Health risks from radioactive particles on Cumbrian beaches near the Sellafield nuclear site.

A monitoring programme, in place since 2006, continues to recover radioactive particles (<2 mm diameter) and larger objects from the beaches of West Cumbria. The potential risks to members of the public using the beaches are mainly related to prolonged skin contact with or the inadvertent ingestion of small particles. Most particles are classified as either 'beta-rich' or 'alpha-rich' and are detected as a result of their caesium-137 or americium-241 content. Beta-rich particles generally also contain strontium-90, with90Sr:137Cs ratios of up to about 1:1, but typically <0.1:1. Alpha-rich particles contain plutonium isotopes, with Pu:241Amαratios usually around 0.5-0.6:1. 'Beta-rich' particles have the greatest potential to cause localised skin damage if held in stationary contact with the skin for prolonged periods. However, it is concluded that only particles of >106Bq of137Cs, with high90Sr:137Cs ratios, would pose a significant risk of causing acute skin ulceration. No particles of this level of activity have been found. Inadvertent ingestion of a particle will result in the absorption to blood of a small proportion of the radionuclide content of the particle. The subsequent retention of radionuclides in body organs and tissues presents a potential risk of the development of cancer. For 'beta-rich' particles with typical activities (mean 2 × 104Bq137Cs, Sr:Cs ratio of 0.1:1), the estimated committed effective doses are about 30µSv for adults and about 40µSv for 1 year old infants, with lower values for 'alpha-rich' particles of typical activities. The corresponding estimates of lifetime cancer incidence following ingestion for both particle types are of the order of 10-6for adults and up to 10-5for infants. These estimates are subject to substantial uncertainties but provide an indication of the low risks to members of the public.

Exposure to multiple ion beams, broadly representative of galactic cosmic rays, causes perivascular cardiac fibrosis in mature male rats.

Long-duration space exploratory missions to the Earth's moon and the planet Mars are actively being planned. Such missions will require humans to live for prolonged periods beyond low earth orbit where astronauts will be continuously exposed to high energy galactic cosmic rays (GCRs). A major unknown is the potential impact of GCRs on the risks of developing degenerative cardiovascular disease, which is a concern to NASA. A ground-based rat model has been used to provide a detailed characterization of the risk of long-term cardiovascular disease from components of GCRs at radiation doses relevant to future human missions beyond low earth orbit. Six month old male WAG/RijCmcr rats were irradiated at a ground-based charged particle accelerator facility with high energy ion beams broadly representative of GCRs: protons, silicon and iron. Irradiation was given either as a single ion beam or as a combination of three ion beams. For the doses used, the single ion beam studies did not show any significant changes in the known cardiac risk factors and no evidence of cardiovascular disease could be demonstrated. In the three ion beam study, the total cholesterol levels in the circulation increased modestly over the 270 day follow up period, and inflammatory cytokines were also increased, transiently, 30 days after irradiation. Perivascular cardiac collagen content, systolic blood pressure and the number of macrophages found in the kidney and in the heart were each increased 270 days after irradiation with 1.5 Gy of the three ion beam grouping. These findings provide evidence for a cardiac vascular pathology and indicate a possible threshold dose for perivascular cardiac fibrosis and increased systemic systolic blood pressure for complex radiation fields during the 9 month follow up period. The development of perivascular cardiac fibrosis and increased systemic systolic blood pressure occurred at a physical dose of the three ion beam grouping (1.5 Gy) that was much lower than that required to show similar outcomes in earlier studies with the same rat strain exposed to photons. Further studies with longer follow up periods may help determine whether humans exposed to lower, mission-relevant doses of GCRs will develop radiation-induced heart disease.

Improving the Accuracy of Biologically Effective Dose Estimates, from a Previously Published Study, After Radiosurgery for Acoustic Neuromas.

OBJECTIVE: To recalculate biological effective dose values (BED) for radio-surgical treatments of acoustic neuroma from a previous study. BEDs values were previously overestimated by only using beam-on times in calculations, so excluding the important beam-off-times (when deoxyribonucleic acid repair continues) which contribute to the overall treatment time. Simple BED estimations using a mono-exponential approximation may not always be appropriate but if used should include overall treatment time. METHODS: Time intervals between isocenters were estimated. These were especially important for the Gamma Knife Model 4C cases since manual changes significantly increase overall treatment times. Individual treatment parameters, such as iso-center number, beam-on-time, and beam-off-time, were then used to calculate BED values using a more appropriate bi-exponential model that includes fast and slow components of DNA damage repair over a wider time range. RESULTS: The revised BED estimates differed significantly from previously published values. The overestimates of BED, obtained using beam-on-time only, varied from 0%-40.3%. BED subclasses, each with a BED range of 5 Gy2.47, indicated that revised values were consistently reduced when compared with originally quoted values, especially for 4C compared with Perfexion cases. Furthermore, subdivision of 4C cases by collimator number further emphasized the impact of scheduled gap times on BED. Further analysis demonstrated important limitations of the mono-exponential model. Target volume was a major confounding factor in the interpretation of the results of this study. CONCLUSIONS: BED values should be estimated by including beam-on and beam-off times. Suggestions are provided for more accurate BED estimations in future studies.

Dr Tikvah Alper: a short history of her scientific career.

PURPOSE: This article can only skim the surface of an extraordinary career of Dr Alper from the early days in South Africa and throughout her life. CONCLUSIONS: She overcame many obstacles to become widely acknowledged as having had an immense effect on the study of radiation biology. Her very considerable personal scientific achievements in no way prevented her from taking time to help and inspire others in the field as well as maintaining a long and happy family life. If an example is needed to show what can be achieved with a combination of total intellectual integrity and determined application, then Tikvah Alper certainly provided this.

Further development of spinal cord retreatment dose estimation: including radiotherapy with protons and light ions.

PURPOSE: A graphical user interface (GUI) was developed to aid in the assessment of changes in the radiation tolerance of spinal cord/similar central nervous system tissues with time between two individual treatment courses. METHODS: The GUI allows any combination of photons, protons (or ions) to be used as the initial, or retreatment, radiotherapy courses. Allowances for clinical circumstances, of reduced tolerance, can also be made. The radiobiological model was published previously and has been incorporated with additional checks and safety features, to be as safe to use as possible. The proton option includes use of a fixed RBE of 1.1 (set as the default), or a variable RBE, the latter depending on the proton linear energy transfer (LET) for organs at risk. This second LET-based approach can also be used for ions, by changing the LET parameters. RESULTS: GUI screenshots are used to show the input and output parameters for different clinical situations used in worked examples. The results from the GUI are in agreement with manual calculations, but the results are now rapidly available without tedious and error-prone manual computations. The software outputs provide a maximum dose limit boundary, which should not be exceeded. Clinicians may also choose to further lower the number of treatment fractions, whilst using the same dose per fraction (or conversely a lower dose per fraction but with the same number of fractions) in order to achieve the intended clinical benefit as safely as possible. CONCLUSIONS: The new GUI will allow scientific-based estimations of time related radiation tolerance changes in the spinal cord and similar central nervous tissues (optic chiasm, brainstem), which can be used to guide the choice of retreatment dose fractionation schedules, with either photons, protons or ions.

The impact of unscheduled gaps and iso-centre sequencing on the biologically effective dose in Gamma Knife radiosurgery.

PURPOSE: Establish the impact of iso-centre sequencing and unscheduled gaps in Gamma Knife® (GK) radiosurgery on the biologically effective dose (BED). METHODS: A BED model was used to study BED values on the prescription iso-surface of patients treated with GK Perfexion™ (Vestibular Schwannoma). The effect of a 15 min gap, simulated at varying points in the treatment delivery, and adjustments to the sequencing of iso-centre delivery, based on average dose-rate, was quantified in terms of the impact on BED. RESULTS: Depending on the position of the gap and the average dose-rate profiles, the mean BED values were decreased by 0.1% to 9.9% of the value in the original plan. A heuristic approach to iso-centre sequencing showed variations in BED of up to 14.2%, relative to the mean BED of the original sequence. CONCLUSION: The treatment variables, like the iso-centre sequence and unscheduled gaps, should be considered during GK radiosurgery treatments.

The influence of the α/ß ratio on treatment time iso-effect relationships in the central nervous system.

Purpose: To investigate the influence of changes in α/ß ratio (range 1.5-3 Gy) on iso-effective doses, with varying treatment time, in spinal cord and central nervous system tissues with comparable radio-sensitivity. It is important to establish if an α/ß ratio of 2 Gy, the accepted norm for neuro-oncology iso-effect estimations, can be used.Methods: The rat spinal cord irradiation data of Pop et al. provided ED50 values for radiation myelopathy for treatment times that varied from minutes to ∼6 days. Analysis using biphasic repair kinetics, allowing for variable dose-rates, provided the best fit with repair half-times of 0.19 and 2.16 hr, each providing ∼50% of overall repair; with an α/ß ratio 2.47 Gy (CI 1.5-3.95 Gy). Using the above data set, graphical methods were used to investigate changes in the repair parameters for differing fixed α/ß ratios between 1.5 and 3.0 Gy. Two different intermittent dose delivery equations were used to evaluate the implications in a radiosurgery setting.Results: Changes in the α/ß ratio (1.5-3.0 Gy) have a minor effect on equivalent doses for radiation myelopathy for treatment durations of a few hours. Changing the α/ß value from 2 Gy to 2.47 Gy, modified equivalent single doses by < 1% when overall treatment times ranged from 0.1 to 5.0 hr. Significant changes were only found for treatment times longer than 5-10 hr. These two α/ß ratios were also compared in a practical radiosurgery situation, using two different models for estimating BED, again there was no significant loss of accuracy.Conclusions: It is reasonable to use an α/ß ratio of 2 Gy for CNS tissue, with the same repair half-times as published in the original publication by Pop et al., in situations where the assessment of the BED in radiosurgery is used with other form of radiotherapy. In radiosurgery, the variation in BED with treatment duration (for a fixed physical dose) is very similar, but absolute BED values depend on the α/ß value. In radiosurgery, clinical recommendations obtained using BED calculations using the originally proposed α/ß ratio of 2.47 Gy are still appropriate. For calculations involving a combination of radiosurgery and other modalities, such as fractionated radiotherapy, it would be appropriate in all cases to apply a value of 2 Gy, the accepted norm in neuro-oncology, without significant loss of accuracy in the radio-surgical component. This may have important applications in retreatment situations.

Establishment of a Therapeutic Ratio for Gamma Knife Radiosurgery of Trigeminal Neuralgia: The Critical Importance of Biologically Effective Dose Versus Physical Dose.

OBJECTIVE: How variations of treatment time affect the safety and efficacy of Gamma Knife (GK) radiosurgery is a matter of considerable debate. With the relative simplicity of treatment planning for trigeminal neuralgia (TN), this question has been addressed in a group of these patients. Using the concept of the biologically effective dose (BED), the effect of the two key variables, dose and treatment time, were considered. METHODS: A retrospective analysis was performed of 408 TN cases treated from 1997 to 2010. Treatment involved the use of a single 4 mm isocenter. If conditions allowed, the isocenter was placed at a median distance of 7.5 mm from the emergence of the trigeminal nerve from the brain stem. The effects were assessed in terms of the incidence of the complication, hypoesthesia, and in terms of efficacy using the incidence of pain free after 30 days and 1 and 2 years. These responses were evaluated with respect to both the physical dose and the BED, the latter using a bi-exponential repair model. RESULTS: RE-evaluation showed that the prescription doses, at the 100% isodose, varied from 75 to 97.9 Gy, delivered in 25-135 minutes. The relationship between the physical dose and the incidence of hypoesthesia was not significant; the overall incidence was ∼20%. However, a clear relationship was found between the BED and the incidence of hypoesthesia, with the incidence increasing from <5% after a BED of ∼1800 Gy2.47 to 42% after ∼2600 Gy2.47. Efficacy, in terms of freedom from pain, was ∼90%, irrespective of the BED (1550-2600 Gy2.47) at 1 and 2 years. The data suggested that "pain free" status developed more slowly at lower BED values. CONCLUSIONS: These results strongly suggest that safety and efficacy might be better achieved by prescribing a specific BED instead of a physical dose. A dose and time to BED conversion table has been prepared to enable iso-BED prescriptions. This finding could dramatically change dose-planning strategies in the future. However, this concept requires validation for other indications for which more complex dose planning is required.

Effects of variations in overall treatment time on the clonogenic survival of V79-4 cells: Implications for radiosurgery.

The importance of effects related to the repair of sublethal radiation damage as treatment duration varies, partly a function of dose-rate, is a current controversy in clinical radiosurgery. Cell survival studies have been performed to verify the importance of this effect in relation to established models. Mammalian V79-4 cells were irradiated in vitro with γ-rays, either as an acute exposure in a few minutes, where the effects of sublethal irradiation damage repair over the period of exposure can be ignored, or as protracted exposures delivered over 15-120 min. Protraction was achieved either by introducing a variable time gap between two doses of 7 Gy, or as a continuous exposure at lower dose rates so that a range of doses were delivered in fixed times of 30, 60 or 120 min. For all doses there was a progressive reduction in efficacy with increasing overall treatment time. This was illustrated by the progressive increase in clonogenic cell survival with a resulting right shift of the survival curves. Cell survival curves for irradiations given either as an acute exposure (6.1 Gy/min), over fixed times (30, 60 and 120 min) or for a fixed low dose-rate (0.2 Gy/min) were well fitted by the Linear Quadratic (LQ) model giving an α/ß ratio of 4.0 Gy and a single repair half-time of 31.5 min. The present results are consistent with published data with respect to the response of solid tumors and normal tissues, whose response to both continuous and fractionated irradiation is also well described by the LQ model. This suggests the need for dose compensation in radiosurgical treatments, and other forms of radiotherapy, where dose is delivered over a similar range of protracted overall treatment times, perhaps as a prerequisite to full biological effective dose treatment planning.

Modelling the influence of treatment time on the biological effectiveness of single radiosurgery treatments: derivation of "protective" dose modification factors.

OBJECTIVE: To provide simpler models for adjusting total dose to compensate for significant variations in central nervous system radiosurgical treatment times, which vary and will influence treatment bioeffectiveness. At present, no allowance is made for time variations. A framework of simpler equations would allow radiosurgical outcomes to be analysed with respect to treatment time, and a system for dose adjustments between radioisotope and linac-based techniques with different treatment durations. METHODS: The standard biological effective dose (BED) equations for fractionated and protracted radiations have been combined, using biexponential DNA repair kinetics, to provide the following equation:BED=x.nd(1+(ndk-dk)f(µ1T)+dkf(µ1t))+(1-x). nd(1+(ndk-dk)f(µ2T)+dkf(µ2t))for "n" isocentres (or subfractions), each treated to a variable dose "d" in time "t", the overall time-being, T, µ1, µ2, are fast and slow repair rate coefficients, with partition factors of x and (1-x), respectively and k is the alpha/beta ratio, with f(µT) being the function that summates sublethal damage repair. Thus, repair during the period of irradiation and in the time interval between each isocentre can be taken into account. Simpler monoexponential and linear models are also used. RESULTS: The results obtained using simpler models are compared with those obtained using more complex retrospective Gamma Knife BED treatment planning by Millar et al. (2015) in a group of 23 patients on a 13 Gy physical isodose surface. The above equation provides a BED value around 3% above their minimum values, 4% below their average value and 10% below their maximum BED values. Changes in isocentre numbers used, due to treatment plan complexity, can influence total treatment time, producing variations in the BED-time data: instead of a unique curve for each "n" value, in aggregate form the data (ranging from around 20 to 140 min treatment times) can be fitted by monoexponential time functions and further approximated to a linear function for more rapid estimations. Worked examples show how dose can then be tailored to the expected treatment times in order to obtain isoeffective treatments for central nervous system tissues. CONCLUSION: The models allow better analysis of radiosurgical treatment time data and guidance to the choice of dose to match the overall time. Although this study is based on Gamma Knife treatments, in principle the methods will also apply to any radiosurgical technique, so that dose-time compensations can be made between differing techniques. ADVANCES IN KNOWLEDGE: The new BED equation-based framework is relevant to analyse and optimise radiosurgical treatments.

Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment.

PURPOSE: To estimate, from experimental data, the retreatment radiation 'tolerances' of the spinal cord at different times after initial treatment. MATERIALS AND METHODS: A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated 'retreatment tolerance' BED value, denoted [Formula: see text] and [Formula: see text]. The primate data of Ang et al. ( 2001 ) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BEDinit). RESULTS: The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted [Formula: see text] value into a formal BED value and then a practical dose fractionation schedule. CONCLUSIONS: Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment.

Effects of Synchrotron X-Ray Micro-beam Irradiation on Normal Mouse Ear Pinnae.

PURPOSE: To analyze the effects of micro-beam irradiation (MBI) on the normal tissues of the mouse ear. METHODS AND MATERIALS: Normal mouse ears are a unique model, which in addition to skin contain striated muscles, cartilage, blood and lymphatic vessels, and few hair follicles. This renders the mouse ear an excellent model for complex tissue studies. The ears of C57BL6 mice were exposed to MBI (50-µm-wide micro-beams, spaced 200 µm between centers) with peak entrance doses of 200, 400, or 800 Gy (at ultra-high dose rates). Tissue samples were examined histopathologically, with conventional light and electron microscopy, at 2, 7, 15, 30, and 240 days after irradiation (dpi). Sham-irradiated animals acted as controls. RESULTS: Only an entrance dose of 800 Gy caused a significant increase in the thickness of both epidermal and dermal ear compartments seen from 15 to 30 dpi; the number of sebaceous glands was significantly reduced by 30 dpi. The numbers of apoptotic bodies and infiltrating leukocytes peaked between 15 and 30 dpi. Lymphatic vessels were prominently enlarged at 15 up to 240 dpi. Sarcomere lesions in striated muscle were observed after all doses, starting from 2 dpi; scar tissue within individual beam paths remained visible up to 240 dpi. Cartilage and blood vessel changes remained histologically inconspicuous. CONCLUSIONS: Normal tissues such as skin, cartilage, and blood and lymphatic vessels are highly tolerant to MBI after entrance doses up to 400 Gy. The striated muscles appeared to be the most sensitive to MBI. Those findings should be taken into consideration in future micro-beam radiation therapy treatment schedules.

Simvastatin mitigates increases in risk factors for and the occurrence of cardiac disease following 10 Gy total body irradiation.

The ability of simvastatin to mitigate the increases in risk factors for and the occurrence of cardiac disease after 10 Gy total body irradiation (TBI) was determined. This radiation dose is relevant to conditioning for stem cell transplantation and threats from radiological terrorism. Male rats received single dose TBI of 10 Gy. Age-matched, sham-irradiated rats served as controls. Lipid profile, heart and liver morphology and cardiac mechanical function were determined for up to 120 days after irradiation. TBI resulted in a sustained increase in total- and LDL-cholesterol (low-density lipoprotein-cholesterol), and triglycerides. Simvastatin (10 mg/kg body weight/day) administered continuously from 9 days after irradiation mitigated TBI-induced increases in total- and LDL-cholesterol and triglycerides, as well as liver injury. TBI resulted in cellular peri-arterial fibrosis, whereas control hearts had less collagen and fibrosis. Simvastatin mitigated these morphological injuries. TBI resulted in cardiac mechanical dysfunction. Simvastatin mitigated cardiac mechanical dysfunction 20-120 days following TBI. To determine whether simvastatin affects the ability of the heart to withstand stress after TBI, injury from myocardial ischemia/reperfusion was determined in vitro. TBI increased the severity of an induced myocardial infarction at 20 and 80 days after irradiation. Simvastatin mitigated the severity of this myocardial infarction at 20 and 80 days following TBI. It is concluded simvastatin mitigated the increases in risk factors for cardiac disease and the extent of cardiac disease following TBI. This statin may be developed as a medical countermeasure for the mitigation of radiation-induced cardiac disease.

The role of the concept of biologically effective dose (BED) in treatment planning in radiosurgery.

Radiosurgery (RS) treatment times vary, even for the same prescription dose, due to variations in the collimator size, the number of iso-centres/beams/arcs used and the time gap between each of these exposures. The biologically effective dose (BED) concept, incorporating fast and slow components of repair, was used to show the likely influence of these variables for Gamma Knife patients with Vestibular Schwannomas. Two patients plans were selected, treated with the Model B Gamma Knife, these representing the widest range of treatment variables; iso-centre numbers 3 and 13, overall treatment times 25.4 and 129.6 min, prescription dose 14 Gy. These were compared with 3 cases treated with the Perfexion(®) Gamma Knife. The iso-centre number varied between 11 and 18, treatment time 35.7 - 74.4 min, prescription dose 13 Gy. In the longer Model B Gamma Knife treatment plan the 14 Gy iso-dose was best matched by the 58 Gy2.47 iso-BED line, although higher and lower BED values were associated with regions on the prescription iso-dose. The equivalent value for the shorter treatment was 85 Gy2.47. BED volume histograms showed that a BED of 85 Gy2.47 only covered ∼65% of the target in the plan with the longer overall treatment time. The corresponding BED values for the 3 cases, treated with the Perfexion(®) Gamma Knife, were 59.5, 68.5 and 71.5 Gy2.47. In conclusion BED calculations, taking account of the repair of sublethal damage, may indicate the importance of reporting overall time to reflect the biological effectiveness of the total physical dose applied.

Alternative models for estimating the radiotherapy retreatment dose for the spinal cord.

PURPOSE: To review the available experimental animal and patient data on response of the spinal cord to re-irradiation in order to identify appropriate data sets to investigate the clinical potential of models that would allow evaluation of the increase in the retreatment dose with elapsed time from the initial exposure. MATERIALS/METHODS: Analysis of published data on irradiated rat and primate spinal cord identified results for the rat cervical spinal cord that could be compared, where the development of myelopathy was caused by selective white matter necrosis. This data, although limited, provide some important insights. Two models, derived from simple differential equations, provide a time- and dose-dependency for recovery and could be fitted to these data. These models predict the remaining tolerance, in a phase space above the line that connects the 100% biological effectiveness (BEDTOL) tolerance dose of the first and second treatment courses when these are plotted together. A third, much simpler, linear model, assumed that recovery was time but not initial dose dependent. RESULTS: The experimental results showed a non-linear time dependency for the change in biological effectiveness (BED) of the re-irradiation dose. Comparison of the three different models paid particular attention to changes in the re-irradiation dose, when the initial radiation dose was either low or high. For each model, cautious data interpretations were also introduced to reduce the effects of the near completeness of recovery with time derived from the important experiments with primates, which include few data points. Model 1 predicts the least recovery following low initial doses, but with greater recovery following larger initial doses. Model 2 allowed no further irradiation after an initial full tolerance dose, but also greater than expected recovery following the use of smaller priming doses. Model 3 gives unrealistically high doses when used after an initial full tolerance irradiation dose. CONCLUSIONS: These results show that it is possible to model these time-dependent relationships for the spinal cord and that Model 1 is probably the most realistic, especially when it is used conservatively. To give greater confidence as to which of the three presented methods is best, further experiments and/or more analysis of human data are necessary. In the meantime clinicians will need to exert caution and judgement as to the choice of the re-irradiation BED, bearing in mind the other clinical factors that influence radio-tolerance. Further research is necessary to provide the safest recommendations and best clinical outcomes. Some suggestions as to what needs to be done are given.