Higher Relative Biological Effectiveness Values Research Articles

Linear energy transfer dependent variation in viability and proliferation along the Bragg peak curve in sarcoma and normal tissue cells

Objective.The energy deposition of photons and protons differs. It depends on the position in the proton Bragg peak (BP) and the linear energy transfer (LET) leading to a variable relative biological effectiveness (RBE). Here, we investigate LET dependent alterations on metabolic viability and proliferation of sarcoma and endothelium cell lines following proton irradiation in comparison to photon exposure.Approach.Using a multi-step range shifter, each column of a 96-well plate was positioned in a different depth along four BP curves with increasing intensities. The high-throughput experimental setup covers dose, LET, and RBE changes seen in a treatment field. Photon irradiation was performed to calculate the RBE along the BP curve. Two biological information out of one experiment were extracted allowing a correlation between metabolic viability and proliferation of the cells.Main results.The metabolic viability and cellular proliferation were column-wise altered showing a depth-dose profile. Endothelium cell viability recovers within 96 h post BP irradiation while sarcoma cell viability remains reduced. Highest RBE values were observed at the BP distal fall-off regarding proliferation of the sarcoma and endothelial cells.Significance.The high-throughput experimental setup introduced here (I) covers dose, LET, and RBE changes seen in a treatment field, (II) measures short-term effects within 48 h to 96 h post irradiation, and (III) can additionally be transferred to various cell types without time consuming experimental adaptations. Traditionally, RBE values are calculated from clonogenic cell survival. Measured RBE profiles strongly depend on physical characteristics such as dose and LET and biological characteristics for example cell type and time point. Metabolic viability and proliferation proofed to be in a similar effect range compared to clonogenic survival results. Based on limited data of combined irradiation with doxorubicin, future experiments will test combined treatment with systemic therapies applied in clinics e.g. cyclin-dependent inhibitors.

Modelling of RBE differences in selected points within similar spread-out Bragg-peaks (SOBP) placed at superficial and deep water phantom locations in passively scattered beams but not in scanned pencil beams: A hypothesis

PurposeTo model relative biological effectiveness (RBE) differences found in two studies which used spread-out Bragg-peaks (SOBP) placed at (a) superficial depth and (b) at the maximum range depth. For pencil beam scanning (PBS), RBE at similar points within the SOBP did not change between the two extreme SOBP placement depths; in passively scattered beams (PSB), high RBE values (typically 1.2–1.3) were found within superficially- placed SOBP but reduced to lower values (1–1.07) at similar points within the extreme-depth positioned SOBP. The dose, LET (linear energy transfer) distributions along each SOBP were closely comparable regardless of placement depth, but significant changes in dose rate occurred with depth in the PSB beam. MethodsThe equations used allow α and β changes with falling dose rate (the converse to FLASH studies) in PSB, resulting in reduced α/β ratios, compatible with a reduction in micro-volumetric energy transfer (the product of Fluence and LET), with commensurate reductions in RBE. The experimental depth-distances, positions within SOBP, observed dose-rates and radiosensitivity ratios were used to estimate the changes in RBE. ResultsRBE values within a 5 % tolerance limit of the experimental results for PSB were found at the deepest SOBP placement. No RBE changes were predicted for PBS beams, as in the published results. ConclusionsEnhanced proton therapy toxicity might occur with PBS when compared with PSB for deeply positioned SOBP due to the maintenance of higher RBE. Scanned pencil beam users need to be vigilant about RBE and further research is indicated.

An empirical model of proton RBE based on the linear correlation between x-ray and proton radiosensitivity.

Proton relative biological effectiveness (RBE) is known to depend on physical factors of the proton beam, such as its linear energy transfer (LET), as well as on cell-line specific biological factors, such as their ability to repair DNA damage. However, in a clinical setting, proton RBE is still considered to have a fixed value of 1.1 despite the existence of several empirical models that can predict proton RBE based on how a cell's survival curve (linear-quadratic model [LQM]) parameters α and β vary with the LET of the proton beam. Part of the hesitation to incorporate variable RBE models in the clinic is due to the great noise in the biological datasets on which these models are trained, often making it unclear which model, if any, provides sufficiently accurate RBE predictions to warrant a departure from RBE=1.1. Here, we introduce a novel model of proton RBE based on how a cell's intrinsic radiosensitivity varies with LET, rather than its LQM parameters. We performed clonogenic cell survival assays for eight cell lines exposed to 6 MV x-rays and 1.2, 2.6, or 9.9keV/µm protons, and combined our measurements with published survival data (n=397 total cell line/LET combinations). We characterized how radiosensitivity metrics of the form DSF% , (the dose required to achieve survival fraction [SF], e.g., D10% ) varied with proton LET, and calculated the Bayesian information criteria associated with different LET-dependent functions to determine which functions best described the underlying trends. This allowed us to construct a six-parameter model that predicts cells' proton survival curves based on the LET dependence of their radiosensitivity, rather than the LET dependence of the LQM parameters themselves. We compared the accuracy of our model to previously established empirical proton RBE models, and implemented our model within a clinical treatment plan evaluation workflow to demonstrate its feasibility in a clinical setting. Our analyses of the trends in the data show that DSF% is linearly correlated between x-rays and protons, regardless of the choice of the survival level (e.g., D10% , D37% , or D50% are similarly correlated), and that the slope and intercept of these correlations vary with proton LET. The model we constructed based on these trends predicts proton RBE within 15%-30% at the 68.3% confidence level and offers a more accurate general description of the experimental data than previously published empirical models. In the context of a clinical treatment plan, our model generally predicted higher RBE-weighted doses than the other empirical models, with RBE-weighted doses in the distal portion of the field being up to 50.7% higher than the planned RBE-weighted doses (RBE=1.1) to the tumor. We established a new empirical proton RBE model that is more accurate than previous empirical models, and that predicts much higher RBE values in the distal edge of clinical proton beams.

Clinical implications of variable relative biological effectiveness in proton therapy for prostate cancer

Purpose To study the potential consequences of differences in the evaluation of variable versus uniform relative biological effectiveness calculations in proton radiotherapy for prostate cancer. Methods and material Experimental data with proton beams suggest that relative biological effectiveness increases with linear energy transfer. This relation also depends on the ratio, characteristic of a tissue and a considered endpoint. Three phenomenological models (Carabe et al., Wedenberg et al. and McNamara et al.) are compared to a mechanistic model based on microdosimetry (microdosimetric kinetic model) and to the current assumption of uniform relative biological effectiveness equal to 1.1 in a prostate case. Results and conclusions Phenomenological models clearly predict higher relative biological effectiveness values compared to microdosimetric kinetic model, that seems to approach to the constant value of 1.1 adopted in the clinics, at least for low linear energy transfer values achieved in typical prostate proton plans. All models predict a higher increase of the relative biological effectiveness-weighted dose for the prostate tumor than for the rest of structures involved due to its lower ratio, even when linear energy transfer is, in general, lower in the tumor than on the surroundings tissues. Prostate cancer is, therefore, a good candidate to take advantage of variable relative biological effectiveness, especially if linear energy transfer is enhanced within the tumor. However, the discrepancies among models hinder the clinical implementation of variable relative biological effectiveness.

Studies on Application of Ion Beam Breeding to Industrial Microorganisms at TIARA

Mutation-breeding technologies are useful tools for the development of new biological resources in plants and microorganisms. In Takasaki Ion Accelerators for Advanced Radiation Application (TIARA) at the National Institutes for Quantum and Radiological Science and Technology, Japan, ion beams were explored as novel mutagens. The mutagenic effects of various ion beams on eukaryotic and prokaryotic microorganisms were described and their application in breeding technology for industrial microorganisms were discussed. Generally, the relative biological effectiveness (RBE) depended on the liner energy transfer (LET) and the highest RBE values were obtained with 12C5+ ion beams. The highest mutation frequencies were obtained at radiation doses that gave 1%–10% of surviving fraction. By using 12C5+ ion beams in this dose range, many microorganisms have been improved successfully at TIARA. Therefore, ion-beam breeding technology for microorganisms will have applications in many industries, including stable food production, sustainable agriculture, environmental conservation, and development of energy resources in the near future. Moreover, genome analyses of the ion-beam-induced mutants are in progress to clear the differences of mutational functions induced by different LET radiations in microorganisms. Further characterizations of mutations induced by different LET radiations will facilitate more effective use of ion beams in microorganisms breeding.

Investigation of the relative biological effectiveness and uniform isobiological killing effects of irradiation with a clinical carbon SOBP beam on DNA repair deficient CHO cells.

Spread-out Bragg peak (SOBP) C ions have been used clinically in charged particle radiation therapy for years. An SOBP beam consists of various monoenergetic Bragg peaks; however, the biological effect of irradiation with an SOBP beam track has not been well-studied. In order to determine the clinically prospective molecular targets, radiosensitivity to the beam track in DNA repair deficient cell lines was investigated. A total of four distinct Chinese hamster ovary (CHO) cell lines, including CHO10B2 (wild-type), V3 (protein kinase DNA-activated catalytic polypeptide deficient), 51D1 (RAD51 paralog D deficient) and PADR9 [poly(ADP-ribose) polymerase (PARP) deficient], were irradiated with gamma-rays, C ions (290 MeV/n) and Fe ions (500 MeV/n), in order to compare cellular lethality. An OptiCell™ culture system was used to evaluate the lethality at distinct depths of SOBP C ions. Relative biological effectiveness (RBE) values of C ions (linear energy transfer (LET), 13 and 70 keV/µm) and Fe ions (LET, 200 keV/µm) were calculated from cell survival using colony formation assay with standard cell dishes. All cell lines exhibited similar sensitivity to 70 keV/µm C ions and 200 keV/µm Fe ions. Furthermore, V3 cells did not exhibit increased sensitivity to high LET C ions and Fe ions, compared with low LET gamma-rays and C ions, and 51D1 cells irradiated with 13 keV/µm C ions exhibited relatively high RBE values among the tested cell lines. Conversely, PADR9 cells exhibited low RBE values for 13 keV/µm C ions and high RBE values for 70 keV/µm C ions. Obtained using the OptiCell system, the survival fractions in the SOBP region were uniform for wild-type and PADR9 cells. Conversely, V3 and 51D1 cells exhibited decreased cell death in the distal region of the SOBP. These results indicated that PARP is a more effective target for clinical beam therapy, compared with the non-homologous end joining repair and homologous recombination repair pathways. PARP deficiency may be an optimal target for C ion therapy and the results of the present study may contribute to the development of a more effective heavy ion radiation therapy.

A phenomenological relative biological effectiveness approach for proton therapy based on an improved description of the mixed radiation field

Proton therapy treatment planning systems (TPSs) are based on the assumption of a constant relative biological effectiveness (RBE) of 1.1 without taking into account the found in vitro experimental variations of the RBE as a function of tissue type, linear energy transfer (LET) and dose. The phenomenological RBE models available in literature are based on the dose-averaged LET (LETD) as an indicator of the physical properties of the proton radiation field. The LETD values are typically calculated taking into account primary and secondary protons, neglecting the biological effect of heavier secondaries. In this work, we have introduced a phenomenological RBE approach which considers the biological effect of primary protons, and of secondary protons, deuterons, tritons (Z = 1) and He fragments (3He and 4He, Z = 2). The calculation framework, coupled with a Monte Carlo (MC) code, has been successfully benchmarked against clonogenic in vitro data measured in this work for two cell lines and then applied to determine biological quantities for spread-out Bragg peaks and a prostate and a head case. The introduced RBE formalism, which depends on the mixed radiation field, the dose and the ratio of the linear–quadratic model parameters for the reference radiation , predicts, when integrated in an MC code, higher RBE values in comparison to LETD-based parameterizations. This effect is particular enhanced in the entrance channel of the proton field and for low tissues. For the prostate and the head case, we found higher RBE-weighted dose values up to about 5% in the entrance channel when including or neglecting the Z = 2 secondaries in the RBE calculation. TPSs able to proper account for the mixed radiation field in proton therapy are thus recommended for an accurate determination of the RBE in the whole treatment field.

SU-F-T-682: In-Vivo Simulation of the Relative Biological Effectiveness in Proton Therapy Using a Monte Carlo Method

Purpose: In proton therapy, the relative biological effectiveness (RBE) – compared with conventional photon therapy – is routinely set to 1.1. However, experimental in vitro studies indicate evidence for the variability of the RBE. To clarify the impact on patient treatment, investigation of the RBE in a preclinical case study should be performed. Methods: The Monte Carlo software TOPAS was used to simulate the radiation field of an irradiation setup at the experimental beamline of the proton therapy facility (OncoRay) in Dresden, Germany. Simulations were performed on cone beam CT-data (CBCT) of a xenogeneous mouse with an orthotopic lung carcinoma obtained by an in-house developed small animal image-guided radiotherapy device. A homogeneous physical fraction dose of 1.8Gy was prescribed for the contoured tumor volume. Simulated dose and linear energy transfer distributions were used to estimate RBE values in the mouse based on an RBE model by Wedenberg et al. To characterize radiation sensitivity of normal and tumor tissue, α/β-ratios were taken from the literature for NB1RGB (10.1Gy) and human squamous lung cancer (6.2Gy) cell lines, respectively. Results: Good dose coverage of the target volume was achieved with a spread-out Bragg peak (SOBP). The contra-lateral lung was completely spared from receiving radiation. An increase in RBE towards the distal end of the SOBP from 1.07 to 1.35 and from 1.05 to 1.3 was observed when considering normal tissue and tumor, respectively, with the highest RBE values located distal to the target volume. Conclusion: Modeled RBE values simulated on CBCT for experimental preclinical proton therapy varied with tissue type and depth in a mouse and differed therefore from a constant value of 1.1. Further translational work will include, first, conducting preclinical experiments and, second, analogous RBE studies in patients using experimentally verified simulation settings for our clinically used patient-specific beam conforming technique.

Effect of oxygen pressure during incubation with a 10B-carrier on 10B uptake capacity of cultured p53 wild-type and mutated tumor cells: dependency on p53 status of tumor cells and types of 10B-carriers

Purpose To evaluate the effect of oxygen pressure during incubation with a 10B-carrier on 10B uptake capacity of cultured p53 wild-type and mutated tumor cells.Materials and methods Cultured human head and neck squamous cell carcinoma cell line transfected with mutant TP53 (SAS/mp53), or with a neo vector as a control (SAS/neo) was incubated with L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH) as a 10B-carrier at the 10B concentration of 60 ppm for 24 h under aerobic (20.7% of oxygen) or hypoxic (0.28% of oxygen) conditions. Immediately after incubation, cultured tumor cells received reactor thermal neutron beams, and a cell survival assay was performed. 10B concentration of cultured SAS/neo or SAS/mp53 cells incubated under aerobic or hypoxic conditions was determined with a thermal neutron guide tube.Results Hypoxic incubation significantly decreased 10B concentration of cultured cells with a clearer tendency observed following BPA than BSH treatment in both SAS/neo and SAS/mp53 cells. Following neutron beam irradiation, SAS/mp53 cells showed significantly higher relative biological effectiveness values than SAS/neo cells because of the significantly lower radiosensitivity of SAS/mp53 to γ-rays than SAS/neo cells.Conclusion Oxygen pressure during incubation with a 10B-carrier had a critical impact on 10B uptake of cultured tumor cells.

WE-C-AUD B-09: Evaluation of Radiobiological Effects of Carbon Ion Beams: Mixed Particle Fields and Fragmentation

Purpose: The purpose of this report is to investigate the effects on the Relative Biological Effectiveness (RBE) due to nuclear fragmentation during irradiation with therapeuticcarbonion beams, by using biological model calculations. Method and Materials: In order to disentangle the biological effects of the mixed particle fields, we evaluated the RBE originated by primary carbon ions and by fragments together and separately. The radiobiological efficiency of charged particles is mainly characterized by their high local ionization density which can be directly correlated to the local density of DNA damage. We developed a code based on the Local Effect Model (LEM) for the calculation of the cell survival after irradiation with carbon ions. As input we use particle distributions sampled at different depths in a water volume, for different energies of the primary ions (between 150 and 400 MeV/u), generated by Monte Carlo simulations using the package GEANT4. The computational effort was performed using the distributed INFN (Istituto Nazionale di Fisica Nucleare) Grid computing resources. Results: For carbon ions, high RBE values were found in the high‐LET region (Bragg peak), as well as in the low‐dose region, the distal region after the Bragg peak, where the contribution to the RBE is mainly due to fragments. We show that the global biological effect can be well reconstructed by a weighted combination of the alpha and beta parameters of the Linear‐Quadratic Model (LQM) evaluated separately for primary ions and fragments. The analysis provided also an estimate of the RBE sensitivity to the uncertainties present in the experimental data of fragment yield. Conclusion: Our work estimated the impact of the fragments in hadrontherapy using carbonion beams. Due to the high RBE values found, the resulting biological dose can be important in regions outside the irradiated target, in presence of organs at risk.

Direct Comparison of Biologically Optimized Spread-out Bragg Peaks for Protons and Carbon Ions

In radiotherapy with hadrons, it is anticipated that carbon ions are superior to protons, mainly because of their biological properties: the relative biological effectiveness (RBE) for carbon ions is supposedly higher in the target than in the surrounding normal tissue, leading to a therapeutic advantage over protons. The purpose of this report is to investigate this effect by using biological model calculations. We compared spread-out Bragg peaks for protons and carbon ions by using physical and biological optimization. The RBE for protons and carbon ions was calculated according to published biological models. These models predict increased RBE values in regions of high linear energy transfer (LET) and an inverse dependency of the RBE on dose. For pure physical optimization, protons yield a better dose distribution along the central axis. In biologically optimized plans, RBE variations for protons were relatively small. For carbon ions, high RBE values were found in the high-LET target region, as well as in the low-dose region outside the target. This means that the LET dependency and dose dependency of the RBE can cancel each other. We show this for radioresistant tissues treated with two opposing beams, for which the predicted carbon RBE within the target volume was lower than outside. For tissue parameters used in this study, the model used does not predict a biologic advantage of carbon ions. More reliable model parameters and clinical trials are necessary to explore the true potential of radiotherapy with carbon ions.

TH‐C‐224C‐01: Relative Biological Effectiveness(RBE) and Dosimetry of Low Energy Photons(8keV) Generated Using Miniature X‐Ray Tubes

Purpose: To study the Relative Biological Effectiveness(RBE) and dosimetric characteristics of an 8keV photon beam generated by an insertable miniature electronic brachytherapy device developed by Advanced X‐ray Technology, Inc.(AXT). Method and Materials: The AXT X‐ray needle consists of a primary conventional X‐ray tube with silver anode producing a 22 keV beam focused through a collimator into the applicator needle which has a secondary copper target generating an 8 keV fluorescent beam. The radio‐resistant human tumor cell lines HGL21(glioblastoma) and MCF7 (breast) were irradiated at 22°C using the AXT miniature needle and compared with a Co‐60 beam at dose rates of approximately 6cGy/min and 12cGy/min. An extrapolation chamber was used in gradient mode to determine the dose rate within the AXT beam after initially determining the effective area of the collecting electrode in a Co‐60 beam using the Bragg‐Gray relationship. Results: Cell surviving fraction (SF) was the primary end point in assessing the radiobiological effect. For the 8 keV beam, SF was found to be 0.056 for HGL21 and 0.018 for MCF7 for a dose of 2 Gy. This yields an RBE of 4.4 for HGL21 and 5.5 for MCF7 cells lines. The dose rate in the 8keV beam was found to vary linearly as a function of extrapolation chamber electrode spacing. This allows the use of the slope of the ionization gradient to determine the dose. The dose rate measured in free space at the location where the cells were irradiated was found to be 15.4 cGy/min.Conclusion: These high RBE values are not surprising given the stopping power of the very low energy recoil electrons produced in this beam, and support the premise that the AXT device will be an effective tool to treat tumor sites like brain, breast and prostate in which radio‐resistance might limit conventional radiotherapy.

The general relation between tissue response to x-radiation (α/β-values) and the relative biological effectiveness (RBE) of protons: Prediction by the Katz track-structure model

Purpose : Experimental data suggest that the relative biological effectiveness (RBE) of protons compared to x-rays may be determined by the α / β -ratio of the x-ray survival curve. The data are referring to the centre of a spread-out Bragg peak (SOBP) formed to deliver a homogeneous dose to the tumour by modulating the proton energy. In an effort to explore the basis for this observation, calculations were performed to investigate the response of different biological targets through a range of proton energies and doses. Materials and methods : To describe the x-ray survival curve, the parameters of the linear-quadratic equation, α and β, as well as those of the multi-target/single-hit equation, n and D 0, were considered. These parameters were varied to investigate the RBE using the Katz track-structure model. Known cell line characterizations, as well as different hypothetical cells assuming different α / β -ratios but similar target size parameters in the framework of the track-structure theory, were considered. Results : The RBE was found to increase with increasing α / β when the parameter n was varied, but to decrease with increasing α / β when D 0 was varied. This held when all other radiosensitivity parameters were assumed to stay constant. Thus, the RBE cannot be predicted by the α / β -ratio alone. Conclusions : Although there is no direct correlation between the proton RBE and the parameters describing the x-ray survival curve, the track-structure model predicts a tendency for late-responding tissues (low α / β) to have higher RBE values than early-responding tissues (high α / β) . These calculations reinforce the experimental findings, but also strongly suggest that there are circumstances in which the tendency for RBE to increase with increasing α / β does not occur, or even could be reversed.

RBE for the induction of apoptosis in human peripheral lymphocytes exposed in vitro to high-LET radiation generated by accelerated nitrogen ions

Purpose: To investigate the relative biological effectiveness (RBE) of accelerated nitrogen ions (32-45 MeV/u) compared with 137Cs gamma -rays for the induction of apoptosis in G lymphocytes. 0 Materials and methods: Human peripheral G lymphocytes were 0 exposed in vitro to doses up to 3 Gy. RBE for the induction of apoptosis was studied at different times after irradiation (0, 24, 48 and 72 h) with the use of three different methods: (1) morphological characterization of apoptotic cells after fluorescence staining; (2) cell size distribution analysis of the cell population to detect apoptotic bodies; and (3) electrophoretic analysis of DNA to detect 'DNA-ladders'. Results: RBE values in the range of 1.3-3.0 were obtained from the linear components of the dose-response curves. The variation in RBE was primarily dependent on post-irradiation time, where the highest RBE values were obtained after 48 h. The three different techniques used for analysis of apoptosis gave similar results. The significantly increased RBE was also seen as an earlier appearance of DNA-ladders, as well as a more rapid disappearance of the total number of viable cells. Conclusions: These results show that nitrogen ions of high linear energy transfer (LET) produce RBE 1.0 and induce a faster apoptotic response as compared with gamma -photons of low-LET radiation.

The Present System of Quantities and Units for Radiation Protection

The International Commission on Radiation Units and Measurements has over the last decade developed operational quantities, the ambient, directional and personal dose equivalent, suitable for the measurement of radiation fields in a variety of circumstances. Experience with the use of these quantities to represent the dose limitation quantities defined by the International Commission on Radiological Protection in 1977 has been an important part of recent radiation protection metrology. The definition by International Commission on Radiological Protection in 1991 of new limitation quantities, the equivalent dose and the effective dose has necessitated a redirection of this work. The metrology field has made good progress, however. It has found that for photons, at least above 50 keV, the effective dose can be measured by the ambient dose equivalent about as well as the former effective dose equivalent. Unfortunately, for neutrons the existing and already quite severe complications have been made somewhat worse by the new quantities although not any worse in the important region between 0.1 and 1 MeV. Neutron measurements over a broad energy range are the subject of extensive evaluation and some new suggestions as the metrology field wrestles with these problems. Values of wR constitute an important part of the International Commission on Radiological Protection recommendations. A brief history of the development of higher relative biological effectiveness values for fission neutrons and alpha particles leading to the selection of 20 for wR in each case, is provided.

Cytotoxicity of 125I decay in the DNA double strand break repair deficient mutant cell line, xrs-5.

The survival of parental Chinese hamster ovary (CHO) K1 cells and the DNA double strand break (DSB) repair deficient mutant, xrs-5 was determined after accumulation of 125I decays. Both CHO and xrs-5 cells were extremely sensitive to accumulated 125I decays. The D0 values for CHO and xrs-5 cells were 40 and approximately 7 decays per cell, respectively. The difference in cell survival between CHO and xrs-5 cells was not due to differences in overall 125IUdR incorporation, differences in labelling index (LI) or differences in plating efficiency (PE). Relative biological effectiveness (RBE) values calculated relative to 137Cs gamma radiation survival values (D0 and D10) were higher in xrs-5 cells compared with CHO cells. Although both CHO and xrs-5 cells have high RBE values that correspond to a high sensitivity of CHO and xrs-5 cells to 125I decay. The higher RBE observed for xrs-5 cells in combination with the known repair defect in xrs-5 cells support the idea that unrepaired DNA double strand breaks are lethal to the cell.

Evidence of dark matter from biological observations

In accordance with the generally accepted properties of dark matter (DM) candidates, the probability of their interaction with living matter must be equal to that for inorganic matter, and the expected effects might be unique and provide the etiology related to the appearance of several biological phenomena having sometimes fatal late effects. Although collisions with DM are rare, the charged secondaries (recoiling atoms) are expected to be high linear energy transfer particles favouring the highest relative biological effectiveness values for this, as yet invisible, part of the natural background radiation. A few cases are given, where a correlation between DM interaction and phenomena in living matter might already exist, or can show up in existing data: biorhythms w with periodicities identical to known cosmic frequencies are explainable with gravitationally clustered DM around the sun, the moon, the earth, etc. The observed arrhythmia, when biological probes are moved (in airplanes, satellites, etc.) support this idea strongly. It is also proposed to implement some of the biological properties and processes (such as element composition and chemical reactions) in future DM detectors in order to improve their sensitivity. The interdisciplinary feedback is bidirectional: huge DM detectors could be used in attempt to understand enigmatic biological behavior.

Actuarial analysis of the hazard for mammary carcinogenesis in different rat strains after X- and neutron irradiation

Mammary carcinogenesis in three different rat strains has been studied after single and fractionated irradiations with X-rays and monoenergetic neutrons of three energies. The aims of the programme are the investigation of the nature of the dose-effect relationships, and the determination of the relative biological effectiveness (RBE) of neutrons. Histopathological examinations of tumours has been completed and dose-effect relations are reported separately for the induction of benign and malignant lesions. Appropriate corrections have been made for competing risks in the tumour rate analysis. The probability curves for survival without evidence of tumours have been described by Weibull distributions. This continuous parametric failuretime model is used to derive the relative excess hazard for exposure to X-rays and neutrons. The different rat strains show considerable differences in susceptibility for the induction of cancer by radiation. In general linear dose-response curves have been observed for mammary tumourigenesis in the three rat strains for both X-rays and fast neutrons. Within the statistical precision of the data a dependence of the RBE on neutron dose cannot be recognised. The highest RBE values, varying between 7 and 15 for different types of tumours in the three rat strains have been observed for 0.5 MeV neutrons. These RBE values are lower in general than those observed by other groups for beams of comparable energy.

Relation between RBE and LET to Inhibit Neural Impulse Conduction

A dose of 285 krad (average) of 200-kV x-rays absorbed by isolated, frog sciatic nerves promptly inactivated impulse transmission. Blockage of neural activity in this type of nerve required 600 krad (average) of 47.5-MeV protons. Protons of this energy have a relative biological effectiveness (RBE) of 0.48 with respect to 200-kV x-rays, which have an assigned value of one. Other investigators exposed frog nerves to different types of radiation and reported inactivation doses. RBE values determined from such doses were 0.66 for 910-MeV α-particles, 0.87 for 260-kV x-rays, and 30.60 for 5.3-MeV α-particles. The RBE values to suppress neural activity depended on the linear energy transfer (LET) of the radiation particles. Radiations with high LET values had high RBE values. A plot of the logarithm of RBE vs the logarithm of LET yielded a linear relation for radiations with LET values between 1.3 and 110.0 keV/μ of tissue. Frog sciatic nerves exposed to either 200-kV x-rays or 47.5-MeV protons exhibited bioel...

Lens Opacification in Mice Exposed to Fast Neutrons

Opacification (cataractogenesis) of the mammalian crystalline lens has long been recognized as a potential hazard of exposure to ionizing radiation. During the past two decades numerous studies have been directed toward determining the cataractogenic effectiveness of radiations of either low linear energy transfer (LET), such as x or y rays, or high LET, such as fission neutrons. Generally, large doses (hundreds of rads) were employed, with resultant ultimate total opacification. The mixture of radiation qualities (and consequent broad spectrum of LET) frequently encountered with radiations of higher LET prevented other than a gross determination of relative biological effectiveness (RBE), which, however, has sufficed for certain clinical and practical applications. Recently, attention has become focused on the employment of lens opacification as a tool for more precise radiobiological determinations. The features of (1) high RBE values with high LET radiations, and (2) multiple serial (nondestructive) visual examinations confer particular value to this system in basic considerations of the influence of LET and dose rate on biological effectiveness. The attempt has been made at this laboratory in recent years to adapt this system in the mouse for more basic investigation by (1) employment of monoenergetic fast neutrons as high LET radiations with minimal smear, and (2) revision of the conventional (serial slit-lamp microscope) lens examination and scoring technique. These studies have become increasingly directed toward early minute opacities, following exposure to low doses of radiation. This paper will describe the more pertinent findings obtained from two separate experiments, covering intermediate and low dose ranges of monoenergetic fast neutrons and x rays.