How Important Is the FLASH Effect in a Nuclear Explosion?

The COMS (Collaborative Ocular Melanoma Study) eye plaques are based on the application of low-energy photon sources such as iodine-125 (125I) and palladium-103 (103Pd). Compared to 125I, 103Pd is characterized by different radiobiological and physical parameters, which include the half-life, relative biological effectiveness (RBE), and average photon energy. Variation of these parameters may increase or decrease the integrated cell-killing effect of eye plaques; therefore, quantitative evaluation of biological effects may be used to optimize the dose prescription and improve the therapeutic ratio. The goal of this article is to show that the higher RBE of lower-energy photons from 103Pd sources counteracts the steeper dose fall-off in heterogeneous eye plaque geometry and the effect of radiation protraction to produce the higher cell killing effect compared to 125I sources. Biological effectiveness of COMS eye plaques with 125I and 103Pd sources is evaluated using the equivalent uniform RBE-weighted dose (EUDRBE). The EUDRBE is defined as the uniform dose distribution with RBE=1 that produces the cell survival equal to a nonuniform dose distribution with variable RBE. The EUDRBE was proposed for comparison of cell survival in radiotherapy with a nonuniform dose and the RBE effect, and such a concept can be applied to both external beam fractionated radiotherapy and continuous irradiation in brachytherapy. The EUDRBE is computed in a 1D model of COMS eye plaques using the dose distributions in a water-equivalent medium with heterogeneity correction from MC calculations. The EUDRBE is computed in five dose fractions using the linear quadratic (LQ) cell survival model corrected for the effects of protracted irradiation and RBE. The EUDRBE for eye plaques is compared to the reference dose of 50 Gy(RBE) that is the lowest total dose (delivered in five fractions) used in hypofractionated proton therapy for ocular melanoma. In the simulations with a hypothetical RBE=1, the EUDRBE for eye plaques with both 125I and 103Pd sources is lower than the reference dose of 50 Gy(RBE) for most of the simulated implant durations and tumor heights. Also, the EUDRBE for eye plaques with 103Pd sources is lower compared to 125I sources. If the measured RBE of 1.4 and 1.9 is applied for 125I and 103Pd, respectively, the EUDRBE for eye plaques becomes larger than the reference dose of 50 Gy(RBE). The range of EUDRBE for 125I is within 50-60 Gy(RBE) depending on the implant duration and tumor height; therefore, the lowest EUDRBE is comparable to the dose used in hypofractionated proton therapy. The range of EUDRBE for 103Pd is within 57-67 Gy(RBE), which is higher compared to 125I. The effects of RBE for COMS eye plaques with 125I and 103Pd sources should be considered to explain the tumor control probability (TCP)>80% observed in clinical practice. The EUDRBE for 103Pd sources is larger than the EUDRBE for both the 125I sources and hypofractionated proton therapy; therefore, the dose de-escalation relative to 85 Gy may be considered.

Alpha-particle radiopharmaceutical therapy (αRPT) is currently enjoying increasing attention as a viable alternative to chemotherapy for targeting of disseminated micrometastatic disease. In theory, αRPT can be personalized through pre-therapeutic imaging and dosimetry. However, in practice, given the particularities of α-particle emissions, a dosimetric methodology that accurately predicts the thresholds for organ toxicity has not been reported. This is in part due to the fact that the biological effects caused by α-particle radiation differ markedly from the effects caused by traditional external beam (photon or electron) radiation or β-particle emitting radiopharmaceuticals. The concept of relative biological effectiveness (RBE) is used to quantify the ratio of absorbed doses required to achieve a given biological response with alpha particles versus a reference radiation (typically a beta emitter or external beam radiation). However, as conventionally defined, the RBE varies as a function of absorbed dose and therefore a single RBE value is limited in its utility because it cannot be used to predict response over a wide range of absorbed doses. Therefore, efforts are underway to standardize bioeffect modeling for different fractionation schemes and dose rates for both nuclear medicine and external beam radiotherapy. Given the preponderant use of external beams of radiation compared to nuclear medicine in cancer therapy, the more clinically relevant quantity, the 2 Gy equieffective dose, EQD2(α/β), has recently been proposed by the ICRU. In concert with EQD2(α/β), we introduce a new, redefined RBE quantity, named RBE2(α/β), as the ratio of the two linear coefficients that characterize the α particle absorbed dose-response curve and the low-LET megavoltage photon 2 Gy fraction equieffective dose-response curve. The theoretical framework for the proposed new formalism is presented along with its application to experimental data obtained from irradiation of a breast cancer cell line. Radiobiological parameters are obtained using the linear quadratic model to fit cell survival data for MDA-MB-231 human breast cancer cells that were irradiated with either α particles or a single fraction of low-LET (137)Cs γ rays. From these, the linear coefficient for both the biologically effective dose (BED) and the EQD2(α/β) response lines were derived for fractionated irradiation. The standard RBE calculation, using the traditional single fraction reference radiation, gave RBE values that ranged from 2.4 for a surviving fraction of 0.82-6.0 for a surviving fraction of 0.02, while the dose-independent RBE2(4.6) value was 4.5 for all surviving fraction values. Furthermore, bioeffect modeling with RBE2(α/β) and EQD2(α/β) demonstrated the capacity to predict the surviving fraction of cells irradiated with acute and fractionated low-LET radiation, α particles and chronic exponentially decreasing dose rates of low-LET radiation. RBE2(α/β) is independent of absorbed dose for α-particle emitters and it provides a more logical framework for data reporting and conversion to equieffective dose than the conventional dose-dependent definition of RBE. Moreover, it provides a much needed foundation for the ongoing development of an α-particle dosimetry paradigm and will facilitate the use of tolerance dose data available from external beam radiation therapy, thereby helping to develop αRPT as a single modality as well as for combination therapies.

Effect of maleic acid content on the thermal stability, swelling behaviour and network structure of gelatin-based hydrogels prepared by gamma irradiation

This SRP Northwest Regional Meeting was the first in a revived series of meetings in the region. The meeting was held at the Visitors' Centre of Heysham 2 Power Station and was sponsored by Nuclear Electric Ltd, who own and operate this advanced gas-cooled reactor (AGR) station.

Epidemiological data on the health effects of A-bomb radiation in Hiroshima and Nagasaki provide the framework for setting limits for radiation risk and radiological protection. However, uncertainty remains in the equivalent dose, because it is generally believed that direct derivation of the relative biological effectiveness (RBE) of neutrons from the epidemiological data on the survivors is difficult. To solve this problem, an alternative approach has been taken. The RBE of polyenergetic neutrons was determined for chromosome aberration formation in human lymphocytes irradiated in vitro, compared with published data for tumor induction in experimental animals, and validated using epidemiological data from A-bomb survivors. The RBE of fission neutrons was dependent on dose but was independent of the energy spectrum. The same RBE regimen was observed for lymphocyte chromosome aberrations and tumors in mice and rats. Used as a weighting factor for A-bomb survivors, this RBE system was superior in eliminating the city difference in chromosome aberration frequencies and cancer mortality. The revision of the equivalent dose of A-bomb radiation using DS02 weighted by this RBE system reduces the cancer risk by a factor of 0.7 compared with the current estimates using DS86, with neutrons weighted by a constant RBE of 10.

Purpose Even though X-ray beams are widely used in medical diagnosis or radiotherapy, the comparisons of their dose rates are scarce. We have recently demonstrated in vitro (clonogenic assay, cell viability, cell cycle, senescence) and in vivo (weight follow-up of animals and bordering epithelium staining of lesion), that for a single dose of irradiation, the relative biological effectiveness (RBE) deviates from 1 (up to twofold greater severe damage at the highest dose rate depending on the assay) when increasing the dose rate of high energy X-ray beams. Material and methods To further investigate the impact of the dose rate on RBE, in this study, we performed in vitro fractionated irradiations by using the same two dose rates (0.63 and 2.5 Gy.min−1) of high-energy X-rays (both at 4 MV) on normal endothelial cells (HUVECs). We investigated the viability/mortality, characterized radiation-induced senescence by using flow cytometry and measured gene analysis deregulations on custom arrays. Results The overall results enlighten that, in fractionated irradiations when varying the dose rate of high-energy X-rays, the RBE of photons deviates from 1 (up to 2.86 for viability/mortality experiments performed 21 days postirradiation). Conclusion These results strengthen the interest of multiparametric analysis approaches in providing an accurate evaluation of the outcomes of irradiated cells in support of clonogenic assays, especially when such assays are not feasible.

The relative biological effectiveness (RBE) of fast neutrons is an important factor influencing the quality of neutron therapy therefore, the assessment of RBE is of great importance. Experimental and clinical studies as well as different mathematical and radiobiological models are used for assessing RBE. Research is conducted for neutron sources differing in the method of producing particles, energy and energy spectrum. Purpose: to find and analyze the dose-dependence of fast neutron RBE in neutron therapy using the U-120 cyclotron and NG-12I generator. Material and methods: The optimal method for assessing the relative biological effectiveness of neutrons for neutron therapy was described. To analyze the dependence of the RBE on neutron dose, the multi-target model of cell survival was applied. Results: The dependence of the RBE of neutrons produced from the U-120 cyclotron and NG-120 generator on the dose level was found for a single irradiation of biological objects. It was shown that the function of neutron dose was consistent with similar dependencies found by other authors in the experimental and clinical studies.

Current lung cancer risk estimates after exposure to low-linear energy transfer radiation such as X rays are based on studies of people exposed to such radiation at high dose rates, for example the atomic bomb survivors. Radiobiology and animal experiments suggest that risks from exposure at low to moderate dose rates, for example medical diagnostic procedures, may be over-estimated by such risk models, but data for humans to examine this issue are limited. In this paper we report on lung cancer mortality between 1950 and 1987 in a cohort of 64,172 Canadian tuberculosis patients, of whom 39% were exposed to highly fractionated multiple chest fluoroscopies leading to a mean lung radiation dose of 1.02 Sv received at moderate dose rates. These data have been used to estimate the excess relative risk per sievert of lung cancer mortality, and this is compared directly to estimates derived from 75,991 atomic bomb survivors. Based on 1,178 lung cancer deaths in the fluoroscopy study, there was no evidence of any positive association between risk and dose, with the relative risk at 1 Sv being 1.00 (95% confidence interval 0.94, 1.07), which contrasts with that based on the atomic bomb survivors, 1.60 (1.27, 1.99). The difference in effect between the two studies almost certainly did not arise by chance (P = 0.0001). This study provides strong support from data for humans for a substantial fractionation/dose-rate effect for low-linear energy transfer radiation and lung cancer risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiological protection is based on the assumption that any additional exposure to ionizing radiation produces an increased risk of stochastic adverse health effects. The ICRP has adopted linear no-threshold (LNT) dose-response relationships to derive health risks associated with low doses of radiation and this implies that the risks of cancer and hereditary effects are directly proportional to the dose received, no matter how small the dose. The LNT assumption has been criticised over the years both by those who consider that it underestimates the risk and by those who believe that it is overly conservative. A few years ago, most of the pressure on ICRP came from those who believed that the risks per unit dose adopted at low doses were too small, but in recent years the pressure has been coming from the opposite direction. Strictly speaking, ICRP feels that the most likely form of the dose-response relationship for low LET radiation is linear-quadratic (i.e. sub-linear at low doses), and for cancer they approximate this by two linear relations, that for the low dose region having a slope (risk per unit dose) half of that for the high dose region, represented by a DDREF of 2. Nevertheless, there are those (particularly in the US and France) who argue that there is no direct evidence for stochastic effects being produced by low doses of radiation, and that the appropriate dose-response relationship has a threshold dose below which no risk to health exists, or even that low doses of radiation are beneficial (`radiation hormesis').

A previous investigation has uncoupled the solid cancer risk coefficient for neutrons from the low dose estimates of the relative biological effectiveness (RBE) of neutrons and the photon risk coefficient, and has related it to two more tangible quantities, the excess relative risk (ERR1) due to an intermediate reference dose D1 = 1 Gy of gamma-rays and the RBE of neutrons, R1, against this reference dose. With tentatively assumed RBE values between 20 and 50 and in terms of organ-averaged doses--rather than the usually invoked colon doses--the neutron risk factor was seen to be in general agreement with the current risk estimate of the International Commission on Radiation Protection (ICRP). The present assessment of the risk coefficient for gamma-rays incorporates--in terms of the unchanged A-bomb dosimetry system, DS86--this treatment of the neutrons, but is otherwise largely analogous to the evaluation of the A-bomb data for the ICRP report and for the recent report of the United Nations Scientific Committee on the effects of ionizing radiation, UNSCEAR. The resulting central estimate of the lifetime attributable risk (LAR) for solid cancer mortality is 0.043/Gy for a working population (ages 25-65), and is nearly the same whether the age at exposure or the attained age model is used for risk projection. For a population of all ages 0.042/Gy is obtained with the attained age model and 0.068/Gy with the age at exposure model. The values do not include a dose and dose rate effectiveness factor (DDREF), and they are only half as large as the new UNSCEAR estimates of 0.082/Gy (attained age model and all ages) and 0.13/Gy (age at exposure model and all ages). The difference is only partly due to the more explicit treatment of the neutrons. It reflects also the fact that UNSCEAR has converted ERR into LAR in a way that differs from the ICRP procedure, and that it has summed the overall risk coefficient for solid tumor mortality and incidence from separate estimates for eight solid tumor categories, whereas the present study employs a combined computation for all solid tumors and uses the ICRP procedure for the conversion of ERR into LAR. The appendix gives results for the solid cancer incidence data.

Differences in clinical results reported with the use of iodine-125 encapsulated implants compared to those with gold-198, radon-222, and iridium-192 prompted a study of the RBE, relative to60 Co γ radiation, of X rays simulating the spectral distribution of radiation from encapsulated125 I. The parameter used for the RBE determination was the killing of surface-attached log-phase HeLa-S3 cells. The RBE was determined at dose rates varying from 15 to 130 rad/min which are about 90 to 500 times greater than those employed in therapy with interstitial ${}^{125}{\rm I} \text{implants}$ . It was found to be approximately 1.4 when measured as a ratio of $D_{0}\text{'}{\rm s}$ and 1.3 as determined on the basis of the ratio of doses for 10% survival (dose rates of 15 and 30 rad/min). The RBE values were found to be dose-rate dependent, increasing linearly from 130 to 30 rad/min and possibly leveling off below this point.

Purpose: Estimated radiation risks used for radiation protection purposes have been based primarily on the Life Span Study (LSS) of atomic bomb survivors who received brief exposures at high dose rates, many with high doses. Information is needed regarding radiation risks from low dose-rate (LDR) exposures to low linear-energy-transfer (low-LET) radiation. We conducted a meta-analysis of LDR epidemiologic studies that provide dose-response estimates of total solid cancer risk in adulthood in comparison to corresponding LSS risks, in order to estimate a dose rate effectiveness factor (DREF).Materials and methods: We identified 22 LDR studies with dose-response risk estimates for solid cancer after minimizing information overlap. For each study, a parallel risk estimate was derived from the LSS risk model using matching values for sex, mean ages at first exposure and attained age, targeted cancer types, and accounting for type of dosimetric assessment. For each LDR study, a ratio of the excess relative risk per Gy (ERR Gy−1) to the matching LSS ERR risk estimate (LDR/LSS) was calculated, and a meta-analysis of the risk ratios was conducted. The reciprocal of the resultant risk ratio provided an estimate of the DREF.Results: The meta-analysis showed a LDR/LSS risk ratio of 0.36 (95% confidence interval [CI] 0.14, 0.57) for the 19 studies of solid cancer mortality and 0.33 (95% CI 0.13, 0.54) when three cohorts with only incidence data also were added, implying a DREF with values around 3, but statistically compatible with 2. However, the analyses were highly dominated by the Mayak worker study. When the Mayak study was excluded the LDR/LSS risk ratios increased: 1.12 (95% CI 0.40, 1.84) for mortality and 0.54 (95% CI 0.09, 0.99) for mortality + incidence, implying a lower DREF in the range of 1–2. Meta-analyses that included only cohorts in which the mean dose was <100 mGy yielded a risk ratio of 1.06 (95% CI 0.30, 1.83) for solid cancer mortality and 0.58 (95% CI 0.10, 1.06) for mortality + incidence data.Conclusions: The interpretation of a best estimate for a value of the DREF depends on the appropriateness of including the Mayak study. This study indicates a range of uncertainty in the value of DREF between 1 and about 2 after protracted radiation exposure. The LDR data provide direct evidence regarding risk from exposures at low dose rates as an important complement to the LSS risk estimates used for radiation protection purposes.

V79 Chinese hamster cells cultured in vitro were used to compare radium gamma rays (dose rate, 50 rads/hour) with the mixed neutron/gamma-ray emission from 252Cf (dose rate, 18 rads/hour). The relative biological effectiveness (RBE) of 252Cf neutrons compared with radium gamma rays was 5.9. The oxygen enhancement ratios (OER) for radium and californium were found to be 2.0 and 1.42, respectively. The implications for radiotherapy are discussed.

The survival of mouse jejunal crypt cells was measured using a microcolony assay following irradiation with one of three different pion stopping volumes. All treatments were done using the beam spot scanning system developed for clinical therapy at TRIUMF. Treatment volumes were Small, 10 ml of volume using 4 beam spots with a narrow stopping peak; Moderate, 40 ml of volume using 4 beam spots with an extended peak; Large, 1.2 liters of volume using 37 spots with an extended peak. The dose rate fluctuated considerably during treatment because of the scanning procedure. The relative biological effectiveness (RBE) values of pions were 1.11, 1.04, and 1.16 for the small, moderate, and large volumes, respectively. As the width of the stopping peak increased, from the narrow 4-cm peak of the small volume to the 12-cm peak of the moderate volume, the effectiveness of the pion beam decreased. This presumably reflects the low linear energy transfer contribution of the large number of passing pions in the wider stopping peak. The results indicate, however, a greater biological effectiveness for the large volume than for the moderate volume. Even though these fields had stopping peaks of similar width, the field size and dose rate were different. Although the increase in RBE may be partly due to an increased neutron flux from the larger volume, our results suggest that much of this apparent increase could be explained by differences in dose rate as a function of time for pions versus X rays.

Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology.