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At least 235 records · Page 13

CarcSeq Measurement of Rat Mammary Cancer Driver Mutations and Relation to Spontaneous Mammary Neoplasia

Abstract The ability to deduce carcinogenic potential from subchronic, repeat dose rodent studies would constitute a major advance in chemical safety assessment and drug development. This study investigated an error-corrected NGS method (CarcSeq) for quantifying cancer driver mutations (CDMs) and deriving a metric of clonal expansion predictive of future neoplastic potential. CarcSeq was designed to interrogate subsets of amplicons encompassing hotspot CDMs applicable to a variety of cancers. Previously, normal human breast DNA was analyzed by CarcSeq and metrics based on mammary-specific CDMs were correlated with tissue donor age, a surrogate of breast cancer risk. Here we report development of parallel methodologies for rat. The utility of the rat CarcSeq method for predicting neoplastic potential was investigated by analyzing mammary tissue of 16-week-old untreated rats with known differences in spontaneous mammary neoplasia (Fischer 344, Wistar Han, and Sprague Dawley). Hundreds of mutants with mutant fractions ≥ 10−4 were quantified in each strain, most were recurrent mutations, and 42.5% of the nonsynonymous mutations have human homologs. Mutants in the mammary-specific target of the most tumor-sensitive strain (Sprague Dawley) showed the greatest nonsynonymous/synonymous mutation ratio, indicative of positive selection consistent with clonal expansion. For the mammary-specific target (Hras, Pik3ca, and Tp53 amplicons), median absolute deviation correlated with percentages of rats that develop spontaneous mammary neoplasia at 104 weeks (Pearson r = 1.0000, 1-tailed p = .0010). Therefore, this study produced evidence CarcSeq analysis of spontaneously occurring CDMs can be used to derive an early metric of clonal expansion relatable to long-term neoplastic outcome.

McKim, Karen L.↗

Decommissioning of the V1 Nuclear Power Plant Jaslovske Bohunice - 20270

The paper focuses on introducing the approach and method applied for decommissioning of the V1 nuclear power plant (further the 'V1 NPP') located in Jaslovske Bohunice in the Slovak Republic, to the conference participants. The Paper outlines activities and steps necessary to comply with the requirements contained in the decision of the Slovak government from 1999 regarding the early shutdown of the V1 NPP. The company responsible for the V1 NPP decommissioning is Jadrova a vyradovacia spolocnost, a.s., (further JAVYS) with the State as a sole shareholder. On the basis of the V1 NPP Decommissioning Conceptual Plan, out of four assessed options, JAVYS selected the immediate decommissioning option (the 'IDO') for the V1 NPP. On the basis of multi-criteria analysis, the IDO specified the approach of immediate and continuous dismantling of equipment followed by demolition of buildings and preparation of the site for its further potential use. The IDO also included the summary of technical, environmental, legislative information as well as the determination of assumed costs for decommissioning of the V1 NPP. Prior to commencement of the V1 NPP decommissioning, within the process of termination of operation, activities connected with de-fuelling, monitoring, processing of historical waste and, not to forget, the process of obtaining the license for the V1 NPP decommissioning were executed. JAVYS decided to divide the decommissioning process into two stages. In 2011, JAVYS obtained a license for the first stage of the V1 NPP decommissioning. Within this stage, dismantling of inactive equipment, demolitions of inactive buildings, monitoring of systems and preparatory works for the upcoming stage of decommissioning were implemented. In 2015, in line with the license for the 2. stage of the V1 NPP decommissioning, the activities of decontamination and dismantling of contaminated and active equipment as well as demolitions of remaining buildings began. In this stage radioactive waste (RAW) produced during the decommissioning is to be processed. After decontamination, the material fulfilling the free release criteria is to be released into the environment, the site is to be cleared from the scope of the Atomic Act and released from the surveillance of the national regulators. Future application of certain methods and techniques for decontamination and dismantling in similar environments might bring an added value to the operators. Paper includes a description of best practices for Nuclear Power Plant VVER type reactors decommissioning. Schedule comparison is given to show how the critical path of certain projects is being managed. Application of the International Standard for Decommissioning Costing (ISDC) methodology provides a uniform method which enables comparison of cost estimates to other nuclear facilities under decommissioning. The cost estimate for the V1 NPP decommissioning has been continuously updated based on more advanced and detailed information on the decommissioning activities and projects. Monitoring of progress of the V1 NPP decommissioning is performed via four key-performance indicators. The Earned Value Management (EVM) methodology is used for evaluating time and cost aspect of decommissioning activities while waste conditioning index is calculated by comparing the actually produced waste to planned values of waste for a respective monitored period. Radiological safety index is assessed by comparison of the personnel records on the individual yearly doses received by each respective employee to the boundary value. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Using Calibrated Sodium Data for Preliminary Validation of the SRT Code for Advanced Reactors

Various types of non-light water reactors are currently engaged in the U.S. licensing process. Because of inherent differences compared with well-established large light water reactors, appropriate assessment tools are needed. Specifically, source term analysis, which determines environmental dose impacts from potential accident scenarios, is a crucial part of design and licensing. The U.S. Nuclear Regulatory Commission has emphasized the importance of mechanistic source term analysis for advanced reactor deployments. To align with these needs, Argonne National Laboratory has developed the Simplified Radionuclide Transport (SRT) source term analysis code for metal fuel Sodium-cooled Fast Reactors (SFRs) and microreactors. SRT conducts time-dependent radionuclide transport and retention in SFRs for core and ex-core radionuclide source accident sequences. The main objective of SRT is to provide rapid sensitivity and uncertainty analyses, incorporating parametric uncertainties and summarizing probabilistic results. As part of the code validation process, a study focused on the bubble scrubbing module was performed using an experiment recently carried out by the University of Wisconsin-Madison. Based on the analysis, the modeling approach in SRT provides accurate results for small and large aerosols, while slight underprediction of radionuclide aerosol removal are observed for medium sized aerosols. However, the deviation is minor, considering the highly uncertain phenomenon and range of results, and is in the conservative direction. In addition, uncertainty information derived from the experiments is further implemented, reflecting the actual span of parameters, which leads to enhanced agreement with code predictions. The results demonstrate that SRT provides reasonable predictions for the bubble scrubbing process in sodium pool.

Kam, Dong Hoon↗

FRMAC Assessment Manual Volume 1 (Overview and Methods)

The Federal Radiological Monitoring and Assessment Center (FRMAC) Assessment Manual is the tool used to organize and guide activities of the FRMAC Assessment Division. The mission of the FRMAC Assessment Division in a radiological emergency is to interpret radiological data and predict worker and public doses. This information is used by Decision Makers to recommend protective actions in accordance with Protection Action Guides (PAGs) issued by government agencies. This manual integrates many health physics tools and techniques used to make these assessments.

54 ENVIRONMENTAL SCIENCES↗

A Multi-Institutional Phase 2 Trial of High-Dose SAbR for Prostate Cancer Using Rectal Spacer

High-dose SABR for prostate cancer offers the radiobiologic potency of the most intensified radiation therapy regimens but was associated with >90% rates of ulceration of the anterior rectal wall on endoscopic assessment; this infrequently progressed to severe rectal toxicity in prior prospective series. A multi-institutional phase 2 prospective trial was conducted to assess whether placement of a perirectal hydrogel spacer would reduce acute periprostatic rectal ulcer events after high-dose (>40 Gy) SABR.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

FY2020 Savannah River Site Composite Analysis Annual Summary Review

This document provides the Department of Energy (DOE) Order 435.1 and its manual, Radioactive Waste Management (DOE 2021a, 2021b) required Annual Review for the Savannah River Site (SRS) Composite Analysis (CA). Progress made to-date toward addressing the secondary issue from the LFRG review of the 2010 SRS CA has focused primarily upon inventory estimate improvements. Inventory impacts dose in a linear fashion and reduces the uncertainty with the CA conclusions. Maintenance items are addressed, as funding allows, based on the relative risk associated with meeting the performance objectives. Currently, there is minimal risk in exceeding the DOE 100 mrem/yr CA primary dose limit or the DOE 30 mrem/yr dose constraint (administrative limit). Proposed activities, discoveries, new information and changes potentially affecting the 2010 SRS CA are documented in this and earlier Annual Summary reports, and a consolidated list of changes since the 2010 CA is documented in this report. The impact to the CA of changes arising from updated performance assessment (PA) baselines [i.e., Saltstone Disposal Facility (SDF), E-Area Low-Level Waste Facility (ELLWF), and F & H Tank Farm (FTF & HTF) closures] is expected to be minor for the following reasons: The primary contributors to the SRS CA dose impact at the Upper Three Runs (UTR) point of assessment (POA) are the H-Canyon and Mixed Waste Management Facility (MWMF), contributing 68% and 9%, respectively, to the dose impact at that POA. The combined contribution to the UTR dose impact from all PA’s (SDF, ELLWF, FTF and HTF) is ~2% of this total. The 2010 SRS CA model validation performed indicates that the CA projected dose, while generally conservative, provides a reasonable representation of the maximum annual doses. Doses evaluated are well below the SRS established 15 mrem/yr administrative limit (Crapse et al. 2011). Based on the assessment presented within this annual review and collective engineering judgement, the conclusions of the 2010 SRS CA remain valid and there is reasonable assurance that SRS will meet the performance objectives delineated in DOE Manual 435.1-1. The 2010 SRS CA should be updated to incorporate PA changes, proposed changes to inventories and sources and model improvements accumulated since the 2010 CA. The timing will be dependent on the completion of the ongoing E-Area PA revision.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Comparison of Ion and Neutron Irradiations to 3 dpa at 500C in Ferritic-Martensitic Alloys

The growing global demand for energy will increasingly call upon advanced nuclear fission reactors to supply safe and reliable electricity. The structural and fuel cladding components of these reactors will be subject to extreme conditions of irradiation damage up to several hundred displacements per atom (dpa) at temperatures as high as 700°C. Ferritic-martensitic (F-M) steels are leading candidates for these challenging conditions due to their strength and dimensional stability under irradiation. In order to accelerate the process for evaluating F-M alloys, charged particles are increasingly being used to emulate neutron irradiations. Charged particle irradiations allow the possibility of conducting irradiation experiments within a shorter time period (i.e. at a rate up to 4 orders of magnitude faster) and with minimal radioactivation of the material, enabling lower cost and faster turnaround of post irradiation examination and analysis. However, the irradiation dose rate, damage cascade morphologies, and irradiation damage depth profiles all differ widely between protons, heavier ions, and neutrons. Currently, there is limited understanding of the significance of these physical differences and how they manifest in the irradiated microstructure and mechanical properties of F-M steels. The objective of this study is to evaluate charged particles as a surrogate for neutron irradiations in F-M alloys by assessing common irradiation conditions using Fe++ ions, protons, and neutrons. Keeping the temperature and dose consistent enables isolation of the effects of each irradiating particle and their respective dose rates and cascade morphologies.

Swenson, M.J.↗

Calculations versus measurements for residual dose rates from SNS spent structures

Here, residual dose rate measurements were conducted on target vessel #13 and proton beam window #5 after extraction from their service locations. These measurements are used to verify calculation methods of radionuclide inventory assessment that are typically performed for nuclear waste characterization and transportation of these structures. Neutronics analyses for predicting residual dose rates are carried out using the transport code MCNPX and the transmutation code CINDER90. For transport analyses a complex and rigorous geometry model of the structures and their surroundings are applied. The neutronics analyses are carried out using the Bertini and CEM high energy physics models for simulating particles interactions above the table-based cross section range. Finally, obtained calculational results are analyzed and compared to the measured dose rates and overall show good agreement within 25%, which shows applicability of the methods used in analyses.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Relationship Between Radiation Dose and Markers of Insulin Resistance and Inflammation in Atomic Bomb Survivors

Abstract Context In recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation; however, no studies have examined low to moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors. Objective To examine the association between radiation dose and markers of inflammation and insulin resistance. Methods This study investigated 3152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance. Results Radiation dose was significantly and positively associated with levels of C-reactive protein, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and high-density lipoprotein cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance. Conclusion Insulin resistance might be a possible factor in radiation-related diabetes incidence in A-bomb survivors.

Endocrinology & Metabolism↗

FRMAC Assessment Manual Volume 3 - Pre-Assessed Default Scenarios

This volume of the Federal Radiological Monitoring and Assessment Center (FRMAC) Assessment Manual was developed to serve as a quick-start guide to expedite response for pre-assessed scenarios before event-specific information becomes available. The objective of Volume 3 is to provide dose assessors with the scenario-specific protective action guidance questions likely to be asked at the start of a response, along with supporting technical information and assumptions that differ from the default assumptions defined in Volume 2 of the Assessment Manual.

61 RADIATION PROTECTION AND DOSIMETRY↗

Forensic tracers of exposure to produced water in freshwater mussels: a preliminary assessment of Ba, Sr, and cyclic hydrocarbons

Hydraulic fracturing is often criticized due in part to the potential degradation of ground and surface water quality by high-salinity produced water generated during well stimulation and production. This preliminary study evaluated the response of the freshwater mussel, Elliptio complanata, after exposure to produced water. A limited number of adult mussels were grown over an 8-week period in tanks dosed with produced water collected from a hydraulically fractured well. The fatty tissue and carbonate shells were assessed for accumulation of both inorganic and organic pollutants. Ba, Sr, and cyclic hydrocarbons indicated the potential to accumulate in the soft tissue of freshwater mussels following exposure to diluted oil and gas produced water. Exposed mussels showed accumulation of Ba in the soft tissue several hundred times above background water concentrations and increased concentrations of Sr. Cyclic hydrocarbons were detected in dosed mussels and principle component analysis of gas chromatograph time-of-flight mass spectrometer results could be a novel tool to help identify areas where aquatic organisms are impacted by oil and gas produced water, but larger studies with greater replication are necessary to confirm these results.

54 ENVIRONMENTAL SCIENCES↗

Microglia are implicated in the development of paclitaxel chemotherapy-associated cognitive impairment in female mice

Chemotherapy remains a mainstay in the treatment of many types of cancer even though it is associated with debilitating behavioral side effects referred to as “chemobrain,” including difficulty concentrating and memory impairment. The predominant hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood. Here, we hypothesized that microglia are activated by chemotherapy and drive chemotherapy-associated cognitive impairments. To test this hypothesis, we treated female C57BL/6 mice with a clinically-relevant regimen of a common chemotherapeutic, paclitaxel (6 i.p. doses at 30 mg/kg), which impairs memory of an aversive stimulus as assessed via a contextual fear conditioning (CFC) paradigm. In this work, paclitaxel increased the percent area of IBA1 staining in the dentate gyrus of the hippocampus. Moreover, using a machine learning random forest classifier we identified immunohistochemical features of reactive microglia in multiple hippocampal subregions that were distinct between vehicle- and paclitaxel-treated mice. Paclitaxel treatment also increased gene expression of inflammatory cytokines in a microglia-enriched population of cells from mice. Lastly, a selective inhibitor of colony stimulating factor 1 receptor, PLX5622, was employed to deplete microglia and then assess CFC performance following paclitaxel treatment. PLX5622 significantly reduced hippocampal gene expression of paclitaxel-induced proinflammatory cytokines and restored memory, suggesting that microglia play a critical role in the development of chemotherapy-associated neuroinflammation and cognitive impairments. This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairments, a key mechanistic detail for determining preventative and intervention strategies for these burdensome side effects.

60 APPLIED LIFE SCIENCES↗

Hypofractionated Postprostatectomy Radiation Therapy for Prostate Cancer to Reduce Toxicity and Improve Patient Convenience: A Phase 1/2 Trial

The phase 1 portion of this multicenter, phase 1/2 study of hypofractionated (HypoFx) prostate bed radiation therapy (RT) as salvage or adjuvant therapy aimed to identify the shortest dose-fractionation schedule with acceptable toxicity. The phase 2 portion aimed to assess the health-related quality of life (QoL) of using this HypoFx regimen.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Verification of RESRAD-BUILD Code Version 4

This report documents the verification of the RESRAD-BUILD code, Version 4.0, which was released on December 22, 2022. Two earlier reports verifying Versions 3.0 and 3.1, respectively, were published in 2001 (Kamboj, et al. 2001) and 2003 (Tetra Tech NUS 2003). Version 4.0 of the RESRAD-BUILD code has many new features and modeling enhancements over the earlier versions, including the previously released Version 3.5. Chapter 2 of this report focuses on verifying the external dose and risk modeling for point, line, area, and volume sources, as well as for floor deposition. Besides verification, the external radiation doses calculated by RESRAD-BUILD were also benchmarked with those calculated by the MCNP code (Briemeister 1993). Section J.3 of the RESRAD-BUILD User’s Manual Vol. 1 (Yu et al. 2022) documents the results of that benchmarking effort. Chapter 3 of this report focuses on verifying the ventilation modeling, from checking the remaining source inventory, releases of radionuclides to the air, air concentrations and deposited floor concentrations over time, to the radiation dose and risk associated with inhalation, ingestion, and air submersion, with and without vacuuming. The verification efforts involve designing spreadsheets to perform calculations the same as or like those performed by the RESRAD-BUILD code and then comparing the spreadsheet results with those produced by the code. When the results agree or the differences are within acceptable range, the accuracy of model implementation in the code is verified. In addition to model implementation, the implementation of key functions and features that facilitate the modeling or the use of the code were also verified during the release testing of the code. Appendix A presents the test cases developed for these verification testing, and Appendix B presents the testing results that verify proper implementation of key functions and features.

54 ENVIRONMENTAL SCIENCES↗

Real-Time Characterization of Salt Aerosols Generated from Static and Sparged Molten Salt

The formation of radionuclide-bearing aerosols in the respirable size range has the potential to significantly influence offsite dose consequences and is, therefore, an important consideration in nuclear facility safety assessments. Molten salt reactor (MSR) developers will likely need to demonstrate an understanding of the conditions under which radionuclide-bearing aerosols may be generated from their reactor under normal operating and accident conditions, as well as the characteristics and transport behavior of these aerosols, to demonstrate to the U.S. Nuclear Regulatory Commission (NRC) that the facility can be operated safely. Recent reviews of the literature identified a lack of experimental data describing the mechanisms of formation and properties (size, concentration, and composition) of salt aerosol particles that are produced from molten salts. Experiments that identify the conditions that lead to radionuclide-bearing salt aerosol releases and quantify the characteristics of salt aerosols formed by different mechanisms are high-priority needs to support MSR licensing. This report describes tests that were conducted within the Argonne Salt Aerosol Test Stand (a sealed vessel and measurement system) to generate salt aerosols from static and sparged molten salts and measure their size and concentration in real-time. The results provide insight into salt aerosol formation by the vapor condensation and bubble bursting mechanisms and inform the potential radiological consequences of aerosol formation from molten fuel salt. Videos of the salt surface were taken during salt sparge tests to observe surface bubble behavior. The data in this report can be used to develop mechanistic source term and accident progression models for MSRs. The real-time salt aerosol characterization technique used in this study will be employed in future integral effects tests that are conducted at an engineering scale to simulate realistic MSR accidents and in future separate effects tests to address additional variables that may impact salt aerosol characteristics (e.g., presence of fission products in salt and humidity in atmosphere).

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

First-of-a-Kind Risk-Informed Digital Twin for Operational Decision Making

A digital twin (DT) is a digital model or a collection of models of a physical entity. DTs in the nuclear arena can be used from plant design through decommissioning. Decisions are typically a priori or made offline. Risk-informed decision making is identifying what can go wrong, its frequency, and the consequences of its failure. Ideally risk-informed decision making reflects the current state of the plant and provides a decision in real time. Traditionally, probabilistic risk assessments (PRAs) evaluate the failures of safety systems, the risk of core damage, and the offsite dose as the consequence. However, this DT evaluates the decisions on the control side rather than the protection side. It uses the same risk methods to probabilistically inform the decision-making process but in a different way. Rather than evaluating the risk of core damage, this DT evaluates the likelihood of avoiding a trip set point while maintaining plant safety. Performance-based assessments are identified via its probabilistic evaluation of operational alternatives based on system status. Because the purpose of the control system is to maintain system variables within prescribed operating ranges, upsets or challenges that can exceed a trip set point resulting in a plant transient and a challenge to plant mitigating systems based on actual plant conditions, are evaluated to safely maintain the plant within the operating ranges. The probabilistic portion of the model is autonomously and automatically adjusted, and the metric of interest (i.e. likelihood of avoiding a trip set point) is recalculated. The digital representation of the physical system (i.e. the DT) performs a deterministic performance–based assessment of the probabilistically identified alternatives identified to validate the probabilistic assessment. A decision-making algorithm selects the appropriate option based on the probabilistic and deterministic assessments and transmits a control signal to a component(s) to initiate a corrective action or informs an operator of its decision.

digital twin↗

Simulated Energy Response in a Multiplicity Detector

Neutron multiplicity analysis is used for many applications, including nonproliferation and criticality safety. Multiplicity detectors have advantages over total neutron counting as they provide the ability to assess both multiplication and mass in fissionable material. In addition, multiplicity detectors can generate real-time information, e.g., dose estimation. The ability to evaluate the detector efficiency in each application is of primary importance in producing meaningful analyses. Multiplicity detectors usually house 3 He tubes within a polyethylene moderator. If the tubes are located behind different thickness of polyethylene, they will have different energy responses. This paper assesses 3 He tube efficiency as a function of neutron energy for a specific multiplicity detector.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Lung Cancer in the Mayak Workers Cohort: Risk Estimation and Uncertainty Analysis

The workers at the Mayak nuclear facility near Ozyorsk, Russia are a primary source of information about exposure to radiation at low-dose rates, since they were subject to protracted exposures to external gamma rays and to internal exposures from plutonium inhalation. Here we re-examine lung cancer mortality rates and assess the effects of external gamma and internal plutonium exposures using recently developed Monte Carlo dosimetry systems. Using individual lagged mean annual lung doses computed from the dose realizations, we fit excess relative risk (ERR) models to the lung cancer mortality data for the Mayak Workers Cohort using risk-modeling software. We then used the corrected information matrix (CIM) approach to widen the confidence intervals of ERR by taking into account the uncertainty in doses represented by multiple realizations from the Monte Carlo dosimetry systems. Findings of this work revealed that there were 930 lung cancer deaths during follow-up. Plutonium lung doses (but not gamma doses) were generally higher in the new dosimetry systems than those used in the previous analysis. This led to a reduction in the risk per unit dose compared to prior estimates. The estimated ERR/Gy for external gamma-ray exposure was 0.19 (95% CI: 0.07 to 0.31) for both sexes combined, while the ERR/Gy for internal exposures based on mean plutonium doses were 3.5 (95% CI: 2.3 to 4.6) and 8.9 (95% CI: 3.4 to 14) for males and females at attained age 60. Accounting for uncertainty in dose had little effect on the confidence intervals for the ERR associated with gamma-ray exposure, but had a marked impact on confidence intervals, particularly the upper bounds, for the effect of plutonium exposure [adjusted 95% CIs: 1.5 to 8.9 for males and 2.7 to 28 for females]. In conclusion, lung cancer rates increased significantly with both external gamma-ray and internal plutonium exposures. Accounting for the effects of dose uncertainty markedly increased the width of the confidence intervals for the plutonium dose response but had little impact on the external gamma dose effect estimate. Adjusting risk estimate confidence intervals using CIM provides a solution to the important problem of dose uncertainty. This work demonstrates, for the first time, that it is possible and practical to use our recently developed CIM method to make such adjustments in a large cohort study.

uncertainty, radiation risk estimation, Mayak Prod↗