Effects of ionising radiation exposure in offspring and next generations: dosimetric aspects and uncertainties.

PURPOSE: The impact of the exposure to ionizing radiation in the offspring and next generation has been investigated in the last decades and currently is the subject of study of the ICRP Task Group 121. Studying the effects of radiation exposure in pre-conceptional and post-conceptional phases can be a challenge since potential effects to the fetus vary depending on the stage of fetal development. Epidemiology and radiobiology studies are the two sources of information one can use to correlate the radiation dose to the human body and tissues and the resulting effects. For a proper evaluation of the outcomes of such studies, and a correct appraisal of the exposure/dose-effect relationship, (i) reliable dosimetry, (ii) accurate reporting, and (iii) reproducibility of results are required. Although variables related to dose, including for instance source of radiation, geometry of irradiation, dose rate etc., are usually known, especially in radiobiology studies, often important details of the irradiation are not reported. CONCLUSIONS: Based on standards developed by the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Disease (NIAID) and the National Institute of Standards and Technology (NIST), a review of the scientific studies used by the UNSCEAR to estimate the risk of hereditary effects, and by the ICRP in its current recommendations, was conducted to evaluate the way dosimetry was reported. Dosimetry and the related uncertainties were not adequately described in the vast majority of those studies. This does not necessarily mean that they do not provide relevant information, however it prevents from a thorough verification and reproduction of their findings. In order to guarantee the reliability and robustness of the process of revision of the estimates of risk and detriment it is therefore considered mandatory to include a careful check of the new relevant literature with regard to the criteria on the completeness and reproducibility of the dosimetric information.

Modelling DTPA therapy following Am contamination in rats.

A major challenge in modelling the decorporation of actinides (An), such as americium (Am), with DTPA (diethylenetriaminepentaacetic acid) is the fact that standard biokinetic models become inadequate for assessing radionuclide intake and estimating the resulting dose, as DTPA perturbs the regular biokinetics of the radionuclide. At present, most attempts existing in the literature are empirical and developed mainly for the interpretation of one or a limited number of specific incorporation cases. Recently, several approaches have been presented with the aim of developing a generic model, one of which reported the unperturbed biokinetics of plutonium (Pu), the chelation process and the behaviour of the chelated compound An-DTPA with a single model structure. The aim of the approach described in this present work is the development of a generic model that is able to describe the biokinetics of Am, DTPA and the chelate Am-DTPA simultaneously. Since accidental intakes in humans present many unknowns and large uncertainties, data from controlled studies in animals were used. In these studies, different amounts of DTPA were administered at different times after contamination with known quantities of Am. To account for the enhancement of faecal excretion and reduction in liver retention, DTPA is assumed to chelate Am not only in extracellular fluids, but also in hepatocytes. A good agreement was found between the predictions of the proposed model and the experimental results for urinary and faecal excretion and accumulation and retention in the liver. However, the decorporation from the skeletal compartment could not be reproduced satisfactorily under these simple assumptions.

Pediatric computed tomography doses in Germany from 2016 to 2018 based on large-scale data collection.

PURPOSE: Accumulating evidence from epidemiological studies that pediatric computed tomography (CT) examinations can be associated with a small but non-zero excess risk for developing leukemia or brain tumor highlights the need to optimize doses of pediatric CT procedures. Mandatory dose reference levels (DRL) can support reduction of collective dose from CT imaging. Regular surveys of applied dose-related parameters are instrumental to decide when technological advances and optimized protocol design allow lower doses without sacrificing image quality. Our aim was to collect dosimetric data to support adapting current DRL to changing clinical practice. METHOD: Dosimetric data and technical scan parameters from common pediatric CT examinations were retrospectively collected directly from Picture Archiving and Communication Systems (PACS), Dose Management Systems (DMS), and Radiological Information Systems (RIS). RESULTS: We collected data from 17 institutions on 7746 CT series from the years 2016 to 2018 from examinations of the head, thorax, abdomen, cervical spine, temporal bone, paranasal sinuses and knee in patients below 18 years of age. Most of the age-stratified parameter distributions were lower than distributions from previously-analyzed data from before 2010. Most of the third quartiles were lower than German DRL at the time of the survey. CONCLUSIONS: Directly interfacing PACS, DMS, and RIS installations allows large-scale data collection but relies on high data-quality at the documentation stage. Data should be validated by expert knowledge or guided questionnaires. Observed clinical practice in pediatric CT imaging suggests lowering some DRL in Germany is reasonable.

A revised compartmental model for biokinetics and dosimetry of 2-[18F]FDG.

BACKGROUND: The aim was to review available biokinetic data, collect own experimental data, and propose an updated compartmental model for 2-[18F]FDG in the frame of the revision of the ICRP report on dose coefficients for radiopharmaceuticals used in diagnostic nuclear medicine. METHODS: The compartmental model was developed based on published biokinetic data for 2-[18F]FDG. Additional data on urinary excretion in 23 patients (11 males, 12 females) undergoing whole-body PET/CT examinations were obtained within this study. The unknown biokinetic model parameters were derived using the software SAAM II and verified with a modified version of IDAC-Iodide. Dose coefficients for reference adults were calculated with the programme IDAC-Dose 2.1. A dynamic bladder model was employed for urinary bladder dosimetry. RESULTS: The proposed model consists of following compartments: blood, heart wall, brain, liver, lungs, pancreas, spleen, kidneys, urinary bladder content and a generic pool compartment "Other". The latter was introduced to account for 2-[18F]FDG in body organ and tissues besides the explicitly modelled ones. The model predictions showed a good agreement with experimental data. Urinary bladder wall received the highest absorbed dose coefficient of 7.5E-02 mGy/MBq under the assumption of initial urine volume of 100 ml, first voiding at 45 min p.i. and 3.75 h voiding intervals thereafter. The effective dose coefficient calculated according to the current dosimetry framework of ICRP amounted to 1.7E-02 mSv/MBq, compared to 1.9E-02 mSv/MBq in ICRP Publication 128. CONCLUSION: A compartmental model for 2-[18F]FDG was proposed and will be used to replace the descriptive biokinetic model of ICRP Publication 128. The revised model and the provided dose coefficients are expected to improve reference dosimetry for patients administered with 2-[18F]FDG.

Radiation field and dose inhomogeneities using an X-ray cabinet in radiation biology research.

PURPOSE: X-ray cabinets are replacing 137 Cs/60 Co sources in radiation biology research due to advantages in size, handling, and radiation protection. However, because of their different physical properties, X-ray cabinets are more susceptible to experimental influences than conventional sources. The aim of this study was to examine the variations related to the experimental setups typically used to investigate biological radiation effects with X-ray cabinets. MATERIALS AND METHODS: A combined approach of physical dose measurements by thermoluminescence dosimetry and detection of biological effects by quantification of γH2AX and 53BP1 foci was used to analyze field inhomogeneity and evaluate the influence of the components of the experimental setup. RESULTS: Irradiation was performed using an X-ray tube (195 kV, 10 mA, 0.5-mm-thick copper filter, dose rate of 0.59 Gy/min). Thermoluminescence dosimetry revealed inhomogeneity and a dose decrease of up to 42.3% within the beam area (diameter 31.1 cm) compared to the dose at the center. This dose decrease was consistent with the observed decline in the number of radiation-induced foci by up to 55.9 %. Uniform dose distribution was measured after reducing the size of the radiation field (diameter 12.5 cm). However, when using 15-ml test tubes placed at different positions within this field, the dose decreased by up to 17% in comparison to the central position. Analysis of foci number revealed significant differences between the tubes for γH2AX (1 h) and 53BP1 (4 h) at different time points after irradiation. Neither removal of some tubes nor of the caps improved the dose decrease significantly. By contrast, when using 1.5-ml tubes, dose differences were less than 4%, and no significant differences in foci number were detected. CONCLUSION: X-ray cabinets are user-friendly irradiation units for investigating biological radiation effects. However, field inhomogeneities and experimental setup components considerably affect the delivered irradiation doses. For this reason, strict dosimetric monitoring of experimental irradiation setups is mandatory for reliable studies.

Method to quickly and accurately calculate absorbed dose from therapeutic and stray photon exposures throughout the entire body in individual patients.

PURPOSE: Photon radiotherapy techniques typically devote considerable attention to limiting the exposure of healthy tissues outside of the target volume. Numerous studies have shown, however, that commercial treatment planning systems (TPSs) significantly underestimate the absorbed dose outside of the treatment field. The purpose of this study was to test the feasibility of quickly and accurately calculating the total absorbed dose to the whole body from photon radiotherapy in individual patients. METHODS: We created an extended TPS by implementing a physics-based analytical model for the absorbed dose from stray photons during photon therapy into a research TPS. We configured and validated the extended TPS using measurements of 6- and 15-MV photon beams in water-box and anthropomorphic phantoms. We characterized the additional computation time required for therapeutic and stray dose calculations in a 44 × 30 × 180 cm3 water-box phantom. RESULTS: The extended TPS achieved superior dosimetric accuracy compared to the research TPS in both water and anthropomorphic phantoms, especially outside of the primary treatment field. In the anthropomorphic phantom, the extended TPS increased the generalized gamma index passing rate by a factor of 10 and decreased the median dosimetric discrepancy in the out-of-field region by a factor of 26. The extended TPS achieved an average discrepancy <1% in and near the treatment field and <1 mGy/Gy far from the treatment field in the anthropomorphic phantom. Characterization of computation time revealed that on average, the extended TPS only required 7% longer than the research TPS to calculate the total absorbed dose. CONCLUSIONS: The results of this work suggest that it is feasible to quickly and accurately calculate whole-body doses inside and outside of the therapeutic treatment field in individual patients on a routine basis using physics-based analytical dose models. This additional capability enables a more personalized approach to minimizing the risk of radiogenic late effects, such as second cancer and cardiac toxicity, as part of the treatment planning process.

Current knowledge on radon risk: implications for practical radiation protection? radon workshop, 1/2 December 2015, Bonn, BMUB (Bundesministerium für Umwelt, Naturschutz, Bau und Reaktorsicherheit; Federal Ministry for the Environment, Nature Conservation, Building and Nuclear Safety).

ICRP suggested a strategy based on the distinction between a protection approach for dwellings and one for workplaces in the previous recommendations on radon. Now, the Commission recommends an integrated approach for the protection against radon exposure in all buildings irrespective of their purpose and the status of their occupants. The strategy of protection in buildings, implemented through a national action plan, is based on the application of the optimisation principle below a derived reference level in concentration (maximum 300 Bq m(-3)). A problem, however, arises that due to new epidemiological findings and application of dosimetric models, ICRP 115 (Ann ICRP 40, 2010) presents nominal probability coefficients for radon exposure that are approximately by a factor of 2 larger than in the former recommendations of ICRP 65 (Ann ICRP 23, 1993). On the basis of the so-called epidemiological approach and the dosimetric approach, the doubling of risk per unit exposure is represented by a doubling of the dose coefficients, while the risk coefficient of ICRP 103 (2007) remains unchanged. Thus, an identical given radon exposure situation with the new dose coefficients would result in a doubling of dose compared with the former values. This is of serious conceptual implications. A possible solution of this problem was presented during the workshop.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

Developing a physiologically based approach for modeling plutonium decorporation therapy with DTPA.

PURPOSE: To develop a physiologically based compartmental approach for modeling plutonium decorporation therapy with the chelating agent Diethylenetriaminepentaacetic acid (Ca-DTPA/Zn-DTPA). MATERIALS AND METHODS: Model calculations were performed using the software package SAAM II (©The Epsilon Group, Charlottesville, Virginia, USA). The Luciani/Polig compartmental model with age-dependent description of the bone recycling processes was used for the biokinetics of plutonium. RESULTS: The Luciani/Polig model was slightly modified in order to account for the speciation of plutonium in blood and for the different affinities for DTPA of the present chemical species. The introduction of two separate blood compartments, describing low-molecular-weight complexes of plutonium (Pu-LW) and transferrin-bound plutonium (Pu-Tf), respectively, and one additional compartment describing plutonium in the interstitial fluids was performed successfully. CONCLUSIONS: The next step of the work is the modeling of the chelation process, coupling the physiologically modified structure with the biokinetic model for DTPA. RESULTS of animal studies performed under controlled conditions will enable to better understand the principles of the involved mechanisms.

A compartmental model for biokinetics and dosimetry of 18F-choline in prostate cancer patients.

UNLABELLED: PET with (18)F-choline ((18)F-FCH) is used in the diagnosis of prostate cancer and its recurrences. In this work, biodistribution data from a recent study conducted at Skåne University Hospital Malmö were used for the development of a biokinetic and dosimetric model. METHODS: The biodistribution of (18)F-FCH was followed for 10 patients using PET up to 4 h after administration. Activity concentrations in blood and urine samples were also determined. A compartmental model structure was developed, and values of the model parameters were obtained for each single patient and for a reference patient using a population kinetic approach. Radiation doses to the organs were determined using computational (voxel) phantoms for the determination of the S factors. RESULTS: The model structure consists of a central exchange compartment (blood), 2 compartments each for the liver and kidneys, 1 for spleen, 1 for urinary bladder, and 1 generic compartment accounting for the remaining material. The model can successfully describe the individual patients' data. The parameters showing the greatest interindividual variations are the blood volume (the clearance process is rapid, and early blood data are not available for several patients) and the transfer out from liver (the physical half-life of (18)F is too short to follow this long-term process with the necessary accuracy). The organs receiving the highest doses are the kidneys (reference patient, 0.079 mGy/MBq; individual values, 0.033-0.105 mGy/MBq) and the liver (reference patient, 0.062 mGy/MBq; individual values, 0.036-0.082 mGy/MBq). The dose to the urinary bladder wall of the reference patient varies between 0.017 and 0.030 mGy/MBq, depending on the assumptions on bladder voiding. CONCLUSION: The model gives a satisfactory description of the biodistribution of (18)F-FCH and realistic estimates of the radiation dose received by the patients.

Nonlinear compartmental model of 18F-choline.

INTRODUCTION: This work develops a compartmental model of (18)F-choline in order to evaluate its biokinetics and so to describe the temporal variation of the radiopharmaceuticals' uptake in and clearance from organs and tissues. METHODS: Ten patients were considered in this study. A commercially available tool for compartmental analysis (SAAM II) was used to model the values of activity concentrations in organs and tissues obtained from PET images or from measurements of collected blood and urine samples. RESULTS: A linear compartmental model of the biokinetics of the radiopharmaceutical was initially developed. It features a central compartment (blood) exchanging with organs. The structure describes explicitly liver, kidneys, spleen, blood and urinary excretion. The linear model tended to overestimate systematically the activity in the liver and in the kidney compartments in the first 20 min post-administration. A nonlinear process of kinetic saturation was considered, according to the typical Michaelis-Menten kinetics. Therefore nonlinear equations were added to describe the flux of (18)F-choline from blood to liver and from blood to kidneys. The nonlinear model showed a tendency for improvement in the description of the activity in liver and kidneys, but not for the urine. CONCLUSIONS: The simple linear model presented is not able to properly describe the biokinetics of (18)F-choline as measured in prostatic cancer patients. The introduction of nonlinear kinetics, although based on physiologically plausible assumptions, resulted in nonsignificant improvements of the model predictive power.

The CONRAD approach to biokinetic modeling of DTPA decorporation therapy.

Diethylene Triamine Pentaacetic Acid (DTPA) is used for decorporation of plutonium because it is known to be able to enhance its urinary excretion for several days after treatment by forming stable Pu-DTPA complexes. The decorporation prevents accumulation in organs and results in a dosimetric benefit, which is difficult to quantify from bioassay data using existing models. The development of a biokinetic model describing the mechanisms of actinide decorporation by administration of DTPA was initiated as a task in the European COordinated Network on RAdiation Dosimetry (CONRAD). The systemic biokinetic model from Leggett et al. and the biokinetic model for DTPA compounds of International Commission on Radiological Protection Publication 53 were the starting points. A new model for biokinetics of administered DTPA based on physiological interpretation of 14C-labeled DTPA studies from literature was proposed by the group. Plutonium and DTPA biokinetics were modeled separately. The systems were connected by means of a second order kinetics process describing the chelation process of plutonium atoms and DTPA molecules to Pu-DTPA complexes. It was assumed that chelation only occurs in the blood and in systemic compartment ST0 (representing rapid turnover soft tissues), and that Pu-DTPA complexes and administered forms of DTPA share the same biokinetic behavior. First applications of the CONRAD approach showed that the enhancement of plutonium urinary excretion after administration of DTPA was strongly influenced by the chelation rate constant. Setting it to a high value resulted in a good fit to the observed data. However, the model was not yet satisfactory since the effects of repeated DTPA administration in a short time period cannot be predicted in a realistic way. In order to introduce more physiological knowledge into the model several questions still have to be answered. Further detailed studies of human contamination cases and experimental data will be needed in order to address these issues. The work is now continued within the European Radiation Dosimetry Group, EURADOS.

(177)Lu- labeled MOv18 as compared to (131)I- or (90)Y-labeled MOv18 has the better therapeutic effect in eradication of alpha folate receptor-expressing tumor xenografts.

INTRODUCTION: The mouse monoclonal antibody MOv18, directed against the alpha-isoform of folate receptor (FR), was investigated to identify the optimal radioconjugate for radioimmunotherapy of minimal residual disease in ovarian cancer. METHODS: Pharmacokinetics, biodistribution, long-term therapeutic efficacy and toxicity of MOv18, labeled with the beta-emitters (131)I, (90)Y and (177)Lu, were compared in a xenografted mouse model, composed by two cell lines, A431FR and A431MK, differing only for FR expression. RESULTS: A shorter blood clearance and a higher tumor uptake were observed for (90)Y- and (177)Lu- compared to (131)I-MOv18, and a shorter blood pharmacokinetics was recorded in A431FR-bearing animals. At equitoxic maximum tolerable doses, the general irradiation by (131)I- and (90)Y-MOv18 gives rise to strong targeted effects on A431FR and nontargeted effects on A431MK tumors, while (177)Lu-MOv18 was able to eradicate small size tumor masses expressing the antigen of interest exerting only mild non-targeted effects. CONCLUSION: (177)Lu-MOv18 at the maximal tolerated dose is the immunoradioconjugate with the best therapeutic window in experimental conditions of small tumor volume.

90Y Labeling of monoclonal antibody MOv18 and preclinical validation for radioimmunotherapy of human ovarian carcinomas.

The monoclonal antibody (mAb) MOv18 binds the membrane alpha isoform of the folate receptor (FR) which is overexpressed in human ovarian carcinoma cells. Exploiting the targeting capacity of this mAb, we developed and preclinically validated a protocol for the stable labeling of the mAb with 90Y, an isotope which has shown promise in cancer radioimmunotherapy. MOv18 was derivatized with the stable macrocyclic ligand p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (Bz-DOTA). MOv18-Bz-DOTA conjugates were labeled with 90Y or 111In under metal-free and good laboratory practice conditions. At the optimal Bz-DOTA/mAb derivatization ratio of 4-5, conjugates maintained binding activity up to 6 months, were efficiently labeled with 90Y or 111In (mean labeling yield 85 and 64%, associated to a final mean specific activity of 74 and 37 MBq/mg) and displayed a mean immunoreactivity of 60 and 58%, respectively. The radiolabeled preparations were stable in human serum, with >97% radioactivity associated to mAb at 48 h after labeling. The ability of 90Y- and 111In-MOv18 to localize FR on tumors in vivo was analyzed in nude mice bearing tumors induced by isogenic cell lines differing only in the presence or absence of the relevant antigen [A431FR (FR-positive) and A431tMock (FR-negative)]. In vivo biodistribution in organs other than tumor was comparable in non-tumor-, A431tMock- and A431FR-bearing mice, whereas the median tumor uptake of the radiolabeled reagents, expressed as area under the curve (AUC) and maximum uptake (Umax), was significantly higher (sixfold to sevenfold) in A431FR than in A431tMock tumors (P=0.0465 and P=0.0332, respectively). Mean maximum uptake (% ID/g) for 90Y-MOv18 was 53.7 and 7.4 in A431FR and A431tMock respectively; corresponding values for 111In-Mov18 were 45.0 and 11.3. These data demonstrate the feasibility of 90Y-labeling of MOv18 without compromising antibody binding ability and the immunoreagent-specific localization in vivo on FR-expressing tumors, suggesting the suitability of 90Y-MOv18 for clinical studies.