A New Standard DNA Damage (SDD) Data Format.

Our understanding of radiation-induced cellular damage has greatly improved over the past few decades. Despite this progress, there are still many obstacles to fully understand how radiation interacts with biologically relevant cellular components, such as DNA, to cause observable end points such as cell killing. Damage in DNA is identified as a major route of cell killing. One hurdle when modeling biological effects is the difficulty in directly comparing results generated by members of different research groups. Multiple Monte Carlo codes have been developed to simulate damage induction at the DNA scale, while at the same time various groups have developed models that describe DNA repair processes with varying levels of detail. These repair models are intrinsically linked to the damage model employed in their development, making it difficult to disentangle systematic effects in either part of the modeling chain. These modeling chains typically consist of track-structure Monte Carlo simulations of the physical interactions creating direct damages to DNA, followed by simulations of the production and initial reactions of chemical species causing so-called "indirect" damages. After the induction of DNA damage, DNA repair models combine the simulated damage patterns with biological models to determine the biological consequences of the damage. To date, the effect of the environment, such as molecular oxygen (normoxic vs. hypoxic), has been poorly considered. We propose a new standard DNA damage (SDD) data format to unify the interface between the simulation of damage induction in DNA and the biological modeling of DNA repair processes, and introduce the effect of the environment (molecular oxygen or other compounds) as a flexible parameter. Such a standard greatly facilitates inter-model comparisons, providing an ideal environment to tease out model assumptions and identify persistent, underlying mechanisms. Through inter-model comparisons, this unified standard has the potential to greatly advance our understanding of the underlying mechanisms of radiation-induced DNA damage and the resulting observable biological effects when radiation parameters and/or environmental conditions change.

RBE of kV CBCT radiation determined by Monte Carlo DNA damage simulations.

Due to the higher LET of kilovoltage (kV) radiation, there is potential for an increase in relative biological effectiveness (RBE) of absorbed doses of radiation from kV cone beam computed tomography (CBCT) sources in reference to megavoltage or Co-60 doses. This work develops a method for accurately coupling a Monte Carlo (MC) radiation transport code (PENELOPE) with the damage simulation (MCDS) to predict relative numbers of DNA double strand breaks (DSBs). The MCDS accounts for slowing down of electrons and delta ray production within the cell nucleus; however, determining the spectrum of electrons incident on the cell nucleus from photons interacting in a larger region of tissue is not trivial. PENELOPE simulations were conducted with a novel tally algorithm invoked where electrons incident on a detection material were tracked and both the incident energy and the final deposited dose were recorded. The DSB yield predicted by a set of MCDS runs of monoenergetic electrons was then looked up in a table and weighted by the specific energy of the incident electron. Our results indicate that the RBE for DSB induction is 1.1 for diagnostic x-rays with energies from 80 to 125 kVp. We found no significant change in RBE with depth or filtration. The predicted absolute DSB yields are about three times lower for cells irradiated under anoxic conditions than the yield in cells irradiated under normoxic (5%) or fully aerobic (100%) conditions. However, oxygen concentration has a negligible (± 0.02) effect on the RBE of kV CBCT x-rays.

Adaptive IMRT using a multiobjective evolutionary algorithm integrated with a diffusion-invasion model of glioblastoma.

We demonstrate a patient-specific method of adaptive IMRT treatment for glioblastoma using a multiobjective evolutionary algorithm (MOEA). The MOEA generates spatially optimized dose distributions using an iterative dialogue between the MOEA and a mathematical model of tumor cell proliferation, diffusion and response. Dose distributions optimized on a weekly basis using biological metrics have the potential to substantially improve and individualize treatment outcomes. Optimized dose distributions were generated using three different decision criteria for the tumor and compared with plans utilizing standard dose of 1.8 Gy/fraction to the CTV (T2-visible MRI region plus a 2.5 cm margin). The sets of optimal dose distributions generated using the MOEA approach the Pareto Front (the set of IMRT plans that delineate optimal tradeoffs amongst the clinical goals of tumor control and normal tissue sparing). MOEA optimized doses demonstrated superior performance as judged by three biological metrics according to simulated results. The predicted number of reproductively viable cells 12 weeks after treatment was found to be the best target objective for use in the MOEA.

Sci-Sat AM: Brachy - 06: Monte carlo DNA damage simulations of kV cbct radiation.

When performed daily, cone beam CT (CBCT) images can accumulate radiation dose to non-negligible levels. Because kV x-rays have a larger relative biological effectiveness (RBE) than its MV x-rays, the accumulated absorbed dose needs to be multiplied by an appropriate RBE to better evaluate the impact of CBCT dose in a treatment planning context. We investigated this question using PENLEOPE simulations to look in detail at the electron energy spectra produced by kV x-rays and Co-60 γ-rays in biologically motivated geometries. The electron spectra were input into the published Monte Carlo Damage Simulation (MCDS) and used to estimate the average number of double strand breaks (DSBs) per Gy per cell. Our results suggest an approximately 10% increase in the RBE for DSB induction. For the majority of treatment planning scenarios where imaging dose is only a small fraction of the total delivered dose to target volumes and organs at risk, the increase in RBE is not critical to be factored in, however for it may play a significant role in predicting the induction of secondary cancers.

An improved in vivo method for atrioventricular node ablation via thoracotomy

The atrioventricular (AV) node is permanently damaged in approximately 3 percent of congenital heart surgery operations, requiring implantation of a permanent pacemaker. Improvements in pacemaker design and in alternative treatment modalities require an effective in vivo model of complete heart block (CHB) before testing can be performed in humans. Such a model should enable accurate, reliable, and detectable induction of the surgical pathology. Through our laboratory’s efforts in developing a tissue engineering therapy for CHB, we describe here an improved in vivo model for inducing chronic AV block. The method employs a right thoracotomy in the adult rabbit, from which the right atrial appendage may be retracted to expose an access channel for the AV node. A novel injection device was designed, which both physically restricts needle depth and provides electrical information via electrocardiogram interface. This combination of features provides real-time guidance to the researcher for confirming contact with the AV node, and documents its ablation upon formalin injection. While all animals tested could be induced to acute AV block, those with ECG guidance were more likely to maintain chronic heart block >12 h. Our model enables the researcher to reproduce both CHB and the associated peripheral fibrosis that would be present in an open congenital heart surgery, and which would inevitably impact the design and utility of a tissue engineered AV node replacement.

An improved in vivo method for atrioventricular node ablation via thoracotomy.

The atrioventricular (AV) node is permanently damaged in approximately 3% of congenital heart surgery operations, requiring implantation of a permanent pacemaker. Improvements in pacemaker design and in alternative treatment modalities require an effective in vivo model of complete heart block (CHB) before testing can be performed in humans. Such a model should enable accurate, reliable, and detectable induction of the surgical pathology. Through our laboratory's efforts in developing a tissue engineering therapy for CHB, we describe here an improved in vivo model for inducing chronic AV block. The method employs a right thoracotomy in the adult rabbit, from which the right atrial appendage may be retracted to expose an access channel for the AV node. A novel injection device was designed, which both physically restricts needle depth and provides electrical information via electrocardiogram interface. This combination of features provides real-time guidance to the researcher for confirming contact with the AV node, and documents its ablation upon formalin injection. While all animals tested could be induced to acute AV block, those with ECG guidance were more likely to maintain chronic heart block >12 h. Our model enables the researcher to reproduce both CHB and the associated peripheral fibrosis that would be present in an open congenital heart surgery, and which would inevitably impact the design and utility of a tissue engineered AV node replacement.

Dissociation between changes in muscle Na+-K+-ATPase isoform abundance and activity with consecutive days of exercise and recovery.

The early plasticity of vastus lateralis Na(+)-K(+)-ATPase to the abrupt onset of prolonged submaximal cycling was studied in 12 untrained participants (Vo(2 peak) 44.8 +/- 2.0 ml x kg(-1) x min(-1), mean +/- SE) using a 6-day protocol (3 days of exercise plus 3 days of recovery). Tissue samples were extracted prior to (Pre) and following exercise (Post) on day 1 (E1) and day 3 (E3) and on each day of recovery (R1, R2, R3) and analyzed for changes in maximal protein (beta(max)) (vanadate-facilitated [(3)H]ouabain binding), alpha- and beta-isoform concentration (quantitative immunoblotting) and maximal Na(+)-K(+)-ATPase activity (V(max)) (3-O-methylfluorescein K(+)-stimulated phosphatase assay). For beta(max) (pmol/g wet wt), an increase (P < 0.05) of 11.8% was observed at R1 compared with E1-Pre (340 +/- 14 vs 304 +/- 17). For the alpha-isoforms alpha(1), alpha(2), and alpha(3), increases (P < 0.05) of 46, 42, and 31% were observed at R1, respectively. For the beta-isoform, beta(1) and beta(2) increased (P < 0.05) by 19 and 28% at R1, whereas beta(3) increased (P < 0.05) by 18% at R2. With the exception of alpha(2) and alpha(3), the increases in the isoforms persisted at R3. Exercise resulted in an average decrease (P < 0.05) in V(max) by 14.3%. No differences were observed in V(max) at E1 - Pre and E3 - Pre or between R1, R2, and R3. It is concluded that 3 days of prolonged exercise is a powerful stimulus for the rapid upregulation of the Na(+)-K(+)-ATPase subunit isoforms. Contrary to our hypothesis, the increase in subunit expression is not accompanied by increases in the maximal catalytic activity.

Monte Carlo simulation of DNA damage induction by x-rays and selected radioisotopes.

To better assess the potential biological consequences of diagnostic x-rays and selected gamma-emitting radioisotopes used in brachytherapy, we used the PENELOPE Monte Carlo radiation transport code to estimate the spectrum of initial electrons produced by photons in single cells and in an irradiation geometry similar to those used in cell culture experiments. We then combined estimates of the initial spectrum of electrons from PENELOPE with DNA damage yields for monoenergetic electrons from the fast Monte Carlo damage simulation (MCDS). The predicted absolute yields (Gbp(-1) Gy(-1)) and RBE values for single-strand break (SSB) and double-strand break (DSB) induction by 220 kVp x-rays are within 1% of the results from detailed track-structure simulations (Friedland et al 1999 Radiat. Environ. Biophys. 38 39). The measured RBE for DSB induction reported by Kühne et al (2005 Radiat. Res. 164 669) for gamma-rays from (60)Co and for 29 kVp x-rays with a 50 microm Rh (mammography) filter are in excellent agreement (1.15 versus 1.16). DSB yields predicted by the MCDS also agree to within 7% with the absolute DSB yields reported by de Lara et al (2001 Radiat. Res. 155 440) and Botchway et al (1997 Radiat. Res. 148 317) for the irradiation of V79 cells by low energy (<2 keV) characteristic x-rays. The predicted RBE for DSB induction by gamma-rays from bare (169)Yb and (131)Cs to (60)Co are 1.06 and 1.14, respectively. Tabulated RBE values for the single-cell and monolayer cell culture geometries differ by at most 15%. The proposed methodology is computationally efficient and may also be useful for the prediction of damage yields for mixtures of other types of charged particles, such as those found in proton therapy, space applications or internal dosimetry.

Designing equivalent treatment regimens for prostate radiotherapy based on equivalent uniform dose.

The purpose of this work was to determine alternative radiotherapy (RT) regimens that are biologically equivalent to clinically proven treatments using different RT modalities or different fractionation schemes. The concept of equivalent uniform dose (EUD) is used with the linear quadratic model to determine equivalent treatment regimens using two representative sets of parameters derived from clinical data: (i) alpha/beta = 3.1 Gy and alpha = 0.15 Gy(-1), and (ii) alpha/beta = 1.5 Gy and alpha = 0.04 Gy(-1). The EUD values for the critical structure (rectum) are also calculated. Representative dose volume histograms were used to account for dose inhomogeneities for different RT modalities. A series of alternative and equivalent fractionation regimens that can be used with different radiotherapy modalities for localized prostate cancer were determined. For example, the alternative regimens, calculated with the alpha/beta ratio of 3.1 Gy, that would be biologically equivalent to external beam RT (EBRT) of 76 Gy (38x2.0 Gy) include: EBRT hypofractionation of 21x3.0 Gy; I-125 implant of 156 Gy; Pd-103 implant of 128 Gy; high dose rate (HDR) brachytherapy of 4x10.5 Gy; I-125 implant of 65 Gy combined with EBRT of 23x2.0 Gy; and HDR brachytherapy of 3x5.9 Gy combined with EBRT of 23x2.0 Gy. Similar data for other parameters are also presented. With caution, the data presented may be useful in designing clinical trials to explore new RT strategies, such as image-guided intensity-modulated RT.

Muscle metabolic, SR Ca(2+) -cycling responses to prolonged cycling, with and without glucose supplementation.

This study investigated the effects of prolonged exercise, with and without glucose supplementation, on metabolism and sarcoplasmic reticulum (SR) Ca(2+)-handling properties in working vastus lateralis muscle. Fifteen untrained volunteers [peak O(2) consumption (Vo(2peak)) = 3.45 +/- 0.17 l/min; mean +/- SE] cycled at approximately 60% Vo(2peak) on two occasions, during which they were provided with either an artificially sweetened placebo beverage (NG) or a 6% glucose (G) beverage (~1.00 g carbohydrate/kg body mass). Beverage supplementation started at 30 min of exercise and continued every 15 min thereafter. SR Ca(2+) handling, metabolic, and substrate responses were assessed in tissue extracted from the vastus lateralis at rest, after 30 min and 90 min of exercise, and at fatigue in both conditions. Plasma glucose during G was 15-23% higher (P < 0.05) than those observed during NG following 60 min of exercise until fatigue. Cycle time to fatigue was increased (P < 0.05) by approximately 19% during G (137 +/- 7 min) compared with NG (115 +/- 6 min). Prolonged exercise reduced (P < 0.05) maximal Ca(2+)-ATPase activity (-18.4%), SR Ca(2+) uptake (-27%), and both Phase 1 (-22.2%) and Phase 2 (-34.2%) Ca(2+)-release rates during NG. The exercise-induced reductions in SR Ca(2+)-cycling properties were not altered during G. The metabolic responses to exercise were all unaltered by glucose supplementation, since no differences in respiratory exchange ratios, carbohydrate and lipid oxidation rates, and muscle metabolite and glycogen contents were observed between NG and G. These results indicate that the maintenance of blood glucose homeostasis by glucose supplementation is without effect in modifying the muscle metabolic, endogenous glycogen, or SR Ca(2+)-handling responses.

Muscle fiber type-specific response of Hsp70 expression in human quadriceps following acute isometric exercise.

To investigate the time course of fiber type-specific heat shock protein 70 (Hsp70) expression in human skeletal muscle after acute exercise, 10 untrained male volunteers performed single-legged isometric knee extensor exercise at 60% of their maximal voluntary contraction (MVC) with a 50% duty cycle (5-s contraction and 5-s relaxation) for 30 min. Muscle biopsies were collected from the vastus lateralis before (Pre) exercise in the rested control leg (C) and immediately after exercise (Post) in the exercised leg (E) only and on recovery days 1 (R1), 2 (R2), 3 (R3), and 6 (R6) from both legs. As demonstrated by Western blot analysis, whole muscle Hsp70 content was unchanged (P > 0.05) immediately after exercise (Pre vs. Post), was increased (P < 0.05) by approximately 43% at R1, and remained elevated throughout the entire recovery period in E only. Hsp70 expression was also assessed in individual muscle fiber types I, IIA, and IIAX/IIX by immunohistochemistry. There were no fiber type differences (P > 0.05) in basal Hsp70 expression. Immediately after exercise, Hsp70 expression was increased (P < 0.05) in type I fibers by approximately 87% but was unchanged (P > 0.05) in type II fibers (Pre vs. Post). At R1 and throughout recovery, Hsp70 content in E was increased above basal levels (P < 0.05) in all fiber types, but Hsp70 expression was always highest (P < 0.05) in type I fibers. Hsp70 content in C was not different from Pre at any time throughout recovery. Glycogen depletion was observed at Post in all type II, but not type I, fibers, suggesting that the fiber type differences in exercise-induced Hsp70 expression were not related to glycogen availability. These results demonstrate that the time course of exercise-induced Hsp70 expression in human skeletal muscle is fiber type specific.

Muscle sarcoplasmic reticulum calcium regulation in humans during consecutive days of exercise and recovery.

The study investigated the hypothesis that three consecutive days of prolonged cycle exercise would result in a sustained reduction in the Ca(2+)-cycling properties of the vastus lateralis in the absence of changes in the sarcoplasmic (endoplasmic) reticulum Ca(2+)-ATPase (SERCA) protein. Tissue samples were obtained at preexercise (Pre) and postexercise (Post) on day 1 (E1) and day 3 (E3) and during recovery day 1 (R1), day 2 (R2), and day 3 (R3) in 12 active but untrained volunteers (age 19.2 +/- 0.27 yr; mean +/- SE) and analyzed for changes (nmol.mg protein(-1).min(-1)) in maximal Ca(2+)-ATPase activity (V(max)), Ca(2+) uptake and Ca(2+) release (phase 1 and phase 2), and SERCA isoform expression (SERCA1a and SERCA2a). At E1, reductions (P < 0.05) from Pre to Post in V(max) (150 +/- 7 vs. 121 +/- 7), Ca(2+) uptake (7.79 +/- 0.28 vs. 5.71 +/- 0.33), and both phases of Ca(2+) release (phase 1, 20.3 +/- 1.3 vs. 15.2 +/- 1.1; phase 2, 7.70 +/- 0.60 vs. 4.99 +/- 0.48) were found. In contrast to V(max), which recovered at Pre E3 and then remained stable at Post E3 and throughout recovery, Ca(2+) uptake remained depressed (P < 0.05) at E3 Pre and Post and at R1 as did phase 2 of Ca(2+) release. Exercise resulted in an increase (P < 0.05) in SERCA1a (14% at R2) but not SERCA2a. It is concluded that rapidly adapting mechanisms protect V(max) following the onset of regular exercise but not Ca(2+) uptake and Ca(2+) release.

Protection of muscle membrane excitability during prolonged cycle exercise with glucose supplementation.

To determine if exercise-induced depressions in neuromuscular function are altered with oral glucose supplementation, 15 untrained participants (Vo2 peak = 45 +/- 2 ml x kg(-1) x min(-1), mean +/- SE) performed prolonged cycle exercise at approximately 60% Vo2 peak on two occasions: without glucose supplementation (NG) and with oral glucose supplementation (G). The oral G began at 30 min of exercise and was administered every 15 min (total ingested = 1.23 +/- 0.11 g carbohydrate/kg body mass). Quadriceps isometric properties and membrane excitability were assessed prior to exercise, after 90 min of exercise, and at fatigue. Cycle time to fatigue was greater (P < 0.05) in G compared with NG (137 +/- 7 vs. 115 +/- 6 min). Progressive reductions (P < 0.05) in maximal voluntary contraction (MVC, N) were observed for NG at 90 min (441 +/- 29) and at fatigue (344 +/- 33) compared with pre-exercise (666 +/- 30). At fatigue in G, the reduction in MVC was not as pronounced (P < 0.05) as in NG. Motor unit activation assessed with the interpolated twitch technique during an MVC following exercise was not different between conditions. During cycling, the G condition also resulted in a higher (P < 0.05) muscle compound potential (M-wave) amplitude (mV) at both 90 min (+50%) and at fatigue (+87%) compared with NG. Similar effects were also found M-wave area (mV/ms). These results suggest that the ergogenic effect of glucose supplementation occurs not as a result of decreased neural activation but to improved muscle function, possibly as a consequence of protection of muscle membrane excitability.

Glucose supplements increase human muscle in vitro Na+-K+-ATPase activity during prolonged exercise.

Regulation of maximal Na(+)-K(+)-ATPase activity in vastus lateralis muscle was investigated in response to prolonged exercise with (G) and without (NG) oral glucose supplements. Fifteen untrained volunteers (14 males and 1 female) with a peak aerobic power (Vo(2)(peak)) of 44.8 +/- 1.9 ml.kg(-1).min(-1); mean +/- SE cycled at approximately 57% Vo(2)(peak) to fatigue during both NG (artificial sweeteners) and G (6.13 +/- 0.09% glucose) in randomized order. Consumption of beverage began at 30 min and continued every 15 min until fatigue. Time to fatigue was increased (P < 0.05) in G compared with NG (137 +/- 7 vs. 115 +/- 6 min). Maximal Na(+)-K(+)-ATPase activity (V(max)) as measured by the 3-O-methylfluorescein phosphatase assay (nmol.mg(-1).h(-1)) was not different between conditions prior to exercise (85.2 +/- 3.3 or 86.0 +/- 3.9), at 30 min (91.4 +/- 4.7 vs. 91.9 +/- 4.1) and at fatigue (92.8 +/- 4.3 vs. 100 +/- 5.0) but was higher (P < 0.05) in G at 90 min (86.7 +/- 4.2 vs. 109 +/- 4.1). Na(+)-K(+)-ATPase content (beta(max)) measured by the vanadate facilitated [(3)H]ouabain-binding technique (pmol/g wet wt) although elevated (P < 0.05) by exercise (0<30, 90, and fatigue) was not different between NG and G. At 60 and 90 min of exercise, blood glucose was higher (P < 0.05) in G compared with NG. The G condition also resulted in higher (P < 0.05) serum insulin at similar time points to glucose and lower (P < 0.05) plasma epinephrine and norepinephrine at 90 min of exercise and at fatigue. These results suggest that G results in an increase in V(max) by mechanisms that are unclear.

Subcortical control of dopamine neurons: the good, the bad and the unexpected.

The function of the phasic dopamine signal, seen in response to salient and rewarding stimuli, has been heavily debated. The reward prediction error hypothesis has been criticised for the suggestion that such a complex signal could be derived at short latencies, relying only on subcortical inputs. However, as more has been learnt about the nature of the subcortical inputs, we are led to challenge this criticism. Here we suggest that the subcortical inputs can indeed support complex calculations and that it would be unwise to underestimate their processing capabilities. Whilst our analysis cannot differentiate between the reward prediction error hypothesis and its opponents, it does suggest that the initial argument against a prediction error is incorrect.

Microdosimetric model for the induction of cell killing through medium-borne signals.

Microbeam, medium-transfer and low-dose experiments have demonstrated that intercellular signals can initiate many of the same biological events and processes as direct exposure to ionizing radiation. These phenomena cast doubt on cell-autonomous modes of action and the linear, no-threshold carcinogenesis paradigm. To account for the effects of intercellular signals, new approaches are needed to relate dosimetric quantities to the emission and processing of signals by irradiated and unirradiated cells. In this paper, microdosimetric principles are used to develop a stochastic model to relate absorbed dose to the emission and processing of cell death signals by unirradiated cells. Our analyses of published results of medium transfer experiments performed using HPV-G human keratinocytes suggest that the emission of death signals is a bi-exponential function of dose with a distinct plateau in the 5- to 100-mGy range. However, the emission of death signals by HPV-G cells may not become fully saturated until the absorbed dose becomes larger than 0.6 Gy. Similar saturation effects have been observed in microbeam and medium-transfer experiments with other mammalian cell lines. The model predicts that the cell-killing effect of medium-borne death signals decreases exponentially as the absorbed dose becomes small compared to the frequency-mean specific energy per radiation event.

Fast Monte Carlo simulation of DNA damage formed by electrons and light ions.

The passage of ionizing radiation through living organisms initiates physical and chemical processes that create clusters of damaged nucleotides within one or two turns of the DNA. These clusters are widely considered an important initiating event for the induction of other biological endpoints, including cell killing and neoplastic transformation. Monte Carlo simulations of the DNA damage formation process are a useful adjunct to experiments because they provide additional information about the spatial configuration of damage within a cluster. In this paper, the fast Monte Carlo damage simulation (MCDS) algorithm is re-parameterized so that yields of double-strand breaks, single-strand breaks and sites of multiple base damage can be simulated for electrons, protons and alpha particles with kinetic energies on the order of GeV. The MCDS algorithm provides a useful, quasi-phenomenological scheme to interpolate damage yields from computationally expensive, but more detailed, track-structure simulations. The predicted characteristics of various classes of damage produced by electrons, protons and alpha particles, such as average number of lesions per DNA damage cluster and cluster length in base pairs, are presented. A study examining the effects on damage complexity of an extrinsic free radical scavenger, dimethyl sulfoxide, is also presented. The reported studies provide new information that will aid efforts to characterize the relative biological effectiveness of high-energy protons and other light ions, which are sometimes used in particle therapy for the treatment of cancer.

Low-LET-induced radioprotective mechanisms within a stochastic two-stage cancer model.

A stochastic two-stage cancer model with clonal expansion was used to investigate the potential impact on human lung cancer incidence of some aspects of the hormesis mechanisms suggested by Feinendegen (Health Phys. 52 663-669, 1987). The model was applied to low doses of low-LET radiation delivered at low dose rates. Non-linear responses arise in the model because radiologically induced adaptations in radical scavenging and DNA repair may reduce the biological consequences of DNA damage formed by endogenous processes and ionizing radiation. Sensitivity studies were conducted to identify critical model inputs and to help define the changes in cellular defense mechanisms necessary to produce a lifetime probability for lung cancer that deviates from a linear no-threshold (LNT) type of response. Our studies suggest that lung cancer risk predictions may be very sensitive to the induction of DNA damage by endogenous processes. For doses comparable to background radiation levels, endogenous DNA damage may account for as much as 50 to 80% of the predicted lung cancers. For an additional lifetime dose of 1 Gy from low-LET radiation, endogenous processes may still account for as much as 20% of the predicted cancers (Fig. 2). When both repair and scavengers are considered as inducible, radiation must enhance DNA repair and radical scavenging in excess of 30 to 40% of the baseline values to produce lifetime probabilities for lung cancer outside the range expected for endogenous processes and background radiation.

A model for low dose effects of low-LET radiation delivered at high dose rates.

In vitro studies show that protective tumour-reducing effects occur for low dose rates (mGy per minute). To account for these phenomena, we have previously developed stochastic and deterministic multi-stage cancer models that include radiation-induced adaptations in DNA repair processes and radical scavenging. Here, these models are extended to account for the induction of radioprotective mechanisms for low doses of low LET radiation delivered at high dose rates. Cellular adaptations in DNA repair are related to temporal changes in the amount of DNA damage in a cell. The combined effects of endogenous DNA damage, background radiation and artificial irradiation are considered.