Effective Dose Concept Research Articles

Practical guidance on the assessment of radiation risks for diagnostic radiological examinations.

Patient doses cannot be limited; instead, radiological examinations should be justified and optimized to ensure the necessary diagnostic or therapeutic effect with the lowest patient dose achievable. Assessment of the radiation risks from patient exposure is important part of the justification process. Hence, medical staff within the framework of their professional activities should possess necessary information on the data on radiation risk from different types of radiological procedures. An approach has been developed that allows considering age and gender dependences of the risk coefficients of radiogenic cancer and the age and gender distribution of patients for various radiological examinations to assess the individual radiation risk for patient and collective risk for population from medical exposure. The approach is based on a new expanded use of the effective dose concept proposed in ICRP Publication 147 and demonstrated using the medical exposure in the Russian Federation as the example. For 30 radiological examinations that compose about 80% of the collective dose from medical exposure of the public in the Russian Federation radiation risk was assessed based on calculated age and gender specific risk coefficients per unit effective dose. For the rest of the examinations a simplified approach was used to assess the risk, which was based on using an age and gender specific risk coefficient determined for one of 4 anatomical regions (head, neck, chest and abdomen) or for uniform irradiation of the whole body. The proposed approach allows significantly improving the assessment of the radiation risk while continuing to use the effective dose as a dosimetric quantity within the framework of the state program in the Russian Federation. As a result the collective risk from medical examinations in the Russian Federation in 2022 was lower by the factor of 3 compared to the previous assessment based on the effective dose with the nominal risk coefficient.

Simultaneous dose and dose rate optimization via dose modifying factor modeling for FLASH effective dose.

Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV). This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED. SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method. SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10mm ring expansion of CTV). We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO.

Radiation exposure during orthodontic treatment: risk to children and adolescents.

To estimate radiation risk to children and adolescents during orthodontic treatment by retrieving number and type of radiographs from the patient records. Radiographs, along with justifications for radiation exposure, were obtained retrospectively from the patient records of 1,790 children and adolescents referred to two Swedish orthodontic clinics. Data were grouped according to treatment stage: treatment planning, treatment, and follow-up. Estimated risk was calculated using the concept of effective dose. Each patient had received around seven radiographs for orthodontic purposes. The most common exposures during treatment planning were one panoramic, one lateral, and three intraoral periapical radiographs. A small number of patients received a tomographic examination (8.2%). Few justifications for treatment planning and follow-up, but more in the actual treatment stage, had been recorded. The most common examinations were to assess root resorption and the positions of unerupted teeth, or simply carry out an unspecified control. The estimated risk of developing fatal cancer was considered low. The radiation risk from orthodontic treatment was equivalent to about 5-10 days of natural background radiation. Children and adolescents sometimes undergo multiple radiographic examinations, but despite the low radiation burden, accumulated radiation exposure should be considered and justified in young patients.

CYP Inhibition and Low-Dose Dasatinib for Chronic Myeloid Leukemia: Preliminary Results of a Promising, Cost-Effective Treatment Option

Introduction The standard treatment for newly diagnosed (ND)-CML is tyrosine kinase inhibitors (TKIs) such as dasatinib. However, the cost of treatment with these drugs can be prohibitively high. The CYP inhibition strategy involves intentionally inhibiting a specific enzyme, in this case CYP3A4, to increase plasma concentration of dasatinib and reduce the required dose from 100mg to 25mg daily. Patients and methods Five consecutive patients older than 18 years, with ND-CML in chronic phase and Eastern Cooperative Oncology Group (ECOG) of 0-2.The diagnosis and classification of CML followed the ESMO guidelines. After diagnostic confirmation, patients continuously received half pill of dasatinib (25mg orally daily) and a strong CYP3A4 inhibitor (ketoconazole, 200mg orally twice daily). Patients were monitored weekly during the first month and then monthly after that. The response to treatment was established according to the ESMO guidelines. Statistical analysis We examined the distribution of variables using the Shapiro-Wilk test, and descriptive analyses were conducted for demographic and clinical characteristics. The proportion of hematological and non-hematological side effects and the proportion of hematological response were obtained. To demonstrate the effect of dasatinib on hematological cells, we constructed a line plot showing the values of hemoglobin, leukocytes, and platelets in each visit. We compared basal hemoglobin, leukocytes, and platelets vs. follow-up counts at each visit with the Kruskal-Wallis test Results The median age of the patients was 42 years. All patients had a median ECOG score of 0. Three patients (60%) presented with thrombocytosis, three (60%) with splenomegaly, and two patients (40%) had B symptoms. Basal median (range) hemoglobin, leukocytes, and platelets counts were 9.9 g/dL , 272×10 9/L and 451×10 9/L, respectively. Three patients (60%) had low-risk CML, and two patients (40%) had high-risk disease, with a median EUTOS score of 71 points. Dasatinib treatment was initiated within a median of 9 days from diagnosis. In the first 28 days of treatment, median leukocytes and platelets were significantly reduced compared to baseline, with a reduction in leukocytes of 93.7% (125×10 9/L vs. 7.9×10 9/L, p=0.005) and in platelets of 64.6% (407×10 9/L, vs. 144×10 9/L, p=0.027). Hemoglobin levels significantly increased by the second month of treatment, with an increase of 26.4% from baseline (10.2 g/dL vs. 12.9 g/dL, p=0.023). All patients (100%) achieved major hematological response within a median of 22 days. Patient number 1 achieved the 3-month and 6-month treatment goals with 6.4% and <1% reduction in BCR-ABL transcript levels, respectively. After 3 months of treatment, 60% of patients achieved the BCR/ABL1 transcript level on the IS <10%, which is the optimal response according to guidelines, in the rest of the patients the time of evaluation has not been reached. Mild and self-limited adverse events were reported in 40% of patients at some point in their treatment. Non-hematological toxicity occurred in one patient (20%) with nausea and galactorrhea due to ketoconazole. Hematological toxicity occurred in (20%) of patients; the platelet count returned to normal after suspending ketoconazole for one week. No serious adverse events were reported. Conclusion Apart from this preliminary study, there is currently no evidence supporting the intentional use of CYP inhibition to reduce the dosage and cost of dasatinib for patients with ND-CML. Dasatinib is primarily metabolized using the CYP3A4 isoenzyme, and studies have shown that ketoconazole, an accessible antifungal, can strongly inhibit CYP3A4, increase dasatinib's plasma concentration and AUC by 5-fold and 385%, respectively, and allow for a reduction in dosage while maintaining therapeutic efficacy. The CYP inhibition strategy can decrease the cost of dasatinib to a point where it is cheaper than full-dose imatinib -the cheapest TKI- and represent a treatment option for patients who cannot afford full-dose dasatinib in low income countries. The CYP inhibition strategy can be of added value to the lower effective dose concept and give rise to ultra-low-dose schemes. This strategy could significantly increase dasatinib accessibility in many countries by reducing costs from $1,343.7 to $40.3-$100.8 monthly

Proposing a Clinical Model for RBE Based on Proton Track-End Counts

In proton therapy, the clinical application of linear energy transfer (LET) optimization remains contentious, in part because of challenges associated with the definition and calculation of LET and its exact relationship with relative biological effectiveness (RBE) because of large variation in experimental in vitro data. This has raised interest in other metrics with favorable properties for biological optimization, such as the number of proton track ends in a voxel. In this work, we propose a novel model for clinical calculations of RBE, based on proton track end counts. We developed an effective dose concept to translate between the total proton track-end count per unit mass in a voxel and a proton RBE value. Dose, track end, and dose-averaged LET (LETd) distributions were simulated using Monte Carlo models for a series of water phantoms, in vitro radiobiological studies, and patient treatment plans. We evaluated the correlation between track ends and regions of elevated biological effectiveness in comparison to LETd-based models of RBE. Track ends were found to correlate with biological effects in in vitro experiments with an accuracy comparable to LETd. In patient simulations, our track end model identified the same biological hotspots as predicted by LETd-based radiobiological models of proton RBE. These results suggest that, for clinical optimization and evaluation, an RBE model based on proton track end counts may match LETd-based models in terms of information provided while also offering superior statistical properties.

Organ Dose Reconstruction Applicable for a Japanese Nuclear Worker Cohort: J-EPISODE.

An evaluation of cancer risk based on organ-absorbed dose is underway for the Japanese Epidemiological Study on Low-Dose Radiation Effects (J-EPISODE), which has analyzed health effects in association with radiation exposure evaluated with the personal dose equivalent Hp(10). Although the concept of effective dose and its operational definition of Hp(10) are widely used for radiological protection purposes, effective dose is not recommended for epidemiological evaluation. Organ-absorbed dose was instead adopted for the IARC 15-Country Collaborative study (15-Country study), the International Nuclear Workers Study (INWORKS), the Mayak worker study, and the Life Span Study (LSS) of atomic bomb survivors. The reconstruction method in J-EPISODE followed in principle the approach adopted in the 15-Country Study. As part of the approach of J-EPISODE, a conversion factor from photon dosimeter reading to air kerma was developed using dosimeter response data, which were measured by the experiment using an anthropomorphic phantom, and it was confirmed that the 15-Country study’s assumption of photon energy and geometry distribution in a work environment applied to Japanese nuclear workers. This article focuses on a method for reconstructing the conversion factor from photon dosimeter reading to organ-absorbed photon dose for a Japanese nuclear worker cohort. The model for estimating the conversion factor was defined under the assumption of a lognormal distribution from three concerned bias factors: (1) a dosimeter reading per air kerma, i.e., dosimeter response; (2) an organ-absorbed dose per air kerma; and (3) a factor relating to the differences in dose concepts and calibration practices between the roentgen dosimeter era and the present. Dosimeter response data were cited from the companion paper. Data on organ-absorbed photon dose per air kerma were estimated using a voxel phantom with the average Japanese adult male height and weight. The bias factor for the recorded dose in the roentgen era was defined, considering the backscatter radiation from the human body. The estimated values of organ-absorbed photon dose per air kerma were almost the same as those in ICRP Publication 116, revealing that the effect of differences in body size was almost negligible. The conversion factors from dosimeter reading to organ-absorbed dose were estimated by period (the roentgen era or from then), nuclear facility type (nuclear power plant or other), dosimeter type, and tissue or organ. The estimated conversion factors ranged from 0.7 to 0.9 (Gy Sv−1). The estimated cumulative organ-absorbed photon dose for the participants of J-EPISODE demonstrated that organ-absorbed dose values were approximately 0.8 times the recorded doses if neglecting dose-unit differences. J-EPISODE reconstructed an organ-absorbed dose conversion factor and will evaluate the risk of cancer mortality and morbidity using the organ-absorbed dose in the future.

Clinical Radiobiology of Fast Neutron Therapy: What Was Learnt?

Neutron therapy was developed from neutron radiobiology experiments, and had identified a higher cell kill per unit dose and an accompanying reduction in oxygen dependency. But experts such as Hal Gray were sceptical about clinical applications, for good reasons. Gray knew that the increase in relative biological effectiveness (RBE) with dose fall-off could produce marked clinical limitations. After many years of research, this treatment did not produce the expected gains in tumour control relative to normal tissue toxicity, as predicted by Gray. More detailed reasons for this are discussed in this paper. Neutrons do not have Bragg peaks and so did not selectively spare many tissues from radiation exposure; the constant neutron RBE tumour prescription values did not represent the probable higher RBE values in late-reacting tissues with low α/β values; the inevitable increase in RBE as dose falls along a beam would also contribute to greater toxicity than in a similar megavoltage photon beam. Some tissues such as the central nervous system white matter had the highest RBEs partly because of the higher percentage hydrogen content in lipid-containing molecules. All the above factors contributed to disappointing clinical results found in a series of randomised controlled studies at many treatment centres, although at the time they were performed, neutron therapy was in a catch-up phase with photon-based treatments. Their findings are summarised along with their technical aspects and fractionation choices. Better understanding of fast neutron experiments and therapy has been gained through relatively simple mathematical models—using the biological effective dose concept and incorporating the RBEmax and RBEmin parameters (the limits of RBE at low and high dose, respectively—as shown in the Appendix). The RBE itself can then vary between these limits according to the dose per fraction used. These approaches provide useful insights into the problems that can occur in proton and ion beam therapy and how they may be optimised. This is because neutron ionisations in living tissues are mainly caused by recoil protons of energy proportional to the neutron energy: these are close to the proton energies that occur close to the Bragg peak region. To some extent, neutron RBE studies contain the highest RBE ranges found within proton and ion beams near Bragg peaks. In retrospect, neutrons were a useful radiobiological tool that has continued to inform the scientific and clinical community about the essential radiobiological principles of all forms of high linear energy transfer therapy. Neutron radiobiology and its implications should be taught on training courses and studied closely by clinicians, physicists, and biologists engaged in particle beam therapies.

Evaluating the biologically effective dose (BED) concept using a dynamic tumor simulation model.

To evaluate three different formulae for calculating the biologically effective dose (BED) by use of a multipopulation reaction-diffusion simulation to determine whether these formulae produce equivalent effects for different treatment regimes. The standard BED formula, BEDs , was updated to account both for spacial nonuniformity in dose and for cellular regrowth between fractions, by creating two new formulae: BEDϕ and BEDϕT . These BED formulae were used to calculate dose per fraction values for two, three, and five fraction treatments and to compare the tumor volumes of those treatments to those of a single fraction. A spherical tumor model based on the reaction-diffusion equation was used to calculate the final volume of each tumor 185days after the delivery of the first fraction. The percent difference in volume between single-fraction and multiple-fraction treatments was used as a measure to test the accuracy of each BED formula. Percent differences in volume between single- and multiple-fraction treatment regimes varied up to approximately 18.5% if the dose per fraction was calculated using BEDs but the delivered dose was nonuniform. Proper application of spacial nonuniformity in dose and tumor regrowth correction factors modified the dose per fraction values by no more than 5%, but resulted in the improvement of simulated tumor volumes down to around 2% or lower difference in volume. Treatment regimes with the same BED value should have the same effect. However, small changes in the dose per fraction delivered in multiple-fraction treatments can have a large effect on the tumor volume of a treatment when the dose is delivered nonuniformly or when tumor regrowth between fractions is ignored. Inclusion of these correction factors is important for the underlying assumption that treatments with equal BED will have equal effects on the clinically observed tumor volume.

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions. In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.

Antipsychotic Dose in Acute Schizophrenia: A Meta-analysis.

Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose-response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.

Radiation dose intensity and local tumour control of non-small cell lung cancer: A radiobiological modelling perspective

Several clinical situations call for the use of radiobiological principles as powerful clinical tools. The aim of this project is to examine the effect of radiotherapy dose intensity on local tumour control for non-small cell lung cancer (NSCLC) using the biological effective dose (BED) concept. A two-year tumour control probability (TCP) model was developed based on the linear-quadratic cell concept combined with Poisson statistics. The two-year local control outcome was analysed for the radiotherapy dose using the BEDs. The BED calculations and the TCP model were fitted to a series of NSCLC patients drawn from the literature. The investigation is based on the two-year local tumour control rate for stage I-II NSCLC for a dose fractionation size that varied from 1.5-20 Gy per fraction delivered via three radiotherapy treatments: 3D-conformal radiation therapy (3D-CRT), continuous hyperfractionated accelerated radiotherapy (CHART) and stereotactic ablative body radiotherapy (SABR). The BED values of 2,280 patients were computed and analysed as a function of local tumour control. To quantitatively assess the correlation between the BED and local tumour control, a residuals analysis and linear regression were performed. Higher radiotherapy doses were associated with improved local tumour control and survival rates for NSCLC, as suggested by the coefficient of the correlation R2 statistical test: 0.83 for the 3D-CRT and 0.91 for the SABR treatment.

Combined internal-external radiotherapy (CIERT) in a cell model

Combined internal-external radiotherapy (CIERT) requires a unified assessment of biologic radiation effects in addition to the total dose. The concept of biological effective dose (BED) was evaluated in a cell model. The thyroid NIS-positive cell line FRTL-5 was irradiated with X-ray and the radiotracer Tc-99m pertechnetate either alone or in combination. The cellular uptake of the radionuclide during the incubation time of 24 h was controlled by the presence or absence of perchlorate. Dose calculation was performed based on measured uptake values. Cell specific radiobiologic parameters were derived from dose effect curves using the colony forming assay as biological endpoint. For the combination of the radiation qualities the sequence and time difference were varied. Cell survival was compared with the prediction of the BED model. The radiobiologic parameters from X-ray dose response were α = (0.22 ± 0.02) Gy-1 and β = (0.021 ± 0.001) Gy-2. The half life for repair was (1.51 ± 0.21) h. These values could also explain the dose response curves for Tc-99m-irradiation with exponential decreasing dose rate. CIERT experiments showed no significant differences in cell survival regarding sequence and irradiation break. When the radionuclide uptake was not prevented the cell survival for the combination of X-ray and Tc-99m was lower than the prediction by BED calculations. The validity of the BED formalism for different dose rates and radiation qualities was verified. Supraaddive effects measured in the combination of X-ray and intracellular Tc-99m might be caused by Auger and conversion electrons, however further experiments are necessary.

The evolution of practical radiobiological modelling.

A summary of the key aspects of radiobiological modelling is provided, based on the theoretical and practical concepts of the linear quadratic model, which gradually replaced other numerical approaches. The closely related biological effective dose concept is useful in many clinical applications. Biological effective dose formulations in conventional photon-based radiotherapy continue to be developed, and can be extended to the now increasingly used proton and ion-beam therapy, to very low or high dose ranges, the dose rate effect, hypoxia and repopulation. Such established and new research developments will be of interest to clinicians, physicists and biologists to better understand the processes underlying radiotherapy and assist their collaborative efforts to make radiotherapy safer and more effective.

The Radiobiology of Proton Therapy: Challenges and Opportunities Around Relative Biological Effectiveness

With the current UK expansion of proton therapy there is a great opportunity for clinical oncologists to develop a translational interest in the associated scientific base and clinical results. In particular, the underpinning controversy regarding the conversion of photon dose to proton dose by the relative biological effectiveness (RBE) must be understood, including its important implications. At the present time, the proton prescribed dose includes an RBE of 1.1 regardless of tissue, tumour and dose fractionation. A body of data has emerged against this pragmatic approach, including a critique of the existing evidence base, due to choice of dose, use of only acute-reacting in vivo assays, analysis methods and the reference radiations used to determine the RBE. Modelling systems, based on the best available scientific evidence, and which include the clinically useful biological effective dose (BED) concept, have also been developed to estimate proton RBEs for different dose and linear energy transfer (LET) values. The latter reflect ionisation density, which progressively increases along each proton track. Late-reacting tissues, such as the brain, where α/β = 2 Gy, show a higher RBE than 1.1 at a low dose per fraction (1.2–1.8 Gy) at LET values used to cover conventional target volumes and can be much higher. RBE changes with tissue depth seem to vary depending on the method of beam delivery used. To reduce unexpected toxicity, which does occasionally follow proton therapy, a more rational approach to RBE allocation, using a variable RBE that depends on dose per fraction and the tissue and tumour radiobiological characteristics such as α/β, is proposed.

Appropriate Use of Effective Dose in Radiation Protection and Risk Assessment.

Effective dose was introduced by the ICRP for the single, over-arching purpose of setting limits for radiation protection. Effective dose is a derived quantity or mathematical construct and not a physical, measurable quantity. The formula for calculating effective dose to a reference model incorporates terms to account for all radiation types, organ and tissue radiosensitivities, population groups, and multiple biological endpoints. The properties and appropriate applications of effective dose are not well understood by many within and outside the health physics profession; no other quantity in radiation protection has been more confusing or misunderstood. According to ICRP Publication 103, effective dose is to be used for "prospective dose assessment for planning and optimization in radiological protection, and retrospective demonstration of compliance for regulatory purposes." In practice, effective dose has been applied incorrectly to predict cancer risk among exposed persons. The concept of effective dose applies generally to reference models only and not to individual subjects. While conceived to represent a measure of cancer risk or heritable detrimental effects, effective dose is not predictive of future cancer risk. The formula for calculating effective dose incorporates committee-selected weighting factors for radiation quality and organ sensitivity; however, the organ weighting factors are averaged across all ages and both genders and thus do not apply to any specific individual or radiosensitive subpopulations such as children and young women. Further, it is not appropriate to apply effective dose to individual medical patients because patient-specific parameters may vary substantially from the assumptions used in generalized models. Also, effective dose is not applicable to therapeutic uses of radiation, as its mathematical underpinnings pertain only to observed late (stochastic) effects of radiation exposure and do not account for short-term adverse tissue reactions. The weighting factors incorporate substantial uncertainties, and linearity of the dose-response function at low dose is uncertain and highly disputed. Since effective dose is not predictive of future cancer incidence, it follows that effective dose should never be used to estimate future cancer risk from specific sources of radiation exposure. Instead, individual assessments of potential detriment should only be based on organ or tissue radiation absorbed dose, together with best scientific understanding of the corresponding dose-response relationships.

Defining an additivity framework for mixture research in inducible whole-cell biosensors.

A novel additivity framework for mixture effect modelling in the context of whole cell inducible biosensors has been mathematically developed and implemented in R. The proposed method is a multivariate extension of the effective dose (EDp) concept. Specifically, the extension accounts for differential maximal effects among analytes and response inhibition beyond the maximum permissive concentrations. This allows a multivariate extension of Loewe additivity, enabling direct application in a biphasic dose-response framework. The proposed additivity definition was validated, and its applicability illustrated by studying the response of the cyanobacterial biosensor Synechococcus elongatus PCC 7942 pBG2120 to binary mixtures of Zn, Cu, Cd, Ag, Co and Hg. The novel method allowed by the first time to model complete dose-response profiles of an inducible whole cell biosensor to mixtures. In addition, the approach also allowed identification and quantification of departures from additivity (interactions) among analytes. The biosensor was found to respond in a near additive way to heavy metal mixtures except when Hg, Co and Ag were present, in which case strong interactions occurred. The method is a useful contribution for the whole cell biosensors discipline and related areas allowing to perform appropriate assessment of mixture effects in non-monotonic dose-response frameworks

Investigation of smoke gases and temperatures during car fire – large‐scale and small‐scale tests and numerical investigations

SummaryThe hazards for passengers during vehicle fires result from the increasing temperature and the emitted smoke gases. A fire was set on a car to investigate the development of temperature and of gaseous fire products in the passenger compartment. The study was based on a full‐scale test with a reconstructed scene of a serious car fire. The aim of this work was to identify the conditions for self‐rescuing of passengers during a car fire. A dummy, equipped with several thermocouples, was placed on the driver's seat. Also, the smoke gases were continuously collected through a removable probe sensor corresponding to the nose of the dummy in the passenger compartment and analyzed using Fourier transform infrared spectroscopy. Additionally, several car components were investigated in the smoke density chamber (smoke emission and smoke gas composition). It was found that the toxic gases already reached hazardous levels by 5 min, while the temperatures at the dummy were at that time less than 80 °C. The toxicity of smoke gases was assessed using the fractional effective dose concept. The various experimentally parameters (temperature and smoke gas composition) were implemented into numerical simulations with fire dynamics simulator. Both the experimental data and the numerical simulations are presented and discussed. Copyright © 2015 John Wiley & Sons, Ltd.

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.

Estimating effective dose from 3D imaging with interventional fluoroscopy systems using limited exposure data.

Estimations of the effective dose from three-dimensional (3D) rotational imaging with interventional fluoroscopy systems are hampered by the fact that not all systems provide individual exposure values for each projection image included in the examination. To investigate the error in resulting effective dose introduced by not using individual exposure values for each projection image in the dose calculations for 3D rotational imaging with interventional fluoroscopy systems. An interventional fluoroscopy system was used to acquire images of two anthropomorphic phantoms. Calculations of the effective dose were performed using two different methods: 1, using individual exposure values for each projection image; and 2, using the mean tube voltage and the total dose-area product (DAP), evenly distributed over a selection of projection images. The second method was also tested in hypothetical examinations to investigate the effects of worst-case scenarios regarding the effect of exposure asymmetry on the error. The error in resulting effective dose obtained when simplifying the dose calculations by using Method 2 instead of Method 1 was within ±14%. The error increased slightly for the worst-case scenarios but was still smaller than ±20%, regardless of anatomical region, tube voltage variation, and patient size. Given the uncertainties associated with the effective dose concept as well as of reported DAP values, the present study indicates that dose calculations based on average exposure values distributed over a smaller selection of projection angles can provide reasonably accurate estimations of the radiation doses from 3D imaging using interventional fluoroscopy systems.

Evaluation of Second Cancer Induction Risk by CT Follow-up in Oncological Long-surviving Patients

The goal of establishing prompt localization of the malignant spread or recurrence of a tumor has found a powerful solution in the definition of follow-up protocols, which include the indication for CT scans on an annual or semiannual basis. In the case of long-surviving patients, however, this approach will lead to a considerable integrated dose level over a period of several years after recovery from the illness. Pathologies treated primarily by surgery and/or chemotherapy have been considered, not taking into account cancers treated with adjuvant or radical radiotherapy. Given that the most likely protocols for these cancers often call for total body scans, an estimation of the consequent effective and organ doses can be performed with acceptable accuracy. The data acquired from five centers have been collected and the related effective and organ doses calculated by means of IMPACT software. Use of the effective dose concept, however, has lately become the subject of criticism, and the recently proposed Effective Risk Model has therefore also been applied. The evaluated absolute additional risk of second tumor induction ranges between 0.1% and 10%, depending primarily on age and pathology. These results depict this additional risk as an issue of significant importance for clinical practice. A revision of follow-up and scan parameter protocols, as well as the introduction of new algorithms for dose reduction, could significantly improve the risk-benefit ratio for all the pathologies studied.