reflect one strategy by which cells avoid accumulating mutations as a result of error-prone DNA repair and may have a broad range of implications for carcinogenesis and, potentially, the clinical treatment of solid tumors.

The bystander effect model of Brenner and Sachs fitted to lung cancer data in 11 cohorts ofunderground miners, and equivalence of fit of a linear relative risk model with adjustmentfor attained age and age at exposure

Bystander effects following exposure toα-particles have been observed in many experimental systems, and imply that linearlyextrapolating low dose risks from high dose data might materially underestimate risk.Brenner and Sachs (2002 Int. J. Radiat. Biol. 78 593–604; 2003 Health Phys. 85 103–8) haverecently proposed a model of the bystander effect which they use to explain the inversedose rate effect observed for lung cancer in underground miners exposed to radondaughters. In this paper we fit the model of the bystander effect proposed by Brenner andSachs to 11 cohorts of underground miners, taking account of the covariance structure ofthe data and the period of latency between the development of the first pre-malignant celland clinically overt cancer. We also fitted a simple linear relative risk model, withadjustment for age at exposure and attained age. The methods that we use for fitting bothmodels are different from those used by Brenner and Sachs, in particular taking account ofthe covariance structure, which they did not, and omitting certain unjustifiableadjustments to the miner data. The fit of the original model of Brenner and Sachs (with 0 yperiod of latency) is generally poor, although it is much improved by assuming a5 or 6 y period of latency from the first appearance of a pre-malignant cell tocancer. The fit of this latter model is equivalent to that of a linear relative riskmodel with adjustment for age at exposure and attained age. In particular, bothmodels are capable of describing the observed inverse dose rate effect in this dataset.

Sensitization to radiation from an implanted 125I source by sustained intratumoral release of chemotherapeutic drugs.

We have investigated tumor response to low-dose-rate irradiation from an implanted 125I source alone or in conjunction with intratumoral drug administration. The drug (cis-DDP or 5-FU) was incorporated homogeneously into the co-polymer CPP-SA, 20:80, and the polymer/drug rods were implanted in the RIF-1 fibrosarcomas growing subcutaneously in C3H mice. Twenty-four hours later, the tumor was implanted with an 125I seed. Tumor growth time was the end point in these experiments. For implanted 125I sources of different dose rates and implant times giving a range of total doses, a consistent dose-response relationship was shown between tumor growth time and total dose. In other experiments, 125I sources of different specific activities were implanted for periods of time adjusted so that the total dose to the tumor was always the same. When the 125I implant was combined with 5-FU, greater than additive responses were seen for both short (30 h) and long (96 h) 125I treatment times. In contrast, a short-duration (30 h) 125I implant combined with cis-DDP was the least effective treatment, giving a combined response that was no better than additive, whereas 96 h exposure to 125I combined with cis-DDP was the most effective combined treatment. It is conjectured that this inverse dose-rate effect seen when cis-DDP is combined with low-dose rate radiation is related to a cell cycle effect and/or to inhibition of repair of radiation damage by cis-DDP.

Risk of fatal versus incidental lung cancer in radon-exposed rats: A reanalysis of French data

This review summarizes data on lung cancer risk from radon experimental studies performed by our group in France with emphasis on the most recent findings and analyses on the influence of dose-rate and that of fatal versus incidental tumors. A dose-effect relationship was established in rats, which was very similar for medium and high cumulative exposures, to that observed in uranium miners. At low cumulative exposures in the range of 0.18 Jhm-3 (50 WLM) to 0.36 Jhm-3 (100 WLM), the proportion of fatal lung cancer is about 80% that of total lung cancers. In contrast, at cumulative exposures of 0.72 Jhm-3 (200 WLM) and higher, the proportion of fatal lung cancer is about half that of total lung cancers. The parameters that influence fatal lung cancer risk are cumulative exposure, potential alpha energy concentration (PAEC), exposure rate, and protraction of exposure. At high cumulative exposures up to 10.8 Jhm-3 (3,000 WLM), an inverse dose-rate effect similar to that observed in uranium miners was also found in rats. The inverse exposure- rate effect was observed mainly at the highest exposure-rates. In contrast, our recent results indicate that at relatively low cumulative exposures of 0.36 Jhm-3 (100 WLM), comparable to lifetime exposures in high-radon houses or current underground mining exposures, the risk of lung cancer in rats decreases with decreasing PAEC, i.e., exposure rate. These data suggest that the induction of lung cancer results from a complex inter- play between cumulative exposure and exposure rate, with an optimal combination of these two parameters that results in a maximum risk of lung cancer induction. They support the hypothesis that, at low doses, the risk of lung cancer is governed by the rate at which the dose is delivered, and not by the total cumulative dose alone. These data are also consistent with those of underground uranium miners showing an inverse dose-rate effect at high cumulative exposures, but an attenuation of this effect at cumulative exposures lower than 0.18 Jhm-3 (50 WLM). They support both an inverse dose-rate effect at high cumulative exposures, as well as its attenuation or disappearance at low cumulative exposures.

Influence of exposure rate on radon-induced lung cancer in rats

A new series of experiments was carried out to investigate specifically theinfluence of exposure rate on lung cancer induction in rats at relatively lowcumulative exposures of about 100 WLM, and at potential alpha energyconcentrations (PAECs) ranging from 13 to 150 WL. The results indicate that atrelatively low cumulative exposures comparable to lifetime exposures inhigh-radon houses or current underground mining exposures, the risk of lungcancer in rats decreases with decreasing PAECs, i.e. exposure rates. They confirmthe results of previous experiments conducted at lower cumulative exposure,showing that for a similar cumulative exposure of 25 WLM, the risk of lungcancer decreases with decreasing exposure rates. These data suggest that theinduction of lung cancer results from a complex interplay between cumulativeexposure and exposure rate, with an optimal combination of these twoparameters, i.e. a combination of cumulative dose and dose rate thatresults in a maximum risk of lung tumour induction. They support thehypothesis that, at low doses, the risk of lung cancer is governed by the rate atwhich the dose is delivered, and not by the total cumulative dose alone.These data are also consistent with that of underground uranium minersshowing an inverse dose-rate effect at high cumulative exposures, but adiminution of this effect at cumulative exposures lower than 50 WLM.

Mutation induction by continuous low dose rate gamma irradiation in human cells

Human teratocarcinoma cells P3 were subjected to 60Co-gamma-rays in continuous exponential growth using a “chemostat” set-up. Mutations at the HPRT-locus were measured with dose rates of 5 mGy/h, 50 mGy/h and after acute exposure. There was a clear reduction of mutation induction efficiency with 50 mGy/h compared to the high dose rates, however, with 5 mGy/h the same results were obtained as with acute exposure, in other words mutation induction increased again with very low dose-rates. This phenomenon of an “inverse dose rate effect” is restricted to cycling cells, as it was not found in plateau phase cells exposed under identical conditions. These results confirm previous findings by others and us in rodent cells, which were so far not available for human cells. In order to explore a possible contribution of “genomic instability”, cells irradiated acutely with a dose of 3 Gy were grown for up to 40 days in an exponential culture, and the mutant frequencies were determined every second day. A rise in mutant frequency after 20–30 days was consistently found in three independent experiments but time course and mutant numbers were not reproducible and seemed to follow a stochastic behaviour. The results cast doubt on the common assumption that a reduction in the dose rate will always lead to smaller effects, although this somewhat artificial system cannot be generalised to the human situation.

Does radiation enhance promotion of already-initiated cells in protracted high-LET carcinogenesis via a bystander effect?

The application of the two-stage clonal expansion (TSCE) model to lung cancer mortality of two populations of miners (the Colorado Plateau miners and the Chinese tin miners) after protracted high-LET radiation exposure (alpha particles of radon-progeny decay) results in the conclusion that the carcinogenesis process in protracted exposures is dominated by the promotion of already-initiated cells. This means that the increase in tumor induction is caused mainly by the modification (i.e., increase) of the net cell proliferation of already-initiated cells during the time of exposure. We hypothesize that this phenomenon is caused by a “bystander effect” whereby normal cells being hit by alpha particles send mitogenic signals to surrounding cells. If the signals are received by (unhit but) already-initiated cells, which are less controlled by homeostasis than the normal cell population, the cells respond by increasing their net cell proliferation, thus increasing the probability of the emergence of a fully malignant cell. Thus, tissue homeostasis (or the lack thereof) plays an important role. Possible modulators at the cellular level include reactive oxygen species (ROS), transforming growth factor-beta (TGF-β) within the extracellular matrix and the subsequent up and/or down regulation of genes controlling mitogenic factors within the cell. This process of proliferative stimulation causes an “inverse dose-rate effect” which is more appropriately termed as a protraction effect to distinguish it from the dose-rate effects usually attributed to cellular repair and other mechanisms (e.g., a radiosensitive window in the cell cycle).

Do low dose-rate bystander effects influence domestic radon risks?

Purpose : Radon risks derive from exposure of bronchio-epithelial cells to high-linear energy transfer (LET) α -particles. α -particle exposure can result in bystander effects, where irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. This can result in non-linear dose-response relations, and inverse dose-rate effects. Domestic radon risk estimates are currently extrapolated from miner data, which are at both higher doses and higher dose-rates, so bystander effects on unhit cells could play a large role in the extrapolation of risks from mines to homes. Therefore, we extend an earlier quantitative mechanistic model of bystander effects to include protracted exposure, with the aim of quantifying the significance of the bystander effect for very prolonged exposures. Materials and methods : A model of high-LET bystander effects, originally developed to analyse oncogenic transformation in vitro, is extended to low dose-rates. The model considers radiation response as a superposition of bystander and linear direct e It attributes bystander effects to a small subpopulation of hypersensitive cells, with the bystander contribution dominating the direct contribution at very low acute doses but saturating as the dose increases. Inverse dose-rate effects are attributed to the replenishment of the hypersensitive subpopulation during prolonged irradiation. Results : The model was fitted to dose- and dose-rate-dependent radon-exposed miner data, suggesting that one directly hit target bronchio-epithelial cell can send bystander signals to about 50 neighbouring target cells. The model suggests that a naïve linear extrapolation of radon miner data to low doses, without accounting for dose-rate, would result in an underestimation of domestic radon risks by about a factor of 4, a value comparable with the empirical estimate applied in the recent BEIR-VI report on radon risk estimation. Conclusions : Bystander effects represent a plausible quantitative and mechanistic explanation of inverse dose-rate effects by high-LET radiation, resulting in non-linear dose-response relations and a complex interplay between the effects of dose and exposure time. The model presented provides a potential mechanistic underpinning for the empirical exposure-time correction factors applied in the recent BEIR-VI for domestic radon risk estimation.

Effect of subsequent acute-dose irradiation on cell survival in vitro following low dose-rate exposures

Purpose : Following acute irradiation, excess radiosensitivity is generally seen at doses <1 Gy, a phenomenon termed 'low-dose hyper-radiosensitivity' (HRS). A very strong, HRS-like inverse dose-rate effect has also been described following continuous low dose-rate (LDR) irradiation at <30 cGy h -1. We report on the sequential irradiation of a cell line by such LDR exposures followed by low acute doses, where either treatment individually would elicit a hypersensitive response. The aim was to determine if a prior LDR exposure would remove the HRS normally seen in response to very small acute radiation doses. Materials and methods : T98G human glioma cells were given single continuous LDR exposures of 5-60 cGy h -1 using a 60 Co γ-source. At intervals of 0 or 4 h following LDR irradiation, cells were further irradiated with a range of acute doses using 240-kVp X-rays. The response to the combined treatment was assessed using high-precision clonogenic cell survival assays, and the amount of HRS at acute doses <1 Gy was determined. Results : LDR at ≥60 cGy h -1 to total doses up to 5 Gy in asynchronously growing cells did not remove HRS in the subsequent acute-dose survival curve. In confluent cultures, subsequent acute-dose HRS was not present after an LDR dose of 5 Gy at either 60 or 30 cGy h -1, but returned if a 4-h interval was left between LDR and acute-dose irradiation. In confluent cultures, acute-dose HRS remained for LDR treatments at 5 or 10 cGy h -1 or if the total dose was 2 Gy. Taking all cultures and dose-rates together, the 'degree' of acute-dose HRS, as measured by α s, was significantly greater in cells irradiated at LDR to a total dose of 2 than of 5Gy. Conclusions : Initial LDR exposure can affect a subsequent HRS response. HRS is reduced after LDR exposures at greater dose intensity, but can recover again within 4 h of completion of LDR exposure. This suggests that processes determining increased resistance to small acute doses (removal of HRS) might be governed by the level of repairable DNA lesions.