Search NASA⌕ Search

SEARCH · Search NASA

Results for “dosing”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.

Oncology↗
DOE OSTI2025

Reconstructing Hanford worker external doses from photons for epidemiology

The accurate reconstruction of external photon doses is essential for credible radiation epidemiology. This article presents the methodology used to derive dose estimates for 37 012 Hanford Site workers included in the Million Person Study. The approach employs historical dose records from the Hanford Radiation Exposure database and a previous epidemiology study. Bias correction factors specific to dosimeter type and period of use were applied and missing annual doses were estimated using a hierarchical nearby method to estimate deep dose equivalent for each worker. For early years with limited detection sensitivity, missed doses were quantified based on expected time-period-specific, low-dose statistical distributions. The revised dose estimates resulted in lower median and mean career doses than unadjusted data, while increasing the number of person-years with nonzero dose. Sensitivity analyses assessed the influence of bias in dosimetry measurements, missed doses and gap years on dose estimates. Differences in cumulative dose estimates between unadjusted and revised annual estimates are most prominent in the early operational years due to the highest bias during that time period.

dose reconstruction↗
DOE OSTI2024

Influence of neutron cross-section resonances on organ/tissue equivalent and effective dose coefficients for the ICRP voxel phantoms

The materials which compose the ICRP Voxel phantoms used in the computation of conversion coefficients involve neutron interaction cross-sections that have resonances at specific energies. Depending on the energy bin structure used in the computations, these cross-section resonances may occur at energies that fall between energies at which dose coefficients are computed, thus their effects may not be completely accounted for in the reported coefficients. Here In this study, a highly refined energy grid that closely follows the resonance structure in the phantom material cross-sections was identified and used to calculate dose coefficients. Both the equivalent organ/tissue doses for male and female voxel phantoms were computed as well as their summation to obtain the effective dose coefficients. The used refined energy grid tracks very closely the cross-sections in the vicinity of the resonances. The resulting refined energy grid coefficients are compared to coefficients for the coarser energy grid used in ICRP Publication 116. Additionally, reference spectra have been folded with both the fine and coarse sets of conversion coefficients. The resulting total effective doses for these reference spectra are used to assess the adequacy of the dose coefficients calculated on the original ICRP 116 energy grid. The dose coefficients were similarly computed for the local skin dose on the trunk of the body using the ICRU Report 95 phantom. The overall impact of the resonances on the organ/tissue equivalent dose, the effective dose, and the local skin dose are presented and discussed. In general, it was found that resonances can impact neutron dose coefficients, but in most cases the wide range of neutron energies encountered minimized this effect. The impact of resonances was further limited when computing effective dose due to organ/tissue summing and sex-averaging. For the neutron fields studied here, the impact was below 5%.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Dose-finding studies in drug development for rare genetic diseases

The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Comparison of All Solid Cancer Mortality and Incidence Dose-Response in the Life Span Study of Atomic Bomb Survivors, 1958–2009

Recent analysis of all solid cancer incidence (1958–2009) in the Life Span Study (LSS) revealed evidence of upward curvature in the radiation dose response among males but not females. Upward curvature in sex-averaged excess relative risk (ERR) for all solid cancer mortality (1950–2003) was also observed in the 0–2 Gy dose range. As reasons for non-linearity in the LSS are not completely understood, we conducted dose response analyses for all solid cancer mortality and incidence applying similar methods (1958–2009 follow-up, DS02R1 doses, including subjects notin-city (NIC) at the time of the bombing) and statistical models. Incident cancers were ascertained from Hiroshima and Nagasaki cancer registries, while cause of death was ascertained from death certificates over entire Japan. The study included 105,444 LSS subjects who were alive and not known to have cancer before Jan 1, 1958 (80,205 with dose estimates and 25,239 NIC subjects). Between 1958 and 2009, there were 3.1 million person-years (PY) and 22,538 solid cancers for incidence analysis and 3.8 million PY and 15,419 solid cancer deaths for mortality analysis. We fitted sex-specific ERR models adjusted for smoking to both types of data. Over the entire range of doses, solid cancer mortality dose response exhibited a borderline significant upward curvature among males (P=0.062) and significant upward curvature among females (P=0.010); for solid cancer incidence, as before, we found a significant upward curvature among males (P=0.001) but not among females (P=0.624). The sex difference in magnitude of dose response curvature was statistically significant for cancer incidence (P=0.017) but not for cancer mortality (P=0.781). The results of analyses in the 0–2 Gy range and restricted lower dose ranges generally supported inferences made about the sex-specific dose response shape over the entire range of doses for each outcome. Patterns of sex-specific curvature by calendar period (1958–1987 vs 1988–2009) and age at exposure (0–19 vs 20–83) varied between mortality and incidence data, particularly among females, although for each outcome there was an indication of curvature among 0–19 year old male survivors in both calendar periods and among 0–19 year old female survivors in the recent period. Collectively, our findings indicate that the upward curvature in all solid cancer dose response in the LSS is neither specific to males nor to incidence data; it appears to depend on composition of case series and age at exposure or time. Further follow-up and site-specific analyses of cancer mortality and incidence will be important to confirm the emerging trend in dose response curvature among young survivors and unveil the contributing factors and sites.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2021

Dose-Rate Effects of Protons and Light Ions for DNA Damage Induction, Survival and Transformation in Apparently Normal Primary Human Fibroblasts

In this work, we report on effects of low-dose exposures of accelerated protons delivered at high-dose rate (HDR) or a simulated solar-particle event (SPE) like low-dose rate (LDR) on immediate DNA damage induction and processing, survival and in vitro transformation of low passage NFF28 apparently normal primary human fibroblasts. Cultures were exposed to 50, 100 and 1,000 MeV monoenergetic protons in the Bragg entrance/plateau region and cesium-137 γ rays at 20 Gy/h (HDR) or 1 Gy/h (LDR). DNA double-strand breaks (DSB) and clustered DNA damages (containing oxypurines and abasic sites) were measured using transverse alternating gel electrophoresis (TAFE) and immunocytochemical detection/scoring of colocalized γ-H2AX pS139/53BP1 foci, with their induction being linear energy transfer (LET) dependent and dose-rate sparing observed for the different damage classes. Relative biological effectiveness (RBE) values for cell survival after proton irradiation at both dose-rates ranged from 0.61–0.73. Transformation RBE values were dose-rate dependent, ranging from ~1.8–3.1 and ~0.6–1.0 at low doses (≤30 cGy) for HDR and LDR irradiations, respectively. However peak transformation frequencies were significantly higher (1.3–7.3-fold) for higher doses of 0.5–1 Gy delivered at SPE-like LDR. Cell survival and transformation frequencies measured after low-dose 500 MeV/n He-4, 290 MeV/n C-12 and 600 MeV/n Si-28 ion irradiations also showed an inverse dose-rate effect for transformation at SPE-like LDR. This work demonstrates the existence of inverse dose-rate effects for proton and light-ion-induced postirradiation cell survival and in vitro transformation for space mission-relevant doses and dose rates.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Fundamentals of wildlife dosimetry and lessons learned from a decade of measuring external dose rates in the field

Methods for determining the radiation dose received by exposed biota require major improvements to reduce uncertainties and increase precision. We share our experiences in attempting to quantify external dose rates to free-ranging wildlife using GPS-coupled dosimetry methods. The manuscript is a primer on fundamental concepts in wildlife dosimetry in which the complexities of quantifying dose rates are highlighted, and lessons learned are presented based on research with wild boar and snakes at Fukushima, wolves at Chornobyl, and reindeer in Norway. GPS-coupled dosimeters produced empirical data to which numerical simulations of external dose using computer software were compared. Our data did not support a standing paradigm in risk analyses: Using averaged soil contaminant levels to model external dose rates conservatively overestimate the dose to individuals within a population. Following this paradigm will likely lead to misguided recommendations for risk management. The GPS-dosimetry data also demonstrated the critical importance of how modeled external dose rates are impacted by the scale at which contaminants are mapped. When contaminant mapping scales are coarse even detailed knowledge about each animal’s home range was inadequate to accurately predict external dose rates. Importantly, modeled external dose rates based on a single measurement at a trap site did not correlate to actual dose rates measured on free ranging animals. These findings provide empirical data to support published concerns about inadequate dosimetry in much of the published Chernobyl and Fukushima dose-effects research. Furthermore, our data indicate that a huge portion of that literature should be challenged, and that improper dosimetry remains a significant source of controversy in radiation dose-effect research.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2025

E-Area Low-Level Waste Facility Inadvertent Human Intruder Limits and Doses in Support of the PA2022

This report documents the inadvertent human intruder (IHI) analysis for the E-Area Low-Level Waste Facility (ELLWF) at the Savannah River Site (SRS), near Aiken, South Carolina. This analysis supports the revised ELLWF Performance Assessment (PA), complying with the Department of Energy standard for operation of low-level waste disposal facilities (USDOE, 2017). The ELLWF is an operating waste disposal facility and is scheduled to continue accepting waste to 2065. One task of the revised PA is to establish waste inventory limits for the various disposal units at ELLWF. This is done by modeling future contaminant release and transport through applicable pathways to human receptors, comparing predicted doses per disposed curie with applicable performance measures, to obtain inventory limits which will assure that doses to receptors do not exceed performance measures. This report documents results of modeling future doses to one class of receptor, the inadvertent human intruder. It is assumed that after site closure, public knowledge of the site is lost, and IHIs will engage in activities on the ELLWF that will disrupt the closure cap, causing dose to the IHI. Following USDOE (2017), six different stylized exposure scenarios are considered, simulating activities by an IHI which could result in a radiological dose. The six scenarios are: • Acute – Basement Construction: IHI constructs a basement and encounters waste during excavation which is inadvertently mixed with clean soil and diluted. • Acute – Well Drilling: IHI drills a water well through waste and is exposed to drill cuttings mixed with clean soil that are brought to the surface. • Acute – Discovery: IHI begins constructing a basement but stops when encountering the riprap in the final closure cap and is exposed to photon radiation from unexcavated material residing in the undisturbed waste zone. • Chronic – Agriculture: Resident IHI is exposed to waste that was excavated for basement construction and mixed with native soil in the intruder’s vegetable garden. • Chronic – Post-Drilling: Resident IHI is exposed to waste from drill cuttings mixed with native soil and scattered in the garden area. • Chronic – Residential: Resident IHI is exposed to external radiation while in home located above waste with shielding provided by the concrete basement floor and any soil or engineered material remaining between the basement and waste. Dose calculations are performed using the SRNL Dose Toolkit (Aleman, 2023), following the approach of Smith et al (2019). Calculations are performed separately for 27 of the 33 disposal units (DUs) at ELLWF and are radionuclide specific. The results of the IHI analysis include: • Dose Factors: mrem per disposed curie (acute) and mrem/yr per disposed curie (chronic) for each parent radionuclide, for each DU. • Inventory Limits: in curies, for each parent radionuclide, for each DU. • Estimated Dose to IHI: mrem (acute) and mrem/yr (chronic), for each DU, given its projected closure inventory without inventory biases applied. Most DU-specific IHI inventory limits are in the range of 10 3 to 10 7 curies per nuclide. The lowest inventory limits are associated with gamma-emitters such as Sn-126, Ra-226, Th-232, and Cm-248. Radionuclides with short half-lives such as Pu-241, and nuclides which are pure beta emitters or which decay by electron capture, such as Ni-59 and Ni-63, have the highest limits. For the 27 evaluated DUs, predicted IHI doses are shown in Table ES-1. The maximum acute dose is 1.18 mrem, at ST23, much less than the DOE performance measure of 500 mrem (USDOE, 2017). The highest chronic dose is 37.2 mrem/yr at ST02, below the DOE performance measure of 100 mrem/yr. Also shown are estimated inventory sums of fractions (SOFs) at closure in 2065, for groundwater (GW) and IHI pathways. For each DU, the inventory is constrained by the GW pathway. For most DUs, the IHI SOFs are approximately 1000 times lower than the GW SOF values, and the IHI pathway does not drive risk for any disposal unit.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2021

Using personal monitoring data to derive organ doses for medical radiation workers in the Million Person Study—considerations regarding NCRP Commentary no. 30

The study of low dose and low-dose rate exposure is of central importance in understanding the possible range of health effects from prolonged exposures to radiation. The One Million Person Study of Radiation Workers and Veterans (MPS) of low-dose health effects was designed to evaluate radiation risks among healthy American workers and veterans. The MPS is evaluating low-dose and dose-rate effects, intakes of radioactive elements, cancer and non-cancer outcomes, as well as differences in risks between women and men. Medical radiation workers make up a large group of individuals occupationally exposed to low doses of radiation from external x-ray/gamma exposures. For the MPS, about 100 000 United States medical radiation workers have been selected for study. The approach to the complex dosimetry circumstances for such workers over three to four decades of occupation were initially and broadly described in National Council on Radiation Protection and Measurements (NCRP) Report No. 178. NCRP Commentary No. 30 provides more detail and describes an optimum approach for using personal monitoring data to estimate lung and other organ doses applicable to the cohort and provides specific precautions/considerations applicable to the dosimetry of medical radiation worker organ doses for use in epidemiologic studies. The use of protective aprons creates dosimetric complexity. It is recommended that dose values from dosimeters worn over a protective apron be reduced by a factor of 20 for estimating mean organ doses to tissues located in the torso and that 15% of the marrow should be assumed to remain unshielded for exposure scenarios when aprons are worn. Conversion coefficients relating personal dose equivalent, H p (10) in mSv, to mean absorbed doses to organs and tissues, D T in mGy, for females and males for six exposure scenarios have been determined and presented for use in the MPS. This Memorandum summarises several key points in NCRP Commentary No. 30.

Environmental Sciences & Ecology↗
DOE OSTI2020

The Relationship Between Dose Rate and Decay Heat for Spent Nuclear Fuel Casks

Decay heat and dose rate are two important limits used for determining the allowable contents of spent fuel (SNF) in dry storage systems and transportation packages. While the decay heat limit is used to maintain fuel cladding integrity and ensure retrievability, dose rates are used to demonstrate compliance with regulatory requirements on radiation protection. Because both dose rate and decay heat result from decay of radioisotopes in SNF, this study is an attempt to examine the relationship between dose rate and decay heat for a given cask design. Dose rates were evaluated for 198 cask configurations, that include various SNF system designs (e.g., storage, transfer, transport), SNF characteristics (e.g., fuel types, burnup, cooling time), and loading maps (e.g., uniform loading, zone loading), while a constant decay heat was maintained. The decay heat was calculated using US Nuclear Regulatory Commission (NRC) Regulatory Guide (RG) 3.54, Revision 2, and verified using ORIGEN sequence within SCALE code system. The ORIGEN outputs were used as source terms in the dose analysis using 198 different configurations. A computer script was developed to calculate the cooling time necessary to achieve a given decay heat for a given enrichment, assembly average burnup, assembly mass, and in-core history using a rootfinder algorithm. Initially the computer script was developed to provide cooling time and burnup calculations directly to the analysis of dose rates and decay heats, so a comparison between Used Nuclear Fuel-Storage Transportation and Disposal Analysis Resource Data System (UNF-ST&DARDS) results and RG3.54 data was made; results are included in the appendix to this document. However, an iterative approach was used to compute cooling time, and its accuracy did not depend on the results of the RG3.54r2 algorithm, although the algorithm was still used. The results of the evaluation presented herein clearly demonstrate that a given decay heat does not correspond to a unique dose rate for a variety of cask and package designs. There is no clear pattern to develop a correlation between decay heat and the source terms. Depending on burnup, enrichment, cask type, and loading pattern, dose rates varied for the exact same decay heat—in some cases by 400% for a given cask. For cases in which decay heat was held constant through selection of the appropriate cooling time, dose rates would decrease with increasing burnup, and in other cases, dose rates would increase. The large variation in dose rates for a constant decay heat indicates that casks loaded based on decay heat—that is allowing any burnup, cooling time, and enrichment combinations that yield the qualified decay heat limit(s) —cannot ensure that an Independent Spent Fuel Storage Installation or a spent fuel transportation package will meet the regulatory limits set forth by the respective regulations, i.e., 10 CFR 72 or 10 CFR 71.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2021

DeepMC: a deep learning method for efficient Monte Carlo beamlet dose calculation by predictive denoising in magnetic resonance-guided radiotherapy

Abstract Emerging magnetic resonance (MR) guided radiotherapy affords significantly improved anatomy visualization and, subsequently, more effective personalized treatment. The new therapy paradigm imposes significant demands on radiation dose calculation quality and speed, creating an unmet need for the acceleration of Monte Carlo (MC) dose calculation. Existing deep learning approaches to denoise the final plan MC dose fail to achieve the accuracy and speed requirements of large-scale beamlet dose calculation in the presence of a strong magnetic field for online adaptive radiotherapy planning. Our deep learning dose calculation method, DeepMC, addresses these needs by predicting low-noise dose from extremely noisy (but fast) MC-simulated dose and anatomical inputs, thus enabling significant acceleration. DeepMC simultaneously reduces MC sampling noise and predicts corrupted dose buildup at tissue-air material interfaces resulting from MR-field induced electron return effects. Here we demonstrate our model’s ability to accelerate dose calculation for daily treatment planning by a factor of 38 over traditional low-noise MC simulation with clinically meaningful accuracy in deliverable dose and treatment delivery parameters. As a post-processing approach, DeepMC provides compounded acceleration of large-scale dose calculation when used alongside established MC acceleration techniques in variance reduction and graphics processing unit-based MC simulation.

Engineering↗
DOE OSTI2026

ACRRF High-Bay Dose Calculations using MCNP (Part A)

Analytical tools and models have been developed as a starting point for directly assessing dose in the Annular Core Research Reactor Facility (ACRRF) due to reactor operation. Key results include peak dose along the Central Cavity (CC) centerline (beamline) at the cavity level, dose throughout the High-Bay (HB), and dose on the facility roof for partially-shielded reactor operation where the 4” insert is removed from the CC Shield Plug (SP). Model results in the beamline are benchmarked against measured doses from passive dosimetry evaluations. Personnel total (neutron and gamma) dose in the ACRRF HB is calculated using Monte Carlo N-Particle (MCNP). Various CC and SP configurations are analyzed, including unshielded (no SP) and partially shielded (SP installed but 4” insert removed). Novel application of Variance Reduction (VR) techniques, namely the Surface Source Write (SSW) and Surface Source Read (SSR) capabilities in MCNP, enable impressive resolution (in a Monte Carlo modeling sense) of dose throughout much the facility. The VR techniques reduce stochastic error for challenging tallies, with more advanced techniques explored in the companion to this report (Part B) [1]. Supplementary studies (including a verification analysis) and pedagogic evaluations in Part B involve neutron spectra, angular distributions, and the dose impact of facility characteristics. With the SP 4” insert removed and the Lead-Boron (44”) Bucket (LB–44) in the reactor cavity, Total Effective Dose (TED) within the CC beamline is ≈140 rem per 300 MJ of reactor yield (or 3900 rem per hour at 100% Steady-State (SS) power). With no SP (unshielded) and a Free-Field (FF) cavity, TED within the beamline is ≈610 rem per 300 MJ (or 17000 rem per hour at 100% SS power). Due to the predicted collimation of radiation by the reactor pool (and partial SP, if present), beamline dose is much greater than the scattered radiation field surrounding the cavity and reactor tank. Comparisons are made to beamline dosimetry measurements to validate the model. Model predictions agree reasonably well (⪅10%) with measured quantities of neutron fluence, gamma fluence, and spectral metrics. Away from the beamline, comparisons made to previous dose measurements in the HB agreement within an order of magnitude.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2023

Impact of simulated reduced injected dose on the assessment of amyloid PET scans

To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [ 18 F]flutemetamol and [ 18 F]florbetaben. Cognitively impaired and unimpaired individuals (N = 250, 36% Aβ-positive) were included and injected with [ 18 F]flutemetamol (N = 175) or [ 18 F]florbetaben (N = 75). PET scans were acquired in list-mode (90–110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aβ-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aβ- and Aβ + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated. At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [ 18 F]flutemetamol and [ 18 F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were < 1.5%. AUCs for discriminating Aβ- from Aβ + scans were high (AUC ≥ 0.94) across dose levels, and visual assessment showed intra-reader agreement of > 80% for both tracers. This proof-of-concept study showed that for both [ 18 F]flutemetamol and [ 18 F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Dose optimization of an adjuvanted peptide-based personalized neoantigen melanoma vaccine

The advancements in next-generation sequencing have made it possible to effectively detect somatic mutations, which has led to the development of personalized neoantigen cancer vaccines that are tailored to the unique variants found in a patient’s cancer. These vaccines can provide significant clinical benefit by leveraging the patient’s immune response to eliminate malignant cells. However, determining the optimal vaccine dose for each patient is a challenge due to the heterogeneity of tumors. To address this challenge, we formulate a mathematical dose optimization problem based on a previous mathematical model that encompasses the immune response cascade produced by the vaccine in a patient. We propose an optimization approach to identify the optimal personalized vaccine doses, considering a fixed vaccination schedule, while simultaneously minimizing the overall number of tumor and activated T cells. To validate our approach, we perform in silico experiments on six real-world clinical trial patients with advanced melanoma. We compare the results of applying an optimal vaccine dose to those of a suboptimal dose (the dose used in the clinical trial and its deviations). Our simulations reveal that an optimal vaccine regimen of higher initial doses and lower final doses may lead to a reduction in tumor size for certain patients. Our mathematical dose optimization offers a promising approach to determining an optimal vaccine dose for each patient and improving clinical outcomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy

Pregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, ‘mrgsolve’, in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Ultra-high dose rate FLASH irradiator at the radiological research accelerator facility

The Radiological Research Accelerator Facility has modified a decommissioned Varian Clinac to deliver ultra-high dose rates: operating in 9 MeV electron mode ( FLASH mode), samples can be irradiated at a Source-Surface Distance (SSD) of 20 cm at average dose rates of up to 600 Gy/s (3.3 Gy per 0.13 µs pulse, 180 pulses per second). In this mode multiple pulses are required for most irradiations. By modulating pulse repetition rate and irradiating at SSD = 171 cm, dose rates below 1 Gy/min can be achieved, allowing comparison of FLASH and conventional irradiations with the same beam. Operating in 6 MV photon mode, with the conversion target removed ( SuperFLASH mode), samples are irradiated at higher dose rates (0.2–150 Gy per 5 µs pulse, 360 pulses per second) and most irradiations can be performed with a single very high dose rate pulse. In both modes we have seen the expected inverse relation between dose rate and irradiated area, with the highest dose rates obtained for beams with a FWHM of about 2 cm and ± 10% uniformity over 1 cm diameter. As an example of operation of the ultra-high dose rate FLASH irradiator, we present dose rate dependence of dicentric chromosome yields.

43 PARTICLE ACCELERATORS↗
DOE OSTI2020

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Rationale and Framework for the Monograph and Overview of Eligible Studies

Abstract Whether low-dose ionizing radiation can cause cancer is a critical and long-debated question in radiation protection. Since the Biological Effects of Ionizing Radiation report by the National Academies in 2006, new publications from large, well-powered epidemiological studies of low doses have reported positive dose-response relationships. It has been suggested, however, that biases could explain these findings. We conducted a systematic review of epidemiological studies with mean doses less than 100 mGy published 2006–2017. We required individualized doses and dose-response estimates with confidence intervals. We identified 26 eligible studies (eight environmental, four medical, and 14 occupational), including 91 000 solid cancers and 13 000 leukemias. Mean doses ranged from 0.1 to 82 mGy. The excess relative risk at 100 mGy was positive for 16 of 22 solid cancer studies and 17 of 20 leukemia studies. The aim of this monograph was to systematically review the potential biases in these studies (including dose uncertainty, confounding, and outcome misclassification) and to assess whether the subset of minimally biased studies provides evidence for cancer risks from low-dose radiation. Here, we describe the framework for the systematic bias review and provide an overview of the eligible studies.

Berrington de Gonzalez, Amy↗
DOE OSTI2024

Application of FISH based G2-PCC assay for the cytogenetic assessment of high radiation dose exposures: Potential implications for rapid triage biodosimetry

The main goal of this study is to test the utility of calyculin A induced G2-PCC assay as a biodosimetry triage tool for assessing a wide range of low and acute high radiation dose exposures of photons. Towards this initiative, chromosome aberrations induced by low and high doses of x-rays were evaluated and characterized in G2-prematurely condensed chromosomes (G2-PCCs) by fluorescence in situ hybridization (FISH) using human centromere and telomere specific PNA (peptide nucleic acid) probes. A dose dependent increase in the frequency of dicentric chromosomes was observed in the G2-PCCs up to 20 Gy of x-rays. The combined yields of dicentrics and rings in the G2-PCCs showed a clear dose dependency up to 20 Gy from 0.02/cell for 0.1 Gy to 14.98/cell for 20 Gy. Centric rings were observed more frequently than acentric ring chromosomes in the G2-PCCs at all the radiation doses from 1 Gy to 20 Gy. A head-to-head comparison was also performed by FISH on the yields of chromosome aberrations induced by different doses of x-rays (0 Gy -7.5 Gy) in colcemid arrested metaphase chromosomes and calyculin A induced G2-PCCs. In general, the frequencies of dicentrics, rings and acentric fragments were slightly higher in G2-PCCs than in colcemid arrested metaphase chromosomes at all the radiation doses, but the differences were not statistically significant. To reduce the turnaround time for absorbed radiation dose estimation, attempt was made to obtain G2-PCCs by reducing the culture time to 36 hrs. The absorbed doses estimated in x-rays irradiated (0,1,2 and 4 Gy) G2-PCCs after 36 hrs of culture were grossly like that of G2-PCCs and colcemid arrested metaphase chromosomes prepared after 48 hrs of culture. Our study indicates that the shortened version of calyculin A induced G2-PCC assay coupled with the FISH staining technique can serve as an effective triage biodosimetry tool for large-scale radiological/nuclear incidents.

Science & Technology - Other Topics↗