Science, Faculty of
Physics and Astronomy, Department of
DSpace
UBCV
Robertson, Andrew Kyle Henderson
Doctor of Philosophy - PhD
University of British Columbia
Targeted alpha therapies using actinium-225 (²²⁵Ac, t₁/₂ = 9.9 d) can treat advanced metastatic disease, yet insufficient ²²⁵Ac availability limits their development (63 GBq/year is produced globally via ²²⁹Th generators). This thesis describes efforts to produce ²²⁵Ac and apply multi-nuclide SPECT imaging in preclinical evaluation of ²²⁵Ac-radiopharmaceuticals. Initial ²²⁵Ac production used ᴺᵃᵗU-spallation-produced and mass-separated ion beams, producing up to 8.6 MBq of ²²⁵Ra (an ²²⁵Ac parent) and 18 MBq of ²²⁵Ac. This material helped characterize the performance of ²²⁵Ac decay chain imaging on a microSPECT/PET/CT scanner in terms of contrast recovery, spatial resolution, and noise. Larger ²²⁵Ac quantities were produced via thorium target irradiation with a 438 MeV, 72 μA proton beam for 36 hours, producing (521 ± 18) MBq of ²²⁵Ac and (91 ± 14) MBq of ²²⁵Ra. These irradiations enabled ²³²Th(p,x) cross sections measurements for ²²⁵Ac, ²²⁵Ra, and ²²⁷Ac: (13.3 ± 1.2) mb, (4.2 ± 0.4) mb, and (17.7 ± 1.7) mb, respectively. Thirty-five other cross sections were measured and compared to FLUKA simulations; measured and calculated values generally agree within a factor of two. Ac separation from irradiated thorium and co-produced radioactive by-products used a thorium peroxide precipitation followed by cation exchange and extraction chromatography. Studies showed this method separates Ac from most elements, providing a directly-produced Ac product (²²⁷˒²²⁵Ac†) with measured ²²⁷Ac content of (0.15 ± 0.04)%, a hazardous long-lived (t₁/₂ = 21.8 y) impurity with prohibitively low waste disposal limits. A second, indirectly-produced ²²⁵Ra/²²⁵Ac-generator-derived Ac product (²²⁵Ac*) with ²²⁷Ac content of <7.5x10⁻⁵% was also obtained. The thorium target design, the simulations benchmarked against newly measured cross sections, and the precipitation-based thorium target processing method are separate novel contributions that together form the first demonstration of ²²⁵Ac* production technology that can be scaled to useful clinical quantities. This thesis therefore presents the scientific foundation for a new potential ²²⁵Ac production paradigm that could substantially increase production of ²²⁷Ac-free ²²⁵Ac using accelerator-based methods that are independent of the fixed ²²⁹Th quantities available from ²³³U stockpiles. Such increased ²²⁵Ac supplies will be required for the widespread clinical adoption of emerging ²²⁵Ac-based targeted alpha therapies to be realized.
Nuclide Production and ImagingApplications of 225Ac for TargetedAlpha TherapybyAndrew Kyle Henderson RobertsonBSc (Hons.), The University of Victoria, 2013A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinThe Faculty of Graduate and Postdoctoral Studies(Physics)THE UNIVERSITY OF BRITISH COLUMBIA(Vancouver)December 2020c© Andrew Kyle Henderson Robertson 2020The following individuals certify that they have read, and recommend tothe Faculty of Graduate and Postdoctoral Studies for acceptance, the thesisentitled:Nuclide Production and Imaging Applications of 225Ac forTargeted Alpha Therapysubmitted by Andrew Kyle Henderson Robertson in partial fulfillmentof the requirements forthe degree of Doctor of Philosophyin PhysicsExamining Committee:Paul Schaffer, RadiologyCo-supervisorVesna Sossi, Physics and AstronomyCo-supervisorStefan Reinsberg, Physics and AstronomySupervisory Committee MemberRob Kiefl, Physics and AstronomySupervisory Committee MemberDouglas Bryman, Physics and AstronomyUniversity ExaminerLaurel Schafer, ChemistryUniversity ExaminerKen Czerwinksi, University of WashingtonExternal ExaminerHarry Brumer, ChemistryChairiiAbstractTargeted alpha therapies using actinium-225 (225Ac, t1/2 = 9.9 d) cantreat advanced metastatic disease, yet insufficient 225Ac availability lim-its their development (63 GBq/year is produced globally via 229Th genera-tors). This thesis describes efforts to produce 225Ac and apply multi-nuclideSPECT imaging in preclinical evaluation of 225Ac-radiopharmaceuticals.Initial 225Ac production used NatU-spallation-produced and mass-separatedion beams, producing up to 8.6 MBq of 225Ra (an 225Ac parent) and 18MBq of 225Ac. This material helped characterize the performance of 225Acdecay chain imaging on a microSPECT/PET/CT scanner in terms of con-trast recovery, spatial resolution, and noise. Larger 225Ac quantities wereproduced via thorium target irradiation with a 438 MeV, 72 µA protonbeam for 36 hours, producing (521 ± 18) MBq of 225Ac and (91 ± 14)MBq of 225Ra. These irradiations enabled 232Th(p,x) cross sections mea-surements for 225Ac, 225Ra, and 227Ac: (13.3 ± 1.2) mb, (4.2 ± 0.4) mb,and (17.7 ± 1.7) mb, respectively. Thirty-five other cross sections weremeasured and compared to Fluka simulations; measured and calculatedvalues generally agree within a factor of two. Ac separation from irradiatedthorium and co-produced radioactive by-products used a thorium perox-ide precipitation followed by cation exchange and extraction chromatogra-phy. Studies showed this method separates Ac from most elements, pro-viding a directly-produced Ac product (227,225Ac†) with measured 227Accontent of (0.15 ± 0.04)%, a hazardous long-lived (t1/2 = 21.8 y) impuritywith prohibitively low waste disposal limits. A second, indirectly-produced225Ra/225Ac-generator-derived Ac product (225Ac*) with 227Ac content of<7.5×10-5% was also obtained. The thorium target design, the simulationsbenchmarked against newly measured cross sections, and the precipitation-based thorium target processing method are separate novel contributionsthat together form the first demonstration of 225Ac* production technologythat can be scaled to useful clinical quantities. This thesis therefore presentsthe scientific foundation for a new potential 225Ac production paradigm thatiiicould substantially increase production of 227Ac-free 225Ac using accelerator-based methods that are independent of the fixed 229Th quantities availablefrom 233U stockpiles. Such increased 225Ac supplies will be required for thewidespread clinical adoption of emerging 225Ac-based targeted alpha thera-pies to be realized.ivLay SummaryActinium-225 is an isotope that has shown potential for the treatment ofcancer using targeted, alpha-particle-emitting pharmaceuticals. However,global production of actinium-225 is too low to support widespread useor development of these drugs. This thesis demonstrates alternative ac-tinium production methods at TRIUMF, a particle accelerator lab in Van-couver, Canada. Initial efforts used TRIUMF’s ISAC facility to producesmall actinium-225 quantities that were used in medical imaging experimentsrelated actinium radiopharmaceutical development. Efforts then shifted to-wards production via scalable methods: accelerated protons travelling 75%the speed of light were collided with thorium targets, resulting in the decom-position of the thorium nuclei into smaller atoms, including actinium-225.A thorium target capable of withstanding the heat deposited by the protonbeam was developed, nuclear reaction rates were measured and comparedwith simulations, and chemical separation methods were developed to purifythe actinium-225 from the thorium and other radioactive by-products.vPrefaceAll of the work presented in this thesis was conducted at TRIUMF or theUniversity of British Columbia’s Centre for Comparative Medicine, bothlocated on the University of British Columbia Point Grey campus, with theexception of radioactive ICP-MS analysis conducted by Canadian NuclearLaboratories (Chalk River, ON).Chapter 1 was written by me, with contributions to the editing by P.Schaffer. Additional contributions to the editing of Sections 1.3.1, 1.3.2,and 1.3.4 were made by C. Ramogida and V. Radchenko as part of thepublication of these sections as Robertson, A. K. H., Ramogida, C. F.,Schaffer, P., and Radchenko, V. (2018). Development of 225Ac Radiophar-maceuticals: TRIUMF Perspectives and Experiences. Current Radiophar-maceuticals 11(3):156-172 [1]. Sections of this publication written by C.Ramogida and V. Radchenko are not included in this thesis. Reuse of thispublished material in this thesis is permitted under the terms of the Cre-ative Commons Attribution-Non-Commercial 4.0 International Public Li-cense (http://creativecommons.org/licenses/by-nc/4.0/).Chapter 2 was written by me with contributions to the editing by P.Schaffer. Hardware setup of the gamma spectrometer in Section 2.1 wasprovided by T. Moskven, and hardware setup of the alpha spectrometer inSection 2.2 was provided by P. Kunz. Besides these contributions, I wassolely responsible for the remainder of the work described in Sections 2.1and 2.2, including all data collection, analysis, and presentation. AppendixA provides additional details on Section 2.1 and is entirely my original work.Appendix B provides additional details on Section 2.2 and was written byB. McNeil, an undergraduate student working under my supervision. Datacollection and analysis for Appendix B was done by B. McNeil under mydirection. A version of Section 2.3.2 was published as Robertson, A. K.H., Ladouceur, K., Nozar, M., Moskven, L., Ramogida, C. F., D’Auria, J.,Sossi, V., and Schaffer, P. (2017). Design and Simulation of a ThoriumTarget for 225Ac Production. AIP Conference Proceedings 1845(1):020019-1–020019-5 [2]. I ran all Fluka simulations used in this work, analyzedand presented the results, and wrote the text with editing contributionsvifrom all co-authors. Additionally, M. Nozar provided guidance on how toset up the simulations and also created the Fluka geometry input based onthe thorium oxide prototype target designed by L. Moskven, K. Ladouceur,and J. D’Auria. Supervisory authors for this publication were V. Sossiand P. Schaffer, with concept formation of the thorium irradiation initiativecredited to P. Schaffer. This published material is used in this thesis withpermission from AIP Publishing.Chapter 3 was written by me with contributions to the editing by P.Schaffer and C. Ramogida. A version of this chapter was published as partof a larger article in Ramogida, C. F., Robertson, A. K. H., Jermilova,U., Zhang, C., Yang, H., Kunz, P., Lassen, J., Bratanovic, I., Brown, V.,Southcott, L., Rodr´ıguez-Rodr´ıguez, C., Radchenko, V., Be´nard, F., Orvig,C., and Schaffer, P. (2019). Evaluation of polydentate picolinic acid chelat-ing ligands and an α-melanocyte-stimulating hormone derivative for targetedalpha therapy using ISOL-produced 225Ac. EJNMMI Radiopharmacy andChemistry 4(1):21-41 [3]. C. Ramogida and I produced the 225Ac used inthis project and these aspects are presented in Chapter 3. The production of225Ac used for this work relied on the ISAC Implantation Station designedby co-author P. Kunz and the operation of the laser ion source by co-authorJ. Lassen. Sample preparation required for the data in Table 3.2 was done byU. Jermilova. The remaining co-authors (H. Yang, I. Bratanovic, V. Brown,L. Southcott, C. Rodr´ıguez-Rodr´ıguez, V. Radchenko, F. Be´nard, and C.Orvig) contributed to other parts of this publication that are not includedin this thesis. Reuse of this published material in this thesis is permit-ted under the terms of the Creative Commons Attribution 4.0 InternationalLicense (http://creativecommons.org/licenses/by/4.0/).Chapter 4 was written by me and published with minor modificationsas Robertson, A. K. H., Ramogida, C. F., Rodr´ıguez-Rodr´ıguez, C., Blin-der, S., Kunz, P., Sossi, V., and Schaffer, P. (2017). Multi-isotope SPECTimaging of the 225Ac Decay Chain: Feasibility Studies. Physics in Medicineand Biology 62:4406-4420 [4]. All co-authors contributed to editing of thismanuscript. Concept formation was done by supervisory authors P. Schafferand V. Sossi. Input to experiment design was provided at the conceptuallevel by V. Sossi, S. Blinder, and me (in particular, the chromatographycolumn concept utilized in Sections 4.2.5 and 4.3.5) with detailed experi-mental design details finalized by S. Blinder, C. Rodr´ıguez-Rodr´ıguez andme. Guidance on SPECT projection data collection and scanner operationwas provided by C. Rodr´ıguez-Rodr´ıguez. The production of 225Ac used forthis work relied on the ISAC Implantation Station designed by co-author P.Kunz and the post-irradiation chemistry done by C. Ramogida and me. Inviithis publication I was responsible for conducting all aspects of the imagingexperiments, including SPECT/CT data acquisition, image reconstruction,image analysis, data presentation, and writing of the manuscript. Chapter 4is included in this thesis under terms of IOP Publishing’s Author Rights Pol-icy (subscription articles). This chapter is the Accepted Manuscript versionof an article accepted for publication in Physics in Medicine and Biology.IOP Publishing Ltd is not responsible for any errors or omissions in thisversion of the manuscript or any version derived from it. The Version ofRecord is available online at doi.org/10.1088/1361-6560/aa6a99.I was the lead investigator for work presented in Chapters 5, 6, and 7where I was responsible for all major areas of concept formation, hiring andtraining of undergraduate students, experiment design, and the majority ofdata collection, analysis, and presentation. I was also the project proponentfor these efforts, representing the project at internal design and safety re-views. The extensive radiation safety analysis reports required were writtenby me and are shown in Appendices C and D.Chapter 5 was written by me and published with minor modifications asRobertson, A. K. H., Lobbezoo, A., Moskven, L., Schaffer, P., and Hoehr,C. (2019). Design of a Thorium Metal Target for 225Ac Production at TRI-UMF. Instruments 3(1):20-26 [5]. For this effort I was responsible for:project definition and proposal; hiring, training, and supervising of an un-dergraduate student, A. Lobbezoo; representing the project at internal de-sign and safety reviews; coordination of target manufacturing and irradia-tion; and the majority of the writing of the manuscript. The final targetdesign was made by A. Lobbezoo, who under my guidance also performedall of the thermal and mechanical simulations that generated the raw datashown in Chapter 5. Co-author L. Moskven reviewed the simulation work.Co-authors C. Hoehr and P. Schaffer were supervisory authors and con-tributed to editing of the manuscript. I was responsible for the majority ofthe manuscript writing, but received contributions in the methods sectionsand figures from A. Lobbezoo. Reuse of this published material in this the-sis is permitted under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/).Chapter 6 is my original and independent work and represents an effortthat I independently conceived of, proposed, and carried out. An expandedversion of Chapter 6, which includes an additional comparison to Geant4simulations has been published as Robertson, A. K. H., Kunz, P., Hoehr,C., and Schaffer, P. (2020). Nuclide Production Cross Sections from Ir-radiation of Thorium by 438 MeV Protons and a Comparison to FLUKAand GEANT4 Simulations. Physical Review C 102:044613 [6]. Collabora-viiitor P. Kunz provided the Geant4 simulations and C. Hoehr contributed toediting of the manuscript; P. Schaffer was the supervisory author. This pub-lished material is reprinted in this thesis with permission from the AmericanPhysical Society.Chapter 7 was written by me and has been published as Robertson, A. K.H., McNeil, B., Yang, H., Gendron, D. Perron, R., Radchenko, V., Zeisler,S., Causey, P., and Schaffer, P. (2020). 232Th-Spallation-Produced 225Acwith Reduced 227Ac Content. Inorganic Chemistry 59(17):12156-12165 [7].I was the lead investigator for this effort who proposed the project andcarried out the majority of the work. I was responsible for experimentdesign, chemistry process development, most data collection, and all dataanalysis and presentation. Co-author B. McNeil prepared all non-radioactiveICP-MS samples used in the creation of Table 7.1 and Figure 7.6. ICP-MS analysis of radioactive samples (Table 7.2 and Figure 7.7) prepared byme was done by collaborators, D. Gendron, R. Perron, and P. Causey, atCanadian Nuclear Laboratories (Chalk River, ON). The publication waswritten by me, with contributions to the editing from co-authors B. McNeil,H. Yang, D. Gendron, R. Perron, P. Causey, and P. Schaffer. Guidanceduring the chemistry process development was provided by H. Yang and S.Zeisler. This published material is reprinted (adapted) in this thesis withpermission from Robertson et al [7]. Copyright (2020) American ChemicalSociety.Chapter 8 was written by me, with contributions to the editing by P.Schaffer.ixTable of ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iiiLay Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vPreface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viTable of Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . xList of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xivList of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviiiList of Acronyms and Abbreviations . . . . . . . . . . . . . . . . xxviAcknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . .xxviiiDedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxix1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1 Targeted Alpha Therapy and 225Ac . . . . . . . . . . . . . . 21.1.1 Radiation therapy for cancer treatment . . . . . . . . 21.1.2 Diagnostic radiopharmaceuticals . . . . . . . . . . . . 51.1.3 Ionizing radiation interactions with matter . . . . . . 71.1.4 Radionuclide therapy . . . . . . . . . . . . . . . . . . 101.1.5 Clinical uses of 225Ac in targeted alpha therapy . . . 141.2 Properties of the 225Ac Decay Chain . . . . . . . . . . . . . . 171.2.1 Radioactive decay and decay chain dynamics . . . . . 181.2.2 225Ac and its progeny . . . . . . . . . . . . . . . . . . 241.2.3 225Ra, the parent of the 225Ac decay chain . . . . . . 271.2.4 Quantification of 225Ac, its parent, and its progeny . 271.2.5 Daughter Recoil . . . . . . . . . . . . . . . . . . . . . 31x1.3 Current 225Ac Production Challenges . . . . . . . . . . . . . 311.3.1 Existing 225Ac supplies . . . . . . . . . . . . . . . . . 321.3.2 The need for new 225Ac production methods . . . . . 351.3.3 Nuclear reactions for radionuclide production . . . . . 361.3.4 Potential alternative 225Ac production methods . . . 401.4 Thesis Outline . . . . . . . . . . . . . . . . . . . . . . . . . . 482 Methods Used for Radioactivity Quantification and Estima-tion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512.1 Gamma Spectroscopy . . . . . . . . . . . . . . . . . . . . . . 512.1.1 Background . . . . . . . . . . . . . . . . . . . . . . . 522.1.2 Energy and shape calibration . . . . . . . . . . . . . . 542.1.3 Background spectra . . . . . . . . . . . . . . . . . . . 582.1.4 Peak-to-total calibration and cascade correction . . . 612.1.5 Efficiency calibration . . . . . . . . . . . . . . . . . . 632.1.6 Effect of cascade summing on nuclides with cascades 712.1.7 Efficiencies calibrations for additional geometries . . . 732.1.8 Gamma spectroscopy for 225Ac quantification . . . . 732.1.9 Summary . . . . . . . . . . . . . . . . . . . . . . . . . 742.2 Alpha Spectroscopy . . . . . . . . . . . . . . . . . . . . . . . 742.3 FLUKA Simulations . . . . . . . . . . . . . . . . . . . . . . . 772.3.1 An Introduction to Fluka . . . . . . . . . . . . . . . 772.3.2 An example Fluka study . . . . . . . . . . . . . . . 783 225Ac Production at TRIUMF’s ISAC Facility . . . . . . . 843.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . 843.2 Methods Used for 225Ac Production at ISAC . . . . . . . . . 843.3 Results from 225Ac Production at ISAC . . . . . . . . . . . . 873.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 944 Multi-Nuclide SPECT of the 225Ac Decay Chain . . . . . . 954.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . 954.2 Materials and Methods . . . . . . . . . . . . . . . . . . . . . 964.2.1 Relevant physical properties, production, and quan-tification of 225Ac . . . . . . . . . . . . . . . . . . . . 964.2.2 Data acquisition and image reconstruction . . . . . . 974.2.3 Image contrast and noise . . . . . . . . . . . . . . . . 994.2.4 Image resolution and limit of detection . . . . . . . . 1014.2.5 Dynamic imaging of differing 221Fr and 213Bi distri-butions . . . . . . . . . . . . . . . . . . . . . . . . . . 103xi4.3 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044.3.1 Image contrast and noise . . . . . . . . . . . . . . . . 1044.3.2 Image resolution and limit of detection . . . . . . . . 1074.3.3 Dynamic imaging of 221Fr and 213Bi distributions . . 1074.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135 Thorium Target Design and Irradiation . . . . . . . . . . . . 1145.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . 1145.2 Materials and Methods . . . . . . . . . . . . . . . . . . . . . 1155.2.1 TRIUMF’s 500 MeV Isotope Production Facility . . . 1155.2.2 Proton beam parameters . . . . . . . . . . . . . . . . 1175.2.3 Thorium target . . . . . . . . . . . . . . . . . . . . . 1175.2.4 Thermomechanical modelling . . . . . . . . . . . . . . 1225.2.5 Yield measurements . . . . . . . . . . . . . . . . . . . 1255.3 Results and Discussion . . . . . . . . . . . . . . . . . . . . . 1255.3.1 Modelling and sensitivity analysis . . . . . . . . . . . 1255.3.2 Test irradiations . . . . . . . . . . . . . . . . . . . . . 1295.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1306 Measured and Simulated 232Th(p,x) Cross Sections . . . . 1326.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . 1326.2 Materials and Methods . . . . . . . . . . . . . . . . . . . . . 1336.2.1 Basic definitions and equations . . . . . . . . . . . . . 1336.2.2 Accounting for non-continuous irradiations . . . . . . 1376.2.3 Thorium irradiations . . . . . . . . . . . . . . . . . . 1386.2.4 Gamma spectra acquisition and analysis . . . . . . . 1396.2.5 Monitor reactions . . . . . . . . . . . . . . . . . . . . 1416.2.6 Cross sections calculations and uncertainties . . . . . 1486.2.7 Fluka simulations . . . . . . . . . . . . . . . . . . . 1496.3 Results and Discussion . . . . . . . . . . . . . . . . . . . . . 1516.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1577 225Ac Purification from Thorium Targets . . . . . . . . . . . 1607.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . 1607.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1617.2.1 Materials and reagents . . . . . . . . . . . . . . . . . 1617.2.2 Fluka simulations . . . . . . . . . . . . . . . . . . . 1627.2.3 Gamma spectroscopy . . . . . . . . . . . . . . . . . . 1627.2.4 Process development using non-irradiated materials . 164xii7.2.5 Process characterization using multi-element ICP-MSstandards and radiotracers . . . . . . . . . . . . . . . 1677.2.6 ICP-MS measurements of 227,225Ac† and 225Ac* . . . 1687.2.7 Radiolabelling tests with 227,225Ac† and 225Ac* . . . 1697.3 Experimental . . . . . . . . . . . . . . . . . . . . . . . . . . . 1707.3.1 225Ra and 225Ac production by thorium irradiation . 1707.3.2 227,225Ac† and 225Ac* purification . . . . . . . . . . . 1717.3.3 Comparison of 227,225Ac† and 225Ac* products . . . . 1767.4 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1797.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1818 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196AppendicesA Additional Details on Gamma Spectroscopy Calibrations 225A.1 Pulse Shape Timing Effects on Energy Resolution . . . . . . 226A.2 Fits to Peaks used in Energy and Shape Calibrations . . . . 228A.3 Peak Width Values Based on Linear Calibration Curve . . . 237A.4 Library Used for Background Analysis . . . . . . . . . . . . . 238A.5 Isotopes in the Genie 2000 v3.2 Cascade Summing Library . 241A.6 Library Used for Peak-to-Total Calibration . . . . . . . . . . 242A.7 Fits to Peaks used in the Efficiency Calibration . . . . . . . 243A.8 List of 133Ba and 152Eu Calibration Sources . . . . . . . . . 260B Alpha Spectroscopy Procedures . . . . . . . . . . . . . . . . . 261C Safety Analysis Report for Irradiation of Thorium Targets 277D Safety Analysis Report for Chemical Processing of ThoriumTargets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320xiiiList of Tables1.1 Summary decay properties for nuclides in the 225Ac decay chain. 261.2 Summary of current and potential 225Ac production meth-ods. Production values for current sources list current pro-duction levels, while values for potential sources list estimatesof maximum possible production at sample of existing and op-erational facilities that have dedicated stations for large-scalemedical isotope production. Details of calculations or refer-ences to cited values can be found in the text. Values listedfor 226Ra targets assume a target mass of 1 g. . . . . . . . . 471.3 Other methods for 225Ac production. . . . . . . . . . . . . . 482.1 Gamma peaks used by the energyCalibration.ctf certifi-cate file along with values from an energy calibration per-formed on 2016-09-24. Peak centroid values were determinedusing Genie 2000’s Interactive Peak Fit Tool. These valuesare plotted in Figure 2.1. . . . . . . . . . . . . . . . . . . . . 552.2 Peak shape calibration values determined during an energycalibration on 2016-09-24. The resulting width and tail cali-brations are shown in Figures 2.2 and 2.3, respectively. . . . 572.3 Peaks (>20 keV) seen in typical 24-hour background acquisi-tion on the detector in TRIUMF’s RCR1 lab, including a com-parison with other detectors at TRIUMF and the naturally-occurring source of the peaks. . . . . . . . . . . . . . . . . . 602.4 Spectra used for the peak-to-total calibration, including theorigins of calibration sources used. . . . . . . . . . . . . . . . 622.5 Expected and measured ratios of individual peak areas withinmultiplets used in the efficiency calibration, as determinedusing the Interactive Peak Fit Tool. . . . . . . . . . . . . . . 64xiv2.6 Measured efficiency values for all peaks used to determine thecalibration curve shown in Figure 2.6. . . . . . . . . . . . . . 652.7 Measured efficiency values for all peaks used to determine thecalibration curves shown in Figure 2.9. . . . . . . . . . . . . 702.8 Measurements of cascade-free isotopes determined using acascade-negligible geometry (20 cm SDD) and a cascade-prone geometry (0 cm SDD). . . . . . . . . . . . . . . . . . . 712.9 Radioactivity composition of a 20 mL sample containing iso-topes with significant cascades, measured using a cascade-negligible geometry (20 cm SDD) and a cascade-prone geom-etry (0 cm SDD). The decay chain containing 225Ac, 221Fr,and 213Bi was in transient equilibrium at the times of mea-surement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722.10 Fluka estimation indicating the radioactive inventory of thethorium target immediately and one week after a 1130 µA*hirradiation at 90 µA. . . . . . . . . . . . . . . . . . . . . . . . 822.11 Predicted amount of 225Ac produced when the Ra/Ac sep-aration is performed 1 week after EOB. Impurities of otheractinium isotopes are expressed as a percent of the 225Ac ac-tivity. Due to their short half-lives, 228Ac and 226Ac percentimpurities decrease with time. . . . . . . . . . . . . . . . . . . 822.12 Predicted amount of 225Ac and impurities (expressed as ac-tivity ratios) produced when the radium fraction (initiallyseparated from actinium in Table 2) is used as an 225Ac gen-erator. 227Ac impurity is significantly reduced from Table 1due to the short half-life of its parent 227Ra. 226Ac impuri-ties are effectively removed since no radium isotopes decayto 226Ac. 228Ac impurities decrease with time after the Ac isremoved from the generator. . . . . . . . . . . . . . . . . . . . 833.1 Summary of 225Ra and 225Ac production runs at ISAC, TRI-UMF’s ISOL facility. aEE = extraction electrode; bLIS =laser ionization source. The values of 225Ra and 225Ac ra-dioactivity produced have uncertainties between 3-5%. . . . . 923.2 Trace metal content in ppb (µg/L) determined by ICP-MS(n=2, average ± standard deviation). Values denoted with(*) were determined by ICP-OES (n=1). . . . . . . . . . . . . 93xv4.1 Activities used, acquisition durations, and counts acquiredin each photopeak for all imaging experiments. Values fordynamic scans list the number of counts in the first frame. . . 1004.2 Image quality results from images of the contrast phantom,including the ideal values expected from a perfect image. . . . 1064.3 Recovery coefficients measured within resolvable rods of theresolution phantom. Omitted values denote rods that are notresolved (inter-rod contrast <0.2). . . . . . . . . . . . . . . . 1085.1 Base properties at room temperature for target components. . 1195.2 Elemental composition of alloys used in IPF targets. Valuesare from supplier certificates of analysis unless otherwise stated.1205.3 Comparison of thorium to select aluminum and copper alloysin terms of material properties relevant to thermal contactresistance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225.4 Thermal contact resistances for select materials under vac-uum conditions. . . . . . . . . . . . . . . . . . . . . . . . . . . 1225.5 Energy deposited in thorium target components by 454 MeVprotons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235.6 Energy deposited in thorium target components by 454 MeVprotons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1266.1 Gamma spectroscopy data derived from analysis of the irra-diation thorium samples, including the time of measurement(tm) since end of irradiation, all gamma lines used in the anal-ysis, and total radioactivity A in the entire thorium foil at thetime of measurement. . . . . . . . . . . . . . . . . . . . . . . 1426.2 Results from gamma spectroscopy measurements of the In-conel foil used for beam monitor reaction and the resultingproton current estimates. . . . . . . . . . . . . . . . . . . . . 1476.3 Measured and calculated cross sections from the 438 MeVproton irradiation of thorium. . . . . . . . . . . . . . . . . . . 1547.1 Results (n = 1) for studies using stable multi-element ICP-MS standards as tracers for the column chromatography sec-tions of the 227,225Ac† purification process (see Section 7.2.5).Values represent the portion of each element found in eachfraction of the process, after correcting for background quan-tities measured when no tracers were present. The boldedcolumn represents the final 227,225Ac† product. . . . . . . . . 175xvi7.2 Average (n = 2) radionuclidic purity of 227,225Ac† and 225Ac*products, decay corrected to the times of final product pu-rification. 227Ac values were determined by ICP-MS (Section7.2.6) while all other values were determined by gamma spec-troscopy (Section 7.2.3). . . . . . . . . . . . . . . . . . . . . . 178A.1 List of calibration sources belonging to TRIUMF Life Sciencesgroup used for the calibration of the detector. All activityvalues refer to the activity on 2016-06-01. . . . . . . . . . . . 260xviiList of Figures1.1 The decay chain of 225Ac and its parent, 225Ra, includinggamma emissions with high branching ratios that are usefulfor radioactivity measurements. . . . . . . . . . . . . . . . . . 171.2 Equation 1.9 for different ratios of parent:daughter half-lives,with the number of parent half-lives on the x-axis. The equi-librium cases in plots a) and b) are also shown in Figure 1.3. 211.3 Equation 1.9 for different ratios of parent:daughter half-lives,with the number of daughter half-lives on the x-axis. Theseplots show a daughter nuclide as it comes into secular (a) ortransient (b) equilibrium with its parent nuclide. . . . . . . . 221.4 In-growth of a daughter nuclide that reaches secular equi-librium with its parent, with individual lines representing adifferent initial amount of daughter activity (between 0 and100% of parent activity at time t = 0). . . . . . . . . . . . . . 231.5 In-growth of 225Ac activity from a 225Ra source containingzero 225Ac at time t = 0. . . . . . . . . . . . . . . . . . . . . . 281.6 In-growth of 225Ac activity from a 225Ra generator, withRa/Ac separation occurring approximately every 17.4 days. . 281.7 In-growth of 225Ac progeny, 221Fr, 213Bi, and 209Tl, from an225Ac source containing zero 225Ac progeny at time t = 0. . . 291.8 Decay schematic showing the decay and generator-based pro-duction pathways for 225Ac. Gamma emissions useful forquantification of 225Ac are shown in red. . . . . . . . . . . . 342.1 Energy calibration curve from 2016-09-24. The uncertaintiesfor each data point are listed in Table 2.1. . . . . . . . . . . 56xviii2.2 Peak width calibration curves determined by Genie 2000 andby a linear fit. The poor agreement of the Genie 2000 cali-bration curve is evident. This calibration was performed on2016-09-24. Verification of the calibration was performed on2016-12-05 using an number of different radionuclides. Thebroader nature of annihilation photons is also shown. . . . . 572.3 Peak low-tail values and the calibration curve determined byGenie 2000 using a linear fit. Values and uncertainties aredetermined by Genie 2000. This calibration was performedon 2016-09-24. . . . . . . . . . . . . . . . . . . . . . . . . . . 582.4 Peak-to-Total Calibration performed 2016-12-23. Figureshows the calculated calibration curve as well as the values(including error bars) measured during the calibration. . . . . 632.5 3D printed sample holders used to reproducibly position 20mL vials at nominal sample-to-detector distances of 5, 10, 15,and 20 cm (left) and 0 cm (right). . . . . . . . . . . . . . . . 662.6 Efficiency calibration curve determined for a 20 mL vial withapproximately 20 cm SDD. The 133Ba and 152Eu peaks usedto fit the curve are also shown. A spline fit with 81 keVcrossover is used, dividing the curve into a low and a highenergy fit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662.7 225Ra decay chain, including gamma emissions with highbranching ratios. . . . . . . . . . . . . . . . . . . . . . . . . . 672.8 Gamma spectroscopy measurements of the 225Ra decay chainof the same sample over time. Dotted lines represent calcu-lated 225Ra , 221Fr , and 213Bi activity concentrations pre-dicted from the first data point at t = 116h, and assumingzero 225Ac at t = 0, as is usually observed. . . . . . . . . . . 682.9 Efficiency calibration curves determined for a 20 mL vial withapproximately 0 cm SDD, determined both with (green) andwithout (blue) cascade correction. The 133Ba and 152Eu peaksused to fit the curves are also shown. A spline fit with 81 keVcrossover is used, dividing the curve into a low and a highenergy fit. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712.10 Gamma ray spectrum of the 225Ac decay chain in equilibrium,shown with both a linear (top) and log (bottom) y-axis. . . . 732.11 An example alpha particle energy spectrum collected from asample containing 225Ac and its progeny in equilibrium. . . . 762.12 Models of the thorium oxide target design made in Fluka(top) and in SolidWorks (bottom). . . . . . . . . . . . . . . . 80xix3.1 Beamlines at TRIUMF’s ISAC facility that are relevant for225Ra and 225Ac production. . . . . . . . . . . . . . . . . . . . 853.2 Solid model of the ISAC implantation chamber for collectionof radioactive ion beams. The inset photograph in the top leftcorner shows the aluminum target used for 225Ra and 225Acion beam collection. . . . . . . . . . . . . . . . . . . . . . . . 863.3 225Ra/225Ac radiochemical separation methods used for pu-rification of ISOL-produced 225Ac. . . . . . . . . . . . . . . . 873.4 SRIM simulation results showing the depth distribution of 40keV 225Ra+ ions incident on an aluminum surface. . . . . . . 883.5 Representative elution profile for 225Ra/225Ac separation onDGA branched resin in nitric acid media. . . . . . . . . . . . 883.6 Representative gamma ray spectrum of a sample containingboth 225Ra and 225Ac, before purification using the procedureshown in Figure 3.3. The spectrum is shown with both a lin-ear (top) and log (bottom) y-axis. Evident is the 40 keV peakused for 225Ra quantification, as well as the 218 keV 221Frpeak and the 440 keV 213Bi peak that can be used for 225Acquantification under decay chain equilibrium conditions (seeSection 1.2.4). The less detectable 100 keV peak of 225Ac canbe used for direct quantification provided there are enoughcounts in the peak to provide a sufficient signal to noise ra-tio. However, as shown in the figure, this 100 keV peak islocated in the energy region with highest background signal(Compton scatter) and near many other potentially overlap-ping peaks, making it less desirable for 225Ac quantification. . 893.7 Gamma ray spectrum of a sample containing 225Ra and un-detectable quantities of 225Ac (fraction 1 of the procedureshown in Figure 3.3). The spectrum is shown with both alinear (top) and log (bottom) y-axis. Evident is the 40 keVpeak used for 225Ra quantification. Small amounts of 213Biare often seen in this fraction as evident from the small 440keV peak. However, the absence of 218 keV 221Fr peak indi-cates that this 213Bi does not result from the decay of 225Acwithin the purified 225Ra fraction. . . . . . . . . . . . . . . . 903.8 Gamma ray spectrum of a sample containing 225Ac and inde-tectable quantities 225Ra (fraction 3 of the procedure shownin Figure 3.3). The spectrum is shown with both a linear(top) and log (bottom) y-axis. . . . . . . . . . . . . . . . . . . 91xx4.1 Energy spectra, normalized by acquisition time, acquired bythe VECTor scanner for both HEUHR (red) and UHS (green)collimators with a comparison to a background spectrum(grey) acquired with no collimator or activity present. Spec-tra were acquired using a uniform source containing 1.05 MBq(28.3 µCi) of 225Ac. The energy regions used to reconstructthe 221Fr and 213Bi are shown in blue and red, respectively.The adjacent grey regions indicate the energy windows de-fined for background and scatter correction. . . . . . . . . . . 994.2 (a) SPECT cross section of the phantom’s contrast region,with green circles indicating the location of ROIs used to de-termine contrast measurements, and the red line showing thelocation of the measured profiles. (b) SPECT cross sectionof the phantom’s uniform region, with blue circle indicatingthe location of the ROI used for the ‘warm’ region, and greencircles indicating the ROIs used for noise measurements. . . . 1024.3 221Fr and 213Bi images of the contrast phantom acquired withboth the HEUHR and UHS collimators and filtered with a1mm 3D Gaussian filter. . . . . . . . . . . . . . . . . . . . . . 1034.4 Profiles through contrast phantom images in the uniform re-gion (a) and the contrast region (b). The ideal profile (solidgrey) showing the known activity concentration and associ-ated error (dashed grey) has been filtered with the same Gaus-sian filter applied to the images. Profiles from 221Fr imagesare shown in blue, and profiles from 213Bi images in red. . . . 1044.5 221Fr and 213Bi images of the resolution phantom acquiredwith both the HEUHR and UHS collimators . . . . . . . . . . 1054.6 Profiles through rods of 0.95 mm diameter (left), 1.30 mmdiameter (centre), and 1.70 mm diameter (right). The appar-ent activity within each rod can be compared to the knownvalue of (0.13 ±0.01) mCi/mL. Profiles from 221Fr images areshown in blue, and profiles from 213Bi images in red. . . . . . 1074.7 Inter-rod contrast measurements from the resolution phantomimages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108xxi4.8 221Fr and 213Bi SPECT images (left) of the cation exchangecolumn acquired with the HEUHR collimator at multiple one-hour intervals after elution. Times for each image indicatethe start time of the image frame. The CT image (right)corresponds to the same region of the phantom as the SPECTimages. The black outlines in the 221Fr SPECT image att = 260 min indicate the boundaries of the volumes usedto determine the total activities within the eluate and resin,plotted in Fig. 4.9. A non-uniform distribution of activity inthe resin is also observed. . . . . . . . . . . . . . . . . . . . . 1094.9 Plots of the total 221Fr and 213Bi activity within the resin(left) and the eluate (right) obtained from images of the cationexchange column. Background values (measured outside thecolumn volume) have been subtracted. . . . . . . . . . . . . . 1105.1 a) IPF target station at beam level, with six cassettes in-serted into the beam. The arrows indicate cooling water flowdirection. (b) An IPF cassette holding two targets. (c) Atypical IPF target. . . . . . . . . . . . . . . . . . . . . . . . . 1165.2 a) Target sub-assembly, including the thorium foil, weldingring, and entrance and exit windows. Note the location ofEB welds that bind the windows to the welding ring, sealingthe thorium within. (b) Welding of the sub-assembly to thetarget frame. (c) Photo of the thorium target. Note theinward deflection of the Inconel R© 718 window. . . . . . . . . 1195.3 Plot of the thorium target sub-assembly thickness. Measure-ment of the inward deflection of the window, as also seen inFigure 5.2c, indicates the region for which the thorium andwindows are in contact. The expected thickness in the centreof the sub-assembly (assuming contact of the thorium withboth windows) is 504 µm. . . . . . . . . . . . . . . . . . . . . 1215.4 a) Example of simulated flow streamlines and temperatures;and b) stresses in the target entrance window for a 100 µA,20 mm beam. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1285.5 Maximum simulated temperatures within target window(left) and thorium foil (right) components during irradiationsof varying beam current and width. . . . . . . . . . . . . . . . 128xxii5.6 Maximum simulated stresses resulting from temperatureswithin window (left) and thorium (right) target componentsduring irradiations. Note that increase in thorium foil stressesas beam width increases (from 15 to 25 mm) is due to deposi-tion of heat in regions of the thorium that are not in contactwith the window. . . . . . . . . . . . . . . . . . . . . . . . . . 1296.1 Gamma spectrum acquired of the irradiated thorium sample,7.3 days after EOB, with select gamma lines from Table 6.1labelled. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1406.2 Independent cross sections for the 438 MeV proton irradiationof thorium determined via Fluka, as described in Section6.2.7.1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1516.3 (a) Independent total mass cross sections determined byFluka (Section 6.2.7.1) are compared to measured mass crosssections. The total mass cross sections could only be deter-mined for mass numbers 228, 227, and 111 – in other cases,cumulative cross sections for a given mass number could onlybe measured on one side of the line of stability and thereforerepresent only a partial contribution to the total independentmass cross section. Cumulative cross sections for 207Bi, 206Po,and 205Bi are excluded since they are cumulative (not inde-pendent) with respect to the total mass, due to mass changesby alpha decay. (b) A comparison of measured (Section 6.2.6)and calculated (Section 6.2.7.2) radioactivities in the the ir-radiated target. . . . . . . . . . . . . . . . . . . . . . . . . . . 1536.4 A comparison of cross sections determined in this work at438 MeV, to literature (from the EXFOR database) and cal-culated values over the 0 to 1000 MeV range. The type ofcross section (independent or cumulative) is indicated in Ta-ble 6.3. The axes label and legend for all plots is shown inthe lower right. . . . . . . . . . . . . . . . . . . . . . . . . . . 1566.5 Energy spectra of primary protons, secondary protons, andsecondary neutrons crossing the thorium foil in the Flukasimulations of the IPF target during irradiation, as describedin Section 6.2.7.2. . . . . . . . . . . . . . . . . . . . . . . . . . 1586.6 Relative contribution of secondary protons and neutrons tonuclide production during the thorium target irradiation, asestimated by Fluka simulations described in Section 6.2.7.2. 159xxiii7.1 Calibration curves and UV-absorption spectra for thorium-arsenazo complexes in 1 M HNO3 (top) and 1 M citric acid(bottom). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1657.2 Example TLC trace data including a negative control (left)showing no 225Ac labelling, a positive control (centre) showingcomplete 225Ac labelling, and an example of a TLC indicatingpartial labelling (right), including the regions used for peakareas and background subtraction. . . . . . . . . . . . . . . . 1697.3 Elements with radioisotopes present inside the irradiated tho-rium at 1 week after the end of irradiation, and from whichAc must be separated in order produce a radiochemicallypure product. Elements in gray have isotopes with activi-ties <0.1% of the 225Ac radioactivity, as estimated by Flukasimulations (see Section 7.2.2). Elements in black have esti-mated activities >0.1% of the estimated 225Ac radioactivity. . 1707.4 Flowchart describing the process used to produce 227,225Ac†and 225Ac* products from thorium metal irradiated with highenergy (>100 MeV) protons. Coloured squares correspond tothe fractions shown in the Figure 7.6 legend. . . . . . . . . . 1827.5 Elution profiles for Th, Ra, and Ac on the cation exchangecolumn (top) and DGA-normal column (bottom) using tho-rium colorimetry, 227Th, 225,224,223Ra, and 228,225Ac as tracers(see Section 7.2.4). Each data point represents the average± standard deviation (n = 3) of independent elution profilemeasurements with the 7 individual tracers. . . . . . . . . . . 1837.6 Results from tracer studies of the thorium processing schemechromatography column steps. Elements with bold bor-ders were evaluated using radiotracers (96Tc, 103Ru, 101mRh,114mIn, 117mSn, 121m,121Te, 205,206Bi, 225,224,223Ra, 228,225Ac).All other elements were evaluated using multi-element ICP-MS standards as tracers. The area of each colour is propor-tional to the amount of the elemental tracer found in thefraction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1847.7 Average ± standard deviation (n = 2) stable elemental im-purities in the 227,225Ac† and 225Ac* products, measured asdescribed in Section 7.2.6. . . . . . . . . . . . . . . . . . . . . 184xxiv7.8 Concentration dependent radiolabelling studies with227,225Ac† and 225Ac* products for both DOTA (85◦C, 30min, pH 7) and macropa (ambient temperature, 30 min, pH7), as described in Section 7.2.7. Each data point representsthe average ± standard deviation of n = 6 replicates (n= 3 replicates for each of the two 227,225Ac† and 225Ac*production runs). . . . . . . . . . . . . . . . . . . . . . . . . . 185xxvList of Acronyms and Abbrevia-tionsARIEL Advanced Rare Isotope LaboratoryBL1A Beamline 1ABNL Brookhaven National LaboratoryBq (kBq, MBq, etc.) bequerel (kilobequerel, megabequerel, etc.)Ci (mCi, etc.) curie (millicurie, etc.)CNL Canadian Nuclear LaboratoriesCT computer tomographyDGA diglycolamineDNA deoxyribonucleic acidDOE Department of EnergyDOTA dodecane tetraacetic acidEB electron beamEOB end of bombardmenteV (keV, MeV, etc.) electronvolt (kiloelectronvolt, megaelectronvolt)EXFOR Exchange FormatFDG fluorodeoxyglucoseFLUKA fluktuierende kaskadeFWHM full width at half maximumHEUHR high-energy ultra high resolutionHPGe high purity germaniumIAEA International Atomic Energy AgencyICP-MS inductively coupled plasma mass spectroscopyICP-OES inductively coupled plasma optical emission spectroscopyIIS ISAC Implantation StationINR Institute for Nuclear ResearchIPF Isotope Production FacilityIPPE Leipunskii Institute for Physics and Power EngineeringxxviISAC Isotope Separator and AcceleratorISOL isotope separation onlineITU Institute for Transuranium ElementsLANL Los Alamos National LaboratoryLET linear energy transferMCA multi-channel analyzerMEDICIS Medical Isotopes Collected from ISOLDENIST National Institute of Standards and TechnologyORNL Oak Ridge National LaboratoryPET positron emission tomographyPSMA prostate specific membrane antigenRCR1 Radiochemistry Room 1ROI region of interestRPG Radiation Protection GroupSDD source-to-detector distanceSI International System of UnitsSPECT single photon emission computed tomographySRIM Stopping Range of Ions in MatterTAT targeted alpha therapyTLC thin layer chromatographyTRIUMF Tri-University Meson FacilityTRT targeted radionuclide therapyUHS ultra high sensitivityUV ultravioletVECTor versatile emission computed tomographyxxviiAcknowledgementsI offer my enduring gratitude to the faculty, staff, and fellow students atTRIUMF and UBC, especially all members of TRIUMF’s Life Sciences Di-vision for their support of me and this work and their scientific and technicalguidance that made it successful. I owe particular thanks to Dr. Paul Schaf-fer for providing me with incredible mentorship and countless opportunitiesto grow as a scientist, individual, and leader.Special thanks is offered to my parents for supporting me through yearsof education. Most of all, I would like to thank my life partner for her endur-ing love, moral support, and sacrifices in time not spent together throughoutmy graduate studies.TRIUMF receives funding via a contribution agreement with the Na-tional Research Council of Canada. This research was supported by schol-arships (NSERC PGS D (518984-2018), IsoSiM CREATE (448110)) and aDiscovery Grant (RGPIN 2016-04413) from the Natural Sciences and Engi-neering Research Council of Canada.xxviiiDedicationTo Sarahxxix1 IntroductionTargeted radionuclide therapy (TRT) combining disease-targetingbiomolecules with radionuclides emitting cytotoxic charged particleradiation is used in the treatment of cancers. While beta-particle-emittingnuclides such as 177Lu, 131I, and 90Y have achieved clinical approval[8–10], there is currently a heightened interest in the potential of alpha-particle-emitting radionuclides as a complementary – and possibly morepotent – therapeutic approach [11–22]. One non-targeted alpha-emittingradiopharmaceutical containing 223Ra has already received clinical adoption[23, 24]. Due to the higher linear energy transfer and shorter range ofalpha-radiation, alpha-emitting nuclides selectively delivered to diseasedcells are more potent and damage fewer surrounding healthy cells thanbeta-emitting nuclides. These advantages have recently been demonstratedby patients who successfully responded to treatment with an alpha-emittingradionuclide after failing to respond to a beta-emitting analog, or notqualifying for treatment with a beta-emitting analog due to the closeproximity of metastases to organs at risk [25]. Alpha particles also causedouble-stranded DNA breaks, which are more resistant to DNA repairmechanisms [26], and unlike other forms of radiation, the biological responseto alpha-radiation has been shown to be independent of dose rate andoxygenation [27]. Sections 1.1.1 through 1.1.4 will discuss TRT in greaterdetail and introduce key concepts such as radiation therapy, radioactivedecay, and radiopharmaceuticals.Actinium-225 (225Ac, t1/2 = 9.92 d) is a promising candidate alpha-emitter for use in TRT due to its suitable half-life, favorable chemistry, anda decay chain that contains four alpha-emissions and no long-lived progeny.The cytotoxic effects of 225Ac were demonstrated decades ago [28], and clin-ical results have since demonstrated the remarkable ability of this nuclideto treat advanced metastatic disease [25, 29–32]. Sections 1.1.4 and 1.1.5will describe what makes 225Ac such a suitable alpha-emitter for TRT andsummarize clinical data demonstrating its effectiveness.1However, the nature of the 225Ac decay chain (detailed in Section 1.2.1)presents challenges for patient dosimetry, a cornerstone of conventional ra-diation therapy that is used to correlate the quantity of radiation deliveredwith resulting biological outcomes. The benefit of the 225Ac decay chain’sfour alpha emissions requires the retention of both 225Ac and its nuclearprogeny at target cells, despite liberation of daughter isotopes after eachdecay [15]. Individual biodistributions of each nuclide (especially 221Fr and213Bi) must therefore be determined when assessing the efficacy of 225Acradiopharmaceuticals. However, this is a quantification problem that iscomplicated by the half-lives and types of radiation emitted by 225Ac andits progeny.Additionally, the development of 225Ac-radiopharmaceuticals has beenhindered by the limited global 225Ac production capacity [1, 33–35], resultingin an intense global effort to increase 225Ac production by methods otherthan the typical 229Th/225Ac generators historically derived from decades-old 233U stockpiles [1, 33, 36–40]. Current and alternative methods for 225Acproduction will be discussed in Section 1.3.Section 1.4 will then detail how this thesis aims to address both theproduction and dosimetry challenges facing the development of 225Ac-radiopharmaceuticals. Before that, Chapter 1 will first introduce key con-cepts and background information, such as: radiation therapy, radiopharma-ceuticals, and targeted alpha therapy with 225Ac (Section 1.1); radioactivityand decay chains, 225Ac properties, and 225Ac decay chain quantification(Section 1.2); and radionuclide production methods, including a review ofcurrent and potential 225Ac production methods (Section 1.3).1.1 Targeted Alpha Therapy and 225Ac1.1.1 Radiation therapy for cancer treatmentIonizing radiation has been used in the treatment of cancer since soon afterthe discovery of the x-ray in 1895 [41, 42]. However, while therapeutic andpalliative benefits of radiation therapy were observed, an incomplete knowl-edge of radiation physics, the biological effects of radiation, the underlyingradiobiological mechanisms led to morbidities and misuse of radiation andradioactivity during the beginning of the 20th century. Our current under-standing of the mechanisms through which radiation can provide therapeuticbenefit – and how it can also cause harm – was not made possible until thediscovery of deoxyribonucleic acid (DNA) and its essential role in life [43],and later, in radiation-induced biological damage.2Cancers are diseases that result from mutations to biological cells. Whilemany different types of mutations can be involved, hallmarks of cancer in-clude: evading growth suppression, inducing angiogenesis, resisting death,sustained proliferative signaling, and evading growth suppression. All can-cers are also characterized by some form of uncontrolled and invasive cellulargrowth. While healthy biological cells will grow, replicate, divide, and dieat a controlled rate, cells that grow too quickly become tumours. Tumoursthat are invasive and grow in a way such that they invade other tissues be-come cancer. Cancer cells can migrate from the tumour and travel throughthe cardiovascular or lymphatic systems to invade distant parts of the body,forming metastases. While this rapid cellular division (rapid relative tohealthy cells) is part of what makes cancers so harmful, it also provides amechanism through which the disease is often targeted.DNA replication is an important step in cell division that allows eachnew cell to retain a copy of the molecule that ultimately controls all cellularchemistry via the synthesis of proteins. When DNA was discovered, theobservation that heredity was a stable process lead to the assumption thatDNA itself must be a stable molecule. However, despite its importance, DNAis actually quite unstable. Instead, a number of DNA repair processes haveevolved. Multiple DNA repair mechanisms exist for different types of DNAdamage, including single-strand breaks (damage to one of the two DNAbackbones, which is more common but more easy to repair) and double-strand breaks (damage to both backbones, which is more rare yet moredifficult to repair). DNA damage, if not repaired, most often leads to celldeath by preventing the cell from functioning or dividing properly. Cellsthat replicate more frequently are more sensitive to DNA damage becausethey are more often in DNA replication stages of the cell cycle where DNArepair cannot occur. By damaging DNA, ionizing radiation is more harmfulto more rapidly dividing cancerous cells than it is to healthy cells.Ionizing radiation causes DNA damage induced by ionization of atomswithin the cell. This damage can be direct or indirect. More often, damageis indirect and caused by the ionization of another molecule, causing radiol-ysis and formation of free radicals that then chemically interact with DNA.Since cells are mostly water, these free radicals are typically reactive oxygenspecies, for example, *OH, H2O2, H3O+, OH-, H+, e-aq, etc. The mecha-nisms through which radiation interacts with matter to cause ionization arefurther explained in Section 1.1.3.It is important to keep in mind that while radiation may be more destruc-tive to cancerous tissues, it is harmful to healthy cells as well. The essentialchallenge in radiation therapy is determining how to deliver radiation to the3cancer while minimizing the dose to nearby healthy tissues. Often, it is thetoxicity to nearby healthy organs-at-risk that limits the radiation dose thatcan be delivered to the tumour. The amount of energy deposited in mat-ter by ionizing radiation is measured by the quantity absorbed dose, whichhas the SI unit gray (Gy) equivalent to one Joule of absorbed energy perkilogram of matter. Decades of research has shown that absorbed dose dis-tributions are correlated with biological outcomes of both targeted tissues(cancer) and healthy tissues (organs-at-risk), allowing this quantity to beused in radiation therapy treatment planning.Radiation therapy is most often delivered with an external beam of ra-diation, including gamma rays (ex. from 60Co sources), bremsstrahlungx-rays (produced by the stopping of electron beams), electron beams, pro-ton beams, or heavy ion beams. Technological advancements over recentdecades have increased the precision with which external beam radiationtherapy delivers dose, shaping and rotating the beam around the patientto contour the dose to the tumour as tightly as possible. However, doseto healthy tissue is still unavoidable, as the radiation must typically passthrough healthy tissue before reaching the tumour. Brachytherapy uses radi-ation sources that are placed inside the patient’s body and near the tumour,either for a short duration or on a permanent basis. Still, such internalsources of radiation may provide dose to nearby healthy tissues. Regardlessof the approach taken, the ability to target diseased cells and only diseasedcells with radiation can only be as good as the ability of localizing thesetissues. Often the boundary between such regions is unclear or the precisionwith which the radiation can be delivered is limited by diagnostic imagingresolution, the precision of radiation therapy technology, or the movementof patient tissues; this results in margins of error being added to the targetregion, potentially increasing dose to healthy tissues. The localization andtargeting of very small and disseminated metastases with external beam ra-diation therapy and brachytherapy is also very challenging, meaning thesecells may not be seen or treated.While external beam radiation therapy and brachytherapy are well es-tablished treatment options that have been widely used for decades, newertechnologies such as targeted radionuclide therapy (TRT) and especiallytargeted alpha therapy (TAT) aim to overcome some of these dose deliverychallenges by targeting disease at the molecular level and delivering radiationsources directly to individual tumour cells. The potential of these treatmentoptions is the main motivation for much of the work in this thesis.The remainder of Section 1.1 will provide background information as tohow TAT works, including an introduction to nuclear medicine and can-4cer targeting in Section 1.1.2 and to radiation interactions with matter inSection 1.1.3. A summary of the clinical data that demonstrates the poten-tial of TAT – and particularly TAT with 225Ac – that currently motivatesthe heightened interest in 225Ac-radiopharmaceutical development is thenpresented in Sections 1.1.4 and 1.1.5.1.1.2 Diagnostic radiopharmaceuticalsNuclear medicine applies radioactive substances inside the body for the di-agnosis or treatment of disease. The internalization of these radiopharma-ceuticals results in the preferential distribution of the radionuclide towardsthe tissues or organs of diagnostic or therapeutic interest. There are multi-ple modes of decay, each characterized by the type of particle emitted in theprocess, the most common being alpha decay, beta decay, gamma decay, andelectron capture. Alpha decay results in the emission of an alpha particle, apositively charged helium nucleus containing two protons and two neutrons.Beta-minus decay results in the emission of an electron and an antineutrinoas a neutron changes into a proton, while beta-plus decay results in emissionof a positron and a neutrino as a proton changes into a neutron. Protons canalso convert to neutrons via electron capture, in which the nucleus capturesan atomic electron and emits a neutrino. More details regarding the physicsof radioactive decay are discussed in Section 1.2.1.The most simple radiopharmaceuticals utilize radionuclides whose ele-mental chemistry naturally results in the desired biodistribution. Examplesinclude: 133Xe (t1/2 = 5.6 d), a radioactive noble gas that, when inhaled, canbe used to image the lungs and assess pulmonary function; 82Rb (t1/2 = 1.26min), a radioactive alkali metal administered intravenously as rubidium chlo-ride that, due to its similar biochemistry to K+, is rapidly absorbed by car-diac muscle where it participates in sodium-potassium exchange and is usedto image cardiac muscle function; and 123I (t1/2 = 13.2 d), a radioactivehalogen administered orally as sodium iodide that is preferentially absorbedby the thyroid (which uses iodine for hormone production) allowing 123I tobe used in thyroid imaging. The range of half-lives, chemical properties,methods of internalization, and applications (pulmonology, cardiology, andoncology) provided by these three example radiopharmaceuticals exemplifiesthe diversity of medical radionuclides and their applications.The above radiopharmaceutical examples are non-targeting agents,meaning they do not have a molecular structure designed to bind to a spe-cific cellular receptor(s) of the tissues they are used to image. Instead,their elemental chemistry results in the desired preferential uptake in the5tissue of interest. These are the first of four generations of radiopharma-ceuticals that have been developed: simple molecules or salts that result indiffusion-based, non-specific imaging. Other examples include [99mTc]TcO4,[99mTc]Tc-methyl diphosphonate, and [18F]F-.Second, third, and fourth generation radiopharmaceuticals are targetedcompounds that combine radionuclides with a molecular structure that tar-gets specific metabolic processes or binds to cell surface receptors that areover-expressed on cells within the tissues of interest. Second generation ra-diopharmaceuticals are imaging agents that typically use small moleculesthat target metabolic functions that are altered by disease. The most com-mon example is the use of 18F (t1/2 = 110 min) in fluorodeoxyglucose (FDG).[18F]FDG is a radioactive glucose analog that, when administered, results ina preferential uptake of 18F in tissues that require more energy and consumemore glucose. This includes rapidly replicating cancer cells that require ex-cess energy to sustain their growth, allowing 18F to be used to image andscreen for metastases. Third generation radiopharmaceuticals are diagnos-tics that use targeting compounds of greater molecular weight, typically pep-tides or antibodies that preferentially bind to cell surface receptors. Thesepharmaceuticals also typically contain a chelating moiety that binds the ra-dionuclide to the targeting compound. A more detailed overview of targeteddrugs and their structure is beyond the scope of this work; for more, thereader is referred to the text by Knapp and Dash [44]. Fourth generationradiopharmaceuticals are targeted compounds (third generation targetingvectors such as peptides and antibodies) that have therapeutic effects, in-cluding the 225Ac-radiopharmaceuticals discussed in Section 1.1.5.Most nuclear medicine applications involve the use of diagnostic radio-pharmaceuticals that use radionuclides emitting gamma rays or positronsthat annihilate with nearby electrons, converting their mass-energy into apair of gamma rays (see Section 1.1.3). These photons originate from thetissues in which the radiopharmaceutical is distributed and travel throughtissues, exiting the body where they are then detected by nearby imagingdevices that count the number of particles detected and convert this datainto an image that is representative of the radiopharmaceutical’s biodistribu-tion within the patient. Imaging modalities include planar imaging gammacameras, SPECT (single photon emission computed tomography), and PET(positron emission computed tomography). The use of these drugs relieson the tracer principle, i.e. that the biological process or function they areimaging is not disturbed or altered during the diagnostic process by thepresence of the tracer. Thus the radiation emitted by diagnostic radionu-clides allows clinicians to observe tissue function and diagnose disease, while6typically avoiding the delivery of radiation doses that result in destructiveand deterministic damage to healthy tissues.Therapeutic radiopharmaceuticals, in contrast, emit radiation that iscomparatively much more destructive to the tissues in which the pharma-ceutical is distributed. This radiation is either electrons (resulting eitherfrom beta minus decay or Auger electron emission) or alpha particles thatare emitted during radioactive decay. Unlike gamma rays used in diagnosticapplications, this charged particle radiation travels a shorter distance anddoes not leave the body. To understand the different effects these types ofradiation have on the body and what radiation properties make for good di-agnostic or therapeutic radionuclides, we must first discuss the mechanismsthrough which ionizing radiation interacts with matter that are presentedin the following section.1.1.3 Ionizing radiation interactions with matterAn understanding of ionizing radiation interactions with matter is not onlyimportant for understanding how targeted radionuclide therapy work, butalso for understanding many aspects of this thesis, including gamma andalpha spectroscopy (Chapter 2), the collection of radioactive ion beams fornuclide production (Chapter 3), nuclear medicine imaging systems (Chapter4), and proton targets for nuclide production (Chapter 5). This section willsummarize the mechanisms through which photons indirectly ionize matter,as well as charged particle interactions that are directly ionizing.Photon (x-ray and gamma ray) interactions with matter are stochastic.In other terms, a photon passing through a thin layer of material of thicknessdl may or may not interact with the material; the probably of interactionis described by the attenuation coefficient, µ. For a beam of photons, thechange in flux, I, after passing through the thin layer is therefore describedby dI = −µdl. Similar to the equations for radioactive decay (Equations 1.4and 1.5 in Section 1.2.1), this leads to the familiar exponential attenuationcurve for photons passing through thick materials, specificallyI = Ioe−µx (1.1)where I is the flux remaining after the initial flux, Io passes through amaterial of thickness x. The value of the attenuation coefficient depends onboth the material and the energy of the photon. Due to the attenuationcoefficient’s energy dependence, Equation 1.1 only holds for monoenergeticphoton beams. The energy dependence of the attenuation coefficient is ex-plained by the three dominant yet different physical mechanisms through7which photons interact with matter: the photoelectric effect, Compton scat-tering, and pair production.The photoelectric effect is the dominant process at low photon energies(i.e. energies below ∼101 keV) and involves the ejection of a bound atomicelectron from an atom after the destruction of the photon and absorptionof the photon’s energy by the electron. A small amount of energy goesinto overcoming the atomic electron binding energy, though the majorityof the photon’s energy is converted to kinetic energy of the now free elec-tron. Compton scattering is dominant in the ∼102 to ∼103 keV range andinvolves the interaction of a photon with a free (or very loosely bound, andapproximately free) electron. This is an inelastic two-body collision wherethe photon transfers only part of its energy to the electron. Relativisticconservation of energy and momentum can be used to relate the final elec-tron and photon energies to the scattering angle of the photon. Finally, pairproduction becomes possible above 1022 keV and involves the interactionof a photon with a nuclei’s magnetic field that results in the destruction ofthe photon and the creation of an electron-positron pair. Again, relativisticconservation of momentum and mass-energy dictate the amount of kineticenergy transferred to the electron and positron. The 1022 keV threshold isequal to the sum of the electron and positron rest masses. The positron thatis created then soon encounters another electron and undergoes annihilation,an inverse process to pair production whereby the positron and electron aredestroyed and their rest masses are converted to energy in the form of –because of conservation of momentum and energy – two 511 keV gammarays travelling in opposite directions. Regardless of whether a photon in-teracts with a material via the photoelectric effect, Compton scattering, orpair production, the result is the creation of energetic charged particles thatgo on to directly ionize the medium via the processes described below forenergetic charged particle interactions with matter.Unlike high-energy photons (x-rays and gamma rays), charged particles(ex. electrons, protons, alpha particles, etc.) interact continuously and non-stochastically with media through which they travel. These interactionscan be described by a series of Coulomb interactions between the chargedparticle and atomic electrons or nuclei within the medium, through whicha small fraction of the particle’s kinetic energy is lost with each collision.The type of interaction that occurs with an individual atom is determined,in general, by the interaction’s impact parameter, defined as the minimumdistance between the particle’s trajectory and the centre of the atom. Whenthe impact parameter is larger than the atomic radius, Coulomb interactionsaffect the entire atom and energy is transferred to the atom by ionizing the8atom or by exciting its atomic electrons to higher energy states. When theimpact parameter is on the order of the atomic radius, collisions with in-dividual atomic electrons occur, resulting in their ejection from the atom.These energetic secondary electrons, or delta rays, then travel through themedium and result in additional charged particle interactions. For small im-pact parameters much smaller than the atomic radius, the charged particleinteracts with the atomic nucleus; while most of these interactions are elas-tic, heavy charged particles with sufficient energy can also induce nuclearreactions (see Section 1.3.3).The large number of discrete interactions together correspond to a pro-cess through which the charged particle continuously loses energy while pass-ing through the media; this is known as the “continuous slowing-down ap-proximation”. The rate of kinetic energy loss, dE, per unit path length, dx,is called the stopping power, −dEdx , and depends on the type of particle, theparticle’s energy, and the material and density of the medium. The integralof the stopping power with respect to kinetic energy defines the particle’srange (i.e. the expected path length) in the material, a non-stochastic valuethat is also characteristic of the charged particle radiation and the mediumthrough which it is travelling. For heavy charged particles such as protonsand alpha particles, the stopping power in a given medium for a given parti-cle velocity is described by the Bethe-Bloch equation; for more on this topic,the reader is referred to the text by Podgorsak [45].While knowledge of the amount of energy deposited along a particle’strajectory enables dose calculations (see Section 1.1.1), the creation of en-ergetic delta rays results in the deposition of some of the primary particle’senergy away from the primary particle’s track. For this reason, the restrictedlinear energy transfer (LET), L∆, is used instead, whereL∆ =−dE∆dx(1.2)and where dE∆ is the energy lost by the primary charged particle, ex-cluding the energy that is transferred to secondary electrons with kineticenergies greater than ∆. In the limit where ∆ approaches infinity, the LETand stopping power are equivalent.These concepts for ionizing radiation interactions with matter are ap-plied in many ways throughout this thesis. For example, differences in LETand range between alpha particles and beta particles (electrons) explain whytargeted radionuclide therapy with alpha-emitting radionuclides has advan-tages over TRT with beta-emitting radionuclides in certain situations (andvice versa), while an understanding of stopping power and heat deposition9plays an important role in the development of proton targets (Chapter 5).Similarly, gamma ray interactions with matter enable gamma spectroscopy,the most widely used analytical technique throughout this work (Section2.1).1.1.4 Radionuclide therapyLike their diagnostic counterparts (Section 1.1.2), therapeutic radiopharma-ceuticals preferentially deliver radioactivity to tissues of interest using eithernon-targeting or targeting compounds. However, unlike diagnostics, ther-apeutic radionuclides emit radiation that is destructive to the surroundingtissues, specifically, charged particles such as beta or alpha radiation thathave a short range and high LET. In this way, therapeutic radiopharmaceu-ticals deliver radiation dose to the diseased tissue using an internal radiationsource that is inside the diseased tissue itself.Radionuclide therapy was first used in 1941, when a mixture of 130I and131I produced by the irradiation of tellurium by deuterons was administeredto patients diagnosed with hyperthyroidism [46]. Soon after, 131I was alsoused to treat patients with thyroid cancer [47], in what was also one of theearliest applications of “theranostic” radionucides: the administration oftherapeutic quantities of 131I was preceded by the administration of smallerquantities to first verify radioiodide uptake in the metastases. In thera-nostic applications, diagnostic radiopharmaceuticals are used to predict thebiodistribution and dose that will later result from the administration of thetherapeutic radiopharmaceutical. The diagnostic radiopharmaceutical canalso then be used to assess the patient’s response to the treatment. Ther-anostic radiopharmaceuticals can involve a single radionuclide, such as 131I(which emits both beta-minus radiation that can be used for therapy as wellas gamma rays that can be used for diagnosis), or a theranostic pair of ra-dionuclides, such as 123I and 131I (123I cannot be used for therapy, but is ableto provide a higher quality diagnostic image than 131I). A key requirementof theranostics is that the diagnostic and therapeutic radiopharmaceuticalsare chemically identical, meaning that identical biodistributions within thepatient can be assumed.Other examples of non-targeting beta-emitting radiophamaceuticals in-clude [89Sr]SrCl2 and [153Sm]Sm-EDTMP (ethylendiaminetetramethylenephosphonate), which are preferentially absorbed in areas of bone growth andare used in the palliative treatment of pain resulting from bone metastases.Targeted examples include [90Y]Y-ibritumomab and [131I]-tositumomab,which combine beta-emitters with monoclonal antibodies directed against10the CD20 antigen that is over-expressed in some non-Hodgkin lymphomas.Most recently, [177Lu]Lu-DOTATATE – a somatostatin analog peptide thatbinds to somatostatin receptors over-expressed on some neuroendocrine tu-mours – has been approved for the treatment of patients with advancedneuroendocrine tumours of the pancreas or gastrointestinal tract.Due to physical differences between how alpha and beta particles inter-act with matter, radionuclide therapy with alpha-emitters has theoreticaladvantages over radionuclide therapy with beta-emitters. First, the higherLET of alpha particles (∼80 keV/µm, compared to ∼0.2 keV/µm for betas)makes alpha particles more destructive, delivering more dose per decay andcausing more free radical formation and double-strand DNA breaks that areharder to repair. This higher cytotoxicity also means that fewer alpha parti-cles are required to kill a cell (possibly as low as 1-5, compared to hundredsfor beta particles), which is potentially advantageous for radiopharmaceu-ticals that target cell surface receptors that are specific to the disease butlimited in number. Second, the shorter range of alpha particles (40-100 µm,compared to 1-10 mm for beta particles) means that fewer nearby healthycells are irradiated, reducing dose to nearby organs and enabling the useof radionuclide therapy for metastases in close proximity to organs at risk.The combination of high LET and short range also means that targetedalpha therapy has the potential to destroy very small metastases that wouldnot be similarly affected if using a beta emitter. These advantages of al-pha particles have recently been demonstrated by early reports of patientswho successfully responded to treatment with an alpha-emitting radionu-clide after failing to respond to a beta-emitting analog, or not qualifying fortreatment with a beta-emitting analog due to the close proximity of metas-tases to organs at risk (in this case, bone marrow), which would receive toomuch dose even from a short-ranged beta-emitter such as 177Lu [25].Another example of the advantages of alpha-emitters is [223Ra]RaCl2(Xofigo), which in 2013 became the first clinically approved alpha-emittingradiopharmaceutical and uses the alpha-emitter 223Ra (t1/2 = 11.4 d). Likepreviously mentioned beta-emitting radiopharmaceuticals, Xofigo was in-tended to treat pain resulting from bone metastases, however, clinical trialsdemonstrated that Xofigo also increased average overall survival by 3 monthsand delayed the onset of more severe skeletal symptoms [24].While 223Ra is currently the only clinically approved alpha-emitter, oth-ers are also under investigation for their use in radionuclide therapy. How-ever, of the approximately 447 known alpha-emitters on the chart of nuclides,only a handful have properties suitable for medical use. The half-life of atherapeutic nuclide must be long enough such that the radionuclide and11radiopharmaceutical can be produced and administered, resulting in the de-livery of the radionuclide to the targeted tissues. This excludes the use ofshort-lived nuclides with half-lives below the tens of minutes; for example,211Bi (t1/2 = 2.1 min), which is part of the223Ra decay chain. However,the nuclide’s half-life should also not be too long, so as to ensure that theradiation is delivered faster than the disease progression and that residualradioactivity does not remain long after treatment and result in the accu-mulation of long-lived radioactive waste; this excludes the use of naturallyoccurring alpha-emitters such as 226Ra (t1/2 = 1600 y),232Th (t1/2 = 14billion y), and 238U (t1/2 = 4.5 billion y). In addition to the half-life, onemust also consider the decay products of the alpha-emitter, especially sincemany alpha-emitting nuclides have long decay chains and can have progenynuclides with unfavourable half-lives or chemical characteristics. A thera-peutic alpha-emitter must also have suitable chemical properties that enableits delivery to the targeted tissues. For example, 222Rn (t1/2 = 3.8 d) is analpha-emitter naturally present in the environment, but is not suitable fortherapy as it is an inert noble gas. Similarly, while 223Ra is approved as anon-targeting alpha-emitting radiopharmaceutical, it does not have suitablechemical properties that allow it to be chelated and bound to disease tar-geting biomolecules. Other practical considerations – such as the ease andcost of radionuclide production – must also be considered if a radionuclideis to be used in the widespread treatment of a disease.The remainder of this section briefly describes the handful of radionu-clides that are studied for their use in TAT, ending with 225Ac. The listof nuclides below represents TAT nuclides that have been investigated tothe point where they have been used in human patients. Other candidateTAT nuclides that have been proposed by the TAT field are not included(examples include 149Tb, 226Th, and 230U).227ThThorium-227 (t1/2 = 18.68 d) decays to stable207Pb via 5 alpha decaysand 2 beta decays. Besides its immediate daughter nuclide, 223Ra (t1/2 =11.4 d), all the radioactive 227Th progeny have half-lives shorter than onehour. 227Th is typically produced via generators containing its parent 227Ac(t1/2 = 21.8 y); note that the use of227Ac/227Th generators is described inSection 7.2.4.2. While clinical results of 227Th-TAT are not yet published,some clinical studies are ongoing; for more, see the review by Frantellizzi etal [48].12213BiBismuth-213 (t1/2 = 45.6 min) decays to stable209Bi via one alpha and twobeta decays. As part of the 225Ac decay chain, 213Bi is typically producedvia 225Ac/213Bi generators [49]. Multiple clinical studies of 213Bi-TAT havebeen reported for various cancers, including neuroendocrine tumours [50],carcinomas [51], myeloid leukemia [52, 53], gliomas [54, 55], and malignantmelanoma [56–58].212Pb and 212BiLead-212 (t1/2 = 10.6 h) decays by beta minus decay to bismuth-212(t1/2 = 60.6 min), which decays to stable208Pb via one alpha decay andone beta minus decay. Though not technically an alpha emitter, the decayof 212Pb to stable 208Pb results in alpha particle emission and both 212Pband 212Bi are nuclides with potential applications in TAT radiopharmaceuti-cals. Both are typically obtained from the generators containing the parentnuclide 224Ra. Reported clinical studies of 212Pb-TAT include treatmentsfor prostate cancers [59] and HER-2 expressing cancers [60, 61].211AtAstatine-211 (t1/2 = 7.2 h) decays to stable207Pb via one alpha decayand one electron capture decay. 211At is typically produced by irradiatingbismuth targets with accelerated alpha particles. Reported clinical studiesof 211At-TAT include treatments for brain tumours [62] and ovarian cancer[63, 64]. For more, the reader is directed towards the review by Lindergrenet al [65].225Ac225Ac (t1/2 = 9.92 d) is an alpha-emitting radionuclide with properties well-suited for use in targeted alpha therapy. Its half-life is sufficiently longfor radionuclides distribution, radiopharmaceutical production, and for thedelivery of 225Ac to tumours using large-molecule targeting vectors that,once injected, can take days to accumulate in their targeted tissues. Thisis useful since it is generally important to match the physical half-life ofthe radionuclide with the pharmacology of the radiopharmaceutical. Foruse with faster-localizing small molecules, the 225Ac progeny nuclide, 213Bi(t1/2 = 45.6 min), can also be separated from the225Ac chain (see Section131.2) and used in TAT if a shorter-lived radionuclide is more pharmacolog-ically desirable. Ac also has – despite a lack of stable isotopes that haslimited the study of its chemistry – favourable chemical properties for in-corporation into targeting biomolecules. The four alpha emissions in the225Ac decay chain additionally provide a potentially more potent source ofalpha radiation. The availability of the radionuclide, though currently lim-ited, has so far been sufficient and reliable enough to enable the early stagedevelopment of many 225Ac-radiopharmaceuticals for TAT.Together, these properties are part of the reason that 225Ac is currentlyone of the most widely studied TAT radionuclides. More details on theproperties of 225Ac and the 225Ac decay chain can be found in Section 1.2,and the clinical experience is summarized in Section 1.1.5. Additionally,existing methods for 225Ac production are discussed in detail in Section1.3, including an examination of how limitations in the current produc-tion methods and 225Ac availability have limited the development of 225Ac-radiopharmaceuticals.1.1.5 Clinical uses of 225Ac in targeted alpha therapySince the use of 225Ac in TAT was first proposed in 1993 by Geerlings etal [38], 225Ac has become the alpha-emitting radionuclide most commonlyused in clinical applications of therapeutic radiopharmaceuticals that usedisease-targeting biomolecules. While several clinical investigations haveexplored treatments for neuroendocrine tumours [66, 67], gliomas [68, 69],leukemia [29, 30, 52, 70–73], and prostate cancer [25, 31, 32, 74–77], no225Ac-radiopharmaceutical compound has yet completed clinical trials andreceived approval for clinical use. This section summarizes the availableliterature on clinical applications of 225Ac; for additional details, the readeris directed to recent reviews by Poty et al [12], or Morgenstern et al [78].Neuroendocrine tumours225Ac-DOTATOC has been studied in a small number of patients for thetreatment of neuroendocrine tumours. Kratochwil et al reported a doseescalation study involving 34 patients with progressive neuroendocrine tu-mours and found that multiple doses of 25 MBq every 4 months or 18.5 MBqevery 2 months were tolerated, up to a cumulative activity of 75 MBq [66].The study also demonstrated treatment efficacy in various patients that wasindependent of the fractionation cycle used. Kunikowska et al published re-sults from a single patient who showed partial response to 225Ac-DOTATOC,14as demonstrated by 68Ga-DOTATATE PET. The patient received 20 MBqof 225Ac-DOTATOC, followed by an additional 40 MBq of 225Ac-DOTATOCand had previously been treated with beta-emitting radiopharmaceuticals90Y-DOTATOC and 177Lu-DOTATOC.GlioblastomaKrolicki et al have studied TAT for treatment of glioblastoma multiformeusing both 213Bi and 225Ac [68, 69]. 225Ac studies were limited to 21 patientswith a recurrence of glial tumour (grade II-IV) who received 1-6 doses (20-40 MBq) of 225Ac-DOTAGA-SP via an intracranial catheter in 2-monthintervals [69]. Details regarding the efficacy are not yet available; the studyis ongoing [69]. It will be interesting to see how this work evolves with theinclusion of control groups and the implementation of formal clinical trials.LeukemiaJurcic et al have studied the use of 225Ac and 213Bi for the treatment ofacute myeloid leukemia using the targeting agent lintuzumab, a humanizedanti-CD33 monoclonal antibody [29, 30, 52, 70–73]. An initial study with225Ac-lintuzumab involved 18 patients who received a single dose of 18.5-148kBq/kg. The maximum tolerable dose was determined to be 111 kBq/kg,based on dose limiting toxicities observed in patients that included deathfrom sepsis in two patients who received 111 kBq/kg and 148 kBq/kg. Re-ductions in myeloblast counts were observed in 10 of 16 patients (peripheralblasts), and in 10 of 15 patients (bone marrow blasts) [73]. A subsequentPhase I trial investigated the toxicity and response rate of 225Ac-lintuzumabadministered in fractionated doses [71, 73]. Patients received two fractions of225Ac-lintuzumab (18.5-74 kBq/kg/fraction), with 7 days between each frac-tion. The maximum tolerable dose was not reached as there were no deathswithin a month of treatment. Five of 18 patients had complete remission (2with incomplete platelet recovery and 2 with incomplete blood count recov-ery); these responses to treatment were only observed for patients receiving≥37 kBq/kg/fraction. Following this, a Phase II trial consisting of 40 pa-tients was conducted [72, 73]. Thirteen and 27 patients were administered225Ac-lintuzumab doses of 74 kBq/kg/fraction and 55.5 kBq/kg/fraction,respectively. Patients in the 55.5 kBq/kg/fraction group experienced feweradverse side effects (specifically, prolonged grade 4 thrombocytopenia) at arate of 30%, compared to a rate of 46% for the 74 kBq/kg/fraction group.However, patients in the lower dose group also experienced a lower rate of15complete remissions (22%) compared to the higher dose group (69%).Prostate cancerThe majority of clinical applications of 225Ac has been as a last-line treat-ment for metastatic castration-resistant prostate cancer [25, 31, 32, 74–77].A recent review by Kratochwil et al provides an excellent summary of thehistory of these treatments, including the preclinical data and a summary ofthe dosimetry [77]. Most of these treatments used the 225Ac-PSMA-617 com-pound that combines 225Ac via a DOTA chelator to a peptide that targetsthe prostate specific membrane antigen (PSMA), which is over-expressed onthe surface of most prostate cancer cells. The clinical use of 225Ac-PSMA-617 was first reported in 2016 by Kratochwil et al [25], which included re-sults from two patients who had undergone all other available conventionaltreatments. The first patient, having significant skeletal metastases wascontraindicated for treatment with 177Lu-PSMA-617 due to expected bonemarrow dose that would result. However, due to the shorter alpha-particlerange compared to the beta-emissions from 177Lu, this patient was thereforetreated with 100 kBq of 225Ac-PSMA-617 per kilogram of body weight. Af-ter two months, PET/CT scans were visually free of PSMA-positive lesionsand the patient’s PSA levels (a blood indicator of prostate cancer progres-sion) had fallen from 3000 ng/mL to 0.26 ng/mL. A final 6 MBq injectionof 225Ac -PSMA-617 resulted in a further PSA reduction to 0.1 ng/mL. Thesecond patient was not contraindicated for 177Lu-PSMA-617, yet did notrespond to successive treatments containing 7.4 GBq of 177Lu-PSMA-617.However, after receiving 3 cycles of 6.4 MBq (100 kBq/kg) of 225Ac-PSMA-617 the patient had a complete remission. The remarkable response of thesepatients to treatment with 225Ac-PSMA-617 came at the expense of the onlyclinically reported side effect of moderate to severe xerostomia (dry mouth)due to uptake of PSMA-617 in the salivary glands.Subsequent studies with larger patient cohorts have found that between10-33% of patients had to stop 225Ac-PSMA-617 treatment due to xerosto-mia [31, 74]. In 2018, Kratochwil et al published results from 40 patientswho were treated with three 100 kBq/kg cycles of 225Ac-PSMA-617 [31], andreported a median duration of tumour control of 9 months; 5/40 patientshad an sustained treatment response after 2 years. These findings have alsobeen independently confirmed by Bal et al [79].Alternative 225Ac-PSMA-617 treatment regimens applied by Sathekgeet al used an initial 8 MBq treatment followed by 7, 6, or 4 MBq based onthe response to previous doses, with 8 weeks between 2-4 cycles as needed16[32, 76]. This resulted in 85-100% of patients experiencing xerostomia, butnone severe enough to discontinue treatment. One study involving 70 pa-tients receiving 225Ac-PSMA-617 as a last-line treatment reported 34/70patients responding to treatment with a delayed disease progression, a me-dian progression-free survival of 15.2 months, and a median overall survivalof 18 months [76]. A second study involving patients who had not pre-viously received chemotherapy included 17 patients, 82% of whom had a≥90% reduction in PSA levels; 41% of patients had undetectable PSA aftertreatment and remained in remission after 1 year [32]. Combination ther-apy of 225Ac-PSMA-617 with 177Lu-PSMA-617 has also been explored as amethod for reducing salivary gland toxicity [80–82].While these clinical results for the treatment of end-stage prostate ap-pear to be quite promising and provide remarkable before-and-after patientimages that often illustrate a reduction of metastases, it is important toconsider the context in which these treatments occurred to date: on an in-dividual patient basis outside of formal clinical trials within jurisdictionspermitting compassionate care use. The patients in these studies thereforehave heterogenous treatment histories and the studies themselves lack spe-cific inclusion or exclusion criteria for patients. Importantly, there is also anabsence of control groups. However, the clinical results with prostate can-cer are nevertheless promising and, combined with clinical results for thetreatment of neuroendocrine tumours and leukemia, provide a strong moti-vation for increasing the availability of 225Ac. In fact, increased radionuclideavailability may itself help to initiate formal clinical trials.1.2 Properties of the 225Ac Decay Chain 5DDQG$FGHFD\YVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRS5DDQG$FGHFD\YVYJ 0H9њ0H9њ 0H9њ0H9 ћ0H9ћ0H9њ0H9ћ0H9њNH9SKRWRQ  $F  G)UP$WPV3RXV 7OP 3EK %LVWDEOHNH9SKRWRQ   NH9ћ5D G%LPNH9SKRWRQ  Figure 1.1: The decay chain of 225Ac and its parent, 225Ra, includinggamma emissions with high branching ratios that are useful for radioactivitymeasurements.225Ac is a radioactive nuclide containing 89 protons (Z = 89) and 13617neutrons that decays with a half-life of 9.92 days to stable 209Bi via 4 alpha-and 2 beta-decays. This 225Ac decay chain, shown in Figure 1.1, thus con-tains 8 nuclei, including 225Ac, the final stable 209Bi state, and 6 radioactiveintermediary nuclides that all have half-lives much shorter than 225Ac.A general understanding of decay chain dynamics combined with specificknowledge of the 225Ac decay chain is essential when working with 225Ac orany of its radioactive progeny. This is especially true when quantification ofradioactivity is concerned, since changes in physical and chemical proper-ties of a nucleus as the decay chain progresses can result in time-dependentradioactive emission rates that dictate methods used for radioactivity mea-surements. An understanding of the dynamics between 225Ac and its parent,225Ra, is also necessary when discussing 225Ac production.This section will introduce these concepts, including a discussion of ra-dioactive decay and a generalized formalism of decay chain dynamics (Sec-tion and 1.2.1), the relevant physical and chemical properties of the nuclei inthe 225Ac decay chain (Section 1.2.2), and the properties of its parent nuclei(Section 1.2.3). The use of these concepts in 225Ac production via 225Radecay (Section 1.2.3) and in 225Ac quantification (Section 1.2.4) will thenbe described. The concept of daughter nuclei recoil and its consequences forTAT with 225Ac are then introduced in Section 1.2.5.1.2.1 Radioactive decay and decay chain dynamicsRadioactive decay is a random process in which a nucleus transitions to alower energy state, resulting in the emission of radiation. As mentioned inSection 1.1.3, there are multiple modes of decay, each characterized by thetype of particle emitted in the process. The most common are alpha decay,beta decay, gamma decay, and electron capture. Other less common formsof decay are also possible (ex. proton decay).Alpha decay results in the emission of an alpha particle, a positivelycharged helium nucleus containing two protons and two neutrons. Beta-minus decay results in the emission of an electron and an antineutrino as aneutron changes into a proton, while beta-plus decay results in emission of apositron and a neutrino as a proton changes into a neutron. Protons can alsoconvert to neutrons via electron capture, in which the nucleus captures anatomic electron and emits a neutrino. Since the proton number, Z, changes,these types of decay all result in nuclear transmutation, the conversion ofthe nucleus into a nucleus of a different element. Of these most-commondecay types, only alpha decay results in a change in mass number, A.Radioactive decay without nuclear transmutation is possible via neutron18emission (in which nuclei that are both neutron-rich and proton-deficientemit a neutron) or isomeric transition decays. Isomeric transitions andgamma decays occur when a nucleus in an excited state transitions to alower energy state via the emission of a gamma ray. Such decays typicallyoccur after an alpha or beta decay (or other nuclear interaction) creates aresidual nucleus in an excited state. (This transition of a nucleus to a lowerenergy state by gamma-emission is analogous to atomic electron transitionsand x-ray emission. Similar to the atomic photoelectric effect, in photonu-clear reactions, gamma rays can interact with nuclei to eject protons orneutrons from the nucleus.) If an excited nuclear state is long-lived enoughsuch that its decay can be considered separate from the previous decay thatcreated it (typically, >10-9 s), then the nucleus is considered metastable andis referred to as a nuclear isomer of its specific nuclide; isomers can transi-tion to the nuclide’s ground state by isomeric transition or undergo othertypes of decay. In contrast, gamma decays occur promptly (10−12 to 10−9s) after creation of the excited nucleus and are thus often included as part ofthe initial decay process that created the excited nucleus. Multiple gammadecays are often emitted as an excited nucleus decays to its ground state.These emissions are referred to as a gamma cascade and, as far as this the-sis is considered, can be considered to occur simultaneously. Interactions ofthese gamma rays with atomic electrons can also result in ejection of theseelectrons from the atom, a type of secondary decay radiation called Augerparticles. Reconfiguration of the remaining atomic electrons also results inthe emission of additional x-rays.Radioactive nuclei are generally not restricted to a single decay path,with some radionuclides having the possibility to undergo either alpha orbeta decay, for example. The probability with which a nuclide decaysthrough a specific process is called its branching ratio, denoted β. Thebranching ratio can also refer to the probability that a decay will result ina specific radioactive emission.The type and energy of the radiation emitted by a nuclide, combinedwith the branching ratios for each of its possible emissions, are character-istic of that specific radioactive nuclide. These radiation signatures enablespectroscopic identification and quantification of radioactive nuclei by tech-niques such as gamma or alpha spectroscopy (see Sections 2.1 and 2.2, re-spectively). Databases of characteristic decay data are therefore essentialresources. For an example of such a database used extensively through-out this work, the reader is referred to the National Nuclear Data Centermaintained by Brookhaven National Laboratory [83].While there are multiple types of radioactive decay, all are stochastic19processes. While it is not possible to predict when a radioactive nucleuswill decay, all nuclides have a specific probability of decaying within a givenunit of time. This probability is called the decay constant, λ, which is alsocharacteristic of the specific nuclide. For a large collection of N nuclei of agiven radioactive species, the number of decays occurring per unit time, orthe radioactivity, A, is described byA = λN (1.3)and the change in the number of radioactive nuclei dN per unit time dt isdescribed bydN = −λNdt (1.4)which has the solutionA(t) = A0e−λt (1.5)where A0 denotes the amount of radioactivity present at time t = 0. Fromthis wee see that the amount of radioactivity present decreases exponentially.The amount of time it takes for the radioactivity to be reduced by half, calledthe half-life, t1/2, is often used to describe how long-lived a specific nuclideis. Note that the half-life and decay constant are related byt1/2 =ln(2)λ(1.6)Equation 1.5 is an important relation when working with radioactiv-ity because it allows multiple radioactivity measurements taken at differenttimes to be decay corrected to a common point of reference. However, thechange in the amount of a nuclide present over time described by Equa-tion 1.5 assumes that none of the nuclide in question is being created – anassumption that does not hold for progeny nuclides in a decay chain.For a radioactive parent nuclide with activity Ap decaying to a radioac-tive daughter nuclide with activity Ad, the change in the number of daughternuclei per unit time is described bydNd = (λpNp − λdNd)dt (1.7)which has a general solutionAd(t) =λdAp0λd − λp e−λpt + Ce−λdt (1.8)20where Ap0 = Ap(t = 0) describes the initial amount of the parent attime t = 0, and C = Ad(t=0)λd −Apλd−λp depends on the initial amount of thedaughter present. In the case where Ad(t = 0) = 0, Equation 1.8 simplifiestoAd(t) =λdAp0λd − λp(e−λpt − e−λdt) (1.9)Equations 1.8 and 1.9 are written assuming a branching ratio of β = 1for the decay of the parent to the daughter; if β 6= 1, these equations mustbe multiplied by the branching ratio.  XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ     SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@D GDXJKWHUSDUHQWKDOIOLIHUDWLR SDUHQWGDXJKWHU    SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@E GDXJKWHUSDUHQWKDOIOLIHUDWLR     SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@F GDXJKWHUSDUHQWKDOIOLIHUDWLR     SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@G GDXJKWHUSDUHQWKDOIOLIHUDWLR   XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ     SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@D GDXJKWHUSDUHQWKDOIOLIHUDWLR SDUHQWGDXJKWHU    SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@E GDXJKWHUSDUHQWKDOIOLIHUDWLR     SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@F GDXJKWHUSDUHQWKDOIOLIHUDWLR     SDUHQWKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@G GDXJKWHUSDUHQWKDOIOLIHUDWLR Figure 1.2: Equation 1.9 for different ratios of parent:daughter half-lives,with the number of parent half-lives on the x-axis. The equilibrium cases inplots a) and b) are also shown in Figure 1.3.21  XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ     GDXJKWHUKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@D SDUHQWGDXJKWHUKDOIOLIHUDWLR SDUHQWGDXJKWHU    GDXJKWHUKDOIOLYHVIUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@E SDUHQWGDXJKWHUKDOIOLIHUDWLR Figure 1.3: Equation 1.9 for different ratios of parent:daughter half-lives,with the number of daughter half-lives on the x-axis. These plots show adaughter nuclide as it comes into secular (a) or transient (b) equilibriumwith its parent nuclide.From Equation 1.9 one can see that the change in daughter activity overtime will depend primarily on the difference between the decay constants ofthe parent and daughter nuclides; examples are shown in Figures 1.2 and 1.3.Two equilibrium cases occur when the parent half-life is at least multipletimes greater than the daughter half-life. Secular equilibrium (Figures 1.2aand 1.3a) occurs when the parent is much more longer lived than the daugh-ter, resulting in the daughter activity increasing until it remains constantand equal to the parent activity. In this situation, the daughter activitycurve is an inverted exponential decay curve: half of the difference betweenthe initial parent and daughter activities at t = 0 is recovered within onedaughter half-life. Transient equilibrium (Figures 1.2b and 1.3b) also occurswhen the parent is longer lived than the daughter, but when the difference inhalf-lives is not as great as in secular equilibrium, resulting in the daughteractivity increasing until it begins to decay with the ratio between the parentand daughter activity remaining approximately constant. For both secularand transient equilibrium, equilibrium is reached after approximately fivedaughter half-lives.The secular and transient equilibrium conditions enable the use of ra-dionuclide generators, in which a parent nuclide is used to create a productthat contains its daughter nuclide of interest. Once equilibrium is estab-lished, the daughter is chemically separated from the parent and used forits intended purpose. The parent then continues to produce more of the22daughter nuclide, which after a sufficient grow-in period, can be once againchemically separated from the parent.Equation 1.8 must be used for decay correction of measurements thatare affected by parent-daughter effects. This could include the measurementof a parent’s activity using a radiation signal emitted by its daughter – insuch situations, it is important that equilibrium is established before themeasurement, if possible. Another situation could be the measurement of adaughter’s activity in a sample that also contains its parent nuclide. In suchsituations, the amount of the daughter present at t = 0 is nonzero – Fig-ure 1.4 shows how the secular equilibrium case changes when the daughternuclide is present at t = 0.  XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ         QXPEHURIGDXJKWHUKDOIOLIHV GDXJKWHUDFWLYLW\>RISDUHQWDFWLYLW\@GDXJKWHULVRWRSHJURZLQIRUORQJOLYHGSDUHQWFigure 1.4: In-growth of a daughter nuclide that reaches secular equilibriumwith its parent, with individual lines representing a different initial amountof daughter activity (between 0 and 100% of parent activity at time t = 0).For decay chains containing multiple decays and daughter products,Equations 1.7 through 1.9 must be further modified to describe the activitiesof all daughter products over time. For a decay chain with n decays, theactivities of each nuclide are described bydN1 = −λ1N1dtdNi =(λi−1Ni−1 − λiNi)dt(1.10)The solution to this series of coupled differential equations can be foundusing Laplace transformation. The result is a solution known as the Batemanequation [84], which has the following general formula23An(t) = λnn∑i=1[Ni(t = 0)×( n−1∏j=iλj)×( n∑j=i(e−λjt∏np=i,p 6=j(λp − λj)))](1.11)1.2.2 225Ac and its progenyMeasurements of 225Ac and its progeny must combine general principlesof radioactive decay (described in Section 1.2.1) with characteristic decaydata regarding the nuclides in the 225Ac decay chain. This sections describesrelevant details for each of these nuclides, with a summary provided in Table1.1. A diagram of the 225Ac decay chain is also shown in Figure 1.1.225Ac225Ac alpha-decays to 221Fr with a half-life of (9.920 ± 0.003) d [85]; pre-vious measurements reported a 10.0 d half-life [86, 87]. While it is oftenapproximated as a pure alpha-emitter (βα ≈ 1), 225Ac also decays by clus-ter emission of a 14C particle with a branching ratio of β14C = (5.3 ±1.0)× 10−12 [88, 89]; this latter decay mode is considered negligible for thiswork.225Ac can decay by emitting alpha-particles with energies between 5021and 5830 keV, though the most common emissions are either at 5830 keV(β = 0.507) or near 5792 keV (5791 keV and 5793 keV emissions withbranching ratios of β = 0.086 and β = 0.181, respectively) [90]. While anumber of gamma rays and x-rays are emitted following 225Ac decay, allhave branching ratios that are too small to be easily or reliably used forquantification; the most intense gamma emissions are at 99.8 keV (β =1.00%), 150.1 keV (β = 0.60%), and 188.0 keV (β = 0.45%) [90].Ac is a metallic element found in the oxidation state +3, and the firstin the actinide series. It is chemically similar to lanthanum and other lan-thanides. Since Ac has no stable isotopes, lanthanum (La) is often usedas an Ac analog when macroscopic quantities are required. This absenceof stable Ac isotopes has resulted in limited available data regarding Acchemistry.221Fr221Fr alpha-decays to 217At with a half-life of (4.801 ± 0.006) min [91–93].It has two dominant alpha-emissions at 6341 keV (β = 0.833) and 612624keV (β = 0.151). 221Fr decay also results in several gamma emissions, ofwhich the 218.0 keV (β = 11.44%) and 100.2 keV (β = 0.14%) are the mostabundant.All isotopes of francium, an alkali metal, are highly radioactive. Themost stable, 223Fr, has a half-life of only 22.8 min.217At217At decays to 213Bi by alpha-decay with a half-life of (32.8 ± 3) ms anda branching ratio of 99.993% [92]. 217At is typically approximated as apure alpha-emitter: the remaining small fraction of decays are beta-decaysto 217Rn (t1/2 = 0.54 ms) followed by an alpha decay to213Po, where itrejoins the conventional 225Ac decay chain (Figure 1.1). 217At emits a 7067keV alpha particle (β = 0.9989); other emissions of alpha particles andgamma rays exist but none are abundant enough to be relevant for mostmeasurements [94]. Like Ac and Fr, At has no stable isotopes, with thelongest-lived being 210At (t1/2 = 8.1 h).213Bi213Bi has a half-life of (45.61 ± 0.06) min and decays either by beta-decayto 213Po (β = (97.86 ± 0.01)%) or by alpha-decay to 209Tl (β = (2.140 ±0.010)%) [95, 96]. 213Bi alpha-emissions either have an energy of 5875 keV(β = 1.96%) or 5558 keV (β = 0.18%) [95]. While most of its many gammaemissions are not abundant enough to be easily used for quantification, the440.5 keV line emitted following beta-decay to 213Po is the most abundantgamma emission in the 225Ac decay chain (β = (25.94± 0.15)%). Followingthis, the 292.8 keV (β = 0.43%) and 807.4 keV (β = 0.29%) emissions arethe most abundant [96].With one (semi)stable isotope, the primordial 209Bi (t1/2 = 2× 1019 y),Bi is the first element in the 225Ac decay chain with well-studied chemicalproperties. 209Bi is also the final nuclide in the 225Ac decay chain.As discussed in Section 1.1.5, 213Bi is another nuclide with applicationin TAT. In this context is it considered a pure alpha-emitter, since the short213Po half-life (3.7 µs) means that each 213Bi decay will promptly result inthe emission of an alpha particle, regardless of whether or not it decays to209Tl. The production of 213Bi via 225Ac/213Bi generators is thus the mostcommon application for 225Ac outside of its direct use in TAT.25213Po213Po decays by alpha emission to 209Pb with a half-life of (3.708 ± 0.008)µs [92]. It has a single 8376 keV alpha emission (β = 1) and no usefulgamma emissions (the most abundant is at 779 keV with a branching ratioof 0.004%) [95].209Tl209Tl beta-decays to 209Pb with a half-life of (2.162±0.007) min [95]. It hasthe highest energy gamma emissions in the 225Ac decay (up to 2.3 MeV),most notably its 1567 keV gamma line with a branching ratio of 99.66%.Other abundant emissions include 117 keV (β = 0.76) and 465 keV (β =0.95) [95]. However, because of the low probability of 213Bi decaying to209Tl, the abundance of these gamma emissions per 225Ac decay is muchlower.209PbThe final radionuclide in the 225Ac decay chain, 209Pb beta-decays to 209Biwith a half-life of (3.234± 0.007) h [95]. Other than its single beta particle,no other radiation is emitted during 209Pb decay.Table 1.1: Summary decay properties for nuclides in the 225Ac decay chain.nuclide t1/2decay mode,branchingratio (%)prominent α and γemissions (energy,branching ratio)225Ac (9.920 ± 0.003) d α, ≈ 100 α: 5830 keV, 50.7%γ: 99.8 keV, 1.00%221Fr (4.801 ± 0.006) min α, 100 α: 6341 keV, 83.3%γ: 218 keV, 11.44%217At (32.8 ± 3) ms α, ≈ 100 α: 7067 keV, 99.89%213Bi (45.61 ± 0.06) min β−, 97.86%α, 2.14%α: 5875 keV, 1.96%γ: 440.5 keV, 25.94%213Po (3.708 ± 0.008) µs α, 100 α: 8376 keV, 100%209Tl (2.162 ± 0.007) min β−, 100% γ: 1567 keV, 99.66%209Pb (3.234 ± 0.007) h β−, 100% none261.2.3 225Ra, the parent of the 225Ac decay chain225Ra is an important nuclide in 225Ac production, since 225Ac productionmethods often produce 225Ac indirectly through 225Ra production and decay(see Section 1.3 for more details). The production of 225Ac via 225Ra decayis especially important to this work, as further detailed and demonstratedin Chapter 7.225Ra decays primarily by beta-decay (β ≈ 1) to 225Ac with a half-lifeof (14.9 ± 0.2) d [97]; it also rarely alpha-decays to 221Rn with a branchingratio of 2.6×10−5 [98]. A single gamma ray is emitted after 225Ra beta-decayat (40.09 ± 0.05) keV with a branching ratio of (30.0 ± 0.07)%, providingthe only direct signal for 225Ra quantification.The grow-in of 225Ac from 225Ra as described by Equation 1.9 is shownin Figure 1.5. Equation 1.9 peaks at time t =lnλd/λpλd−λp , which for225Raand 225Ac occurs at 17.4 d, at which point 225Ac activity reaches 44.5%of the initial 225Ra activity. Ra and Ac have different chemical propertiesthat make 225Ra/225Ac separation easy. Ra is an alkaline earth metal withoxidation state +2, and has chemical properties that are well-known throughthe study of the naturally occurring 226Ra (t1/2 = 1600 y) [99]. Figure 1.6shows the 225Ac activity over time for a theoretical 225Ra/225Ac generatorthat is used on an operational schedule that separates 225Ac every 17.4 d.The total amount of 225Ac that can be obtained from a generator operated onsuch a schedule is described by a geometric series and is equal to 11−0.445−1 =0.80, or 80% of the initial amount of 225Ra.Other parents of the 225Ac Decay Chain225Ac also has other parent nuclides that are often ignored since they playminor roles in 225Ac production. 229Pa (t1/2 = 1.50 d) alpha-decays to225Ac with a branching ratio of 0.48% [97]. 225Th also decays to 225Ac byelectron capture with a branching ratio of 0.1 [97]. These decay pathwaysare important when considering spallation-based production of 225Ac (seeChapter 6).1.2.4 Quantification of 225Ac, its parent, and its progenyMeasurements of radioactivity typically involve detecting and counting theamount of radiation emitted from a sample. Combined with knowledge ofthe efficiency of the detector and sample-detector geometry, the branch-ing ratio of the emitted radiation, and the measurement time, a measure27 $FBJURZ,QVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRS$FBJURZ,QVYJ           WLPH>KRXUV@IUDFWLRQRILQLWLDOSDUHQWDFWLYLW\5D$FFigure 1.5: In-growth of 225Ac activity from a 225Ra source containing zero225Ac at time t = 0. XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ        WLPH>G@IUDFWLRQRILQLWLDOSDUHQWDFWLYLW\>@ 5D$FFigure 1.6: In-growth of 225Ac activity from a 225Ra generator, with Ra/Acseparation occurring approximately every 17.4 days.28 $F'DXJKWHUBJURZ,QVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRS$F'DXJKWHUBJURZ,QVYJ         WLPH>PLQ@IUDFWLRQRILQLWLDOSDUHQWDFWLYLW\ $F)U%L7O Figure 1.7: In-growth of 225Ac progeny, 221Fr, 213Bi, and 209Tl, from an225Ac source containing zero 225Ac progeny at time t = 0.of counts can be converted to a radioactivity value. Detection methodscan include both spectroscopic and gross counting methods, depending onwhether or not the energy of the detected particles is also measured. Onlyspectroscopic methods can be used to quantify radioactivity in samples con-taining either: 1) an unknown radionuclide species, or 2) multiple radionu-clide species, unless the relative abundance of all nuclides in the sample areknown. 225Ac can complicate both these measurement methods since thedifferent chemistry of the various nuclides in the decay chain can lead tophysical separation of 225Ac and its progeny, resulting in an unknown time-dependence in the radiation emitted by the sample. This time dependencecan be seen in Figure 1.7, which shows the in-growth of 225Ac progeny, asdescribed by Equation 1.11, from a sample that contains no 225Ac progenyat time t = 0; similar plots for 225Ra and 225Ac are shown in Figure 1.5.Radioactivity measurements of 225Ra, 225Ac, or any of the 225Ac progenymust account for these effects by considering the state of decay chain atthe time of measurement and the amount of time between the time of mea-surement and the sample time (the time to which radioactivity values willbe decay-corrected). The remainder of this section provides examples ofsuch considerations that may need to be applied to measurements of 225Ra,225Ac, 221Fr, and 213Bi.29Measuring 225RaSpectroscopic methods for 225Ra quantification rely on the nuclide’s onlygamma-emission at 40.0 keV. As the parent nuclide for 225Ac and its de-cay chain, 225Ra is not subject to parent-daughter effects provided thatno 229Th is present in the sample. If necessary, the absence of significant229Th quantities can be verified by the absence of 229Th gamma lines inthe same spectrum. With no parents present, measured 225Ra activities canbe decay-corrected using Equation 1.5. However, it should be noted that225Ra measurements using the low-energy peak at 40 keV are not withoutchallenges, as described in Section 2.1.5.2.Gross counting methods for 225Ra must occur in the absence of 225Ac,since this parent-daughter pair does not reach an equilibrium state (seeFigures 1.2, 1.3, and 1.5). The length of the 225Ac half-life permits this,provided that 225Ra measurements are completed within a couple hoursafter Ra/Ac separation.Measuring 225Ac225Ac can be directly quantified by gamma spectroscopy using its 150 and188 keV gamma lines. A 100 keV peak may also be used, though can be lessreliable due to interferences from the many other gamma and x-ray peaksin this energy range, as well as uncertainties in the efficiency calibration inthis energy range. However, the low branching ratio of these gamma lines(β ≤ 1%) means that 225Ac may not be detected in samples containingsmall amounts of 225Ac, measurements with low counting times, or spectracontaining a high background.In such situations, 225Ac is better quantified indirectly using the 218keV (β = 11.44%) peak of 221Fr. This requires equilibrium between 225Acand 221Fr, which as shown in Figure 1.7 occurs relatively quickly: the 221Fractivity is within 95% and 99% of the 225Ac activity within 21 and 31 min,respectively. Note that interferences from the 216 keV peak of 225Ac shouldbe accounted for in the analysis. 225Ac can similarly be measured indirectlyvia the 440 keV peak of 213Bi, though equilibrium between 225Ac and 213Bitakes longer to establish (213Bi activity is within 95% and 99% of the 225Acactivity within 201 and 292 min, respectively). Both direct and indirect225Ac measurements can then be decay-corrected using Equation 1.5 or 1.7,depending on the amount of 225Ra present. Gross counting measurementsof 225Ac are also possible, but must occur only after the decay chain hasreached secular equilibrium and in the absence of other nuclides.30Measuring 221Fr and 213BiDue to its short half-life, gamma spectroscopy measurements of 221Fr ac-tivity via its 218 keV gamma line must occur promptly, before the samplecan decay or, if 225Ac is also present, before additional 221Fr is generated.Even though parent-daughter decay-correction using Equation 1.7 can beapplied, the resulting uncertainties in the final radioactivity will increase asthe time between sample collection and measurement also increases. Similarconsiderations apply to 213Bi, though its longer half-life means samples canbe counted with less urgency; additional corrections for 221Fr content mayneed to be applied to 213Bi measurements, though any decay correction for217At can be neglected due to its short half-life.1.2.5 Daughter RecoilA final topic relevant to decay chains and TAT is the daughter recoil effectand its consequences for dosimetry. Alpha particle emission causes recoil ofthe daughter nucleus to occur after alpha decay because of conservation ofmomentum. The considerable energy of alpha particles means that the ki-netic energy imparted to the daughter nucleus can be substantial. For 225Ac,the emission of a 5.8 MeV alpha particle implies that the 221Fr daughter nu-cleus will gain approximately 104 keV in kinetic energy and travel a distanceon the order of 10-100 nm in water-based media. Since this recoil energyis ∼ 103 times greater than the strength of any chemical bond, the 225Acprogeny will no longer be bound to any targeting vector that delivers 225Acto the targeted tissue. The 225Ac progeny (especially the longest-lived alpha-emitting progeny, 213Bi) are then, in principle, free to migrate to other partsof the body when they can irradiate non-target tissues (most likely excretoryorgans such as the kidneys), potentially resulting in dose-limiting toxicity.While a complete discussion of this topic is beyond the scope of this sec-tion, it should be noted that this effect is considered to be one the greatestlimitations of TAT using decay chains of multiple alpha-emitters, particu-larly 225Ac and 227Th. For more information, the reader is directed to thereviews on this topic by de Kruijff et al [100] and Poty et al [11].1.3 Current 225Ac Production ChallengesDespite the promising early clinical results for 225Ac-radiopharmaceuticalsdescribed in Section 1.1, the development of these drugs has for many yearsbeen hindered by the limited global supply of 225Ac – currently only about3163 GBq (1.7 Ci) annually (see Section 1.3.1). Not only is this small sup-ply inadequate to support a widely used and clinically approved drug, italso results in a prohibitively high cost to researchers developing 225Ac-radiopharmaceuticals. This section will provide a detailed overview of exist-ing and potential 225Ac production methods, including relevant backgroundinformation and literature, while demonstrating the need for increased 225Acsources and highlighting the potential of TRIUMF’s facilities for achievingthis goal.1.3.1 Existing 225Ac supplies1.3.1.1 229Th GeneratorsCurrent sources of 225Ac are primarily derived from radionuclide generators(see Section 1.2.1) originating from the build-up of 229Th through the decayof 233U stockpiles (see Fig. 1.8 of the 233U decay chain). The majority of this233U (t1/2 = 1.6× 105 y) was produced between 1954 and 1970 via neutronirradiation of 232Th while being investigated for its use in nuclear weaponsand reactors that were never fully deployed [39]. Between 1995 and 2005,229Th (t1/2 = 7340 y) generated from233U decay was extracted from stock-piles stored at Oak Ridge National Laboratory (ORNL, Oak Ridge, TN).This 229Th now exists in two sources: one at ORNL (∼5.55 GBq (150 mCi),or ∼704 mg) [37] and another (1.7 GBq (46 mCi), or 215 mg) [36] transferredto the Institute for Transuranium Elements (ITU, Karlsruhe, Germany). Athird 229Th source (5.55 GBq (150 mCi), 704 mg) obtained from Russia 233Ustockpiles exists at the Leipunskii Institute for Physics and Power Engineer-ing (IPPE, Obninsk, Russia) [40]. These three sources serve as generatorsof 225Ac and its parent 225Ra (t1/2 = 14.9 d) and act as the world’s primary225Ac sources, producing approximately 26.6 GBq (720 mCi) (ORNL) [34]and 13.1 GBq (350 mCi) (ITU) [36] of 225Ac annually. While the IPPEsource contains as much 229Th as the ORNL source, reported values indi-cate 225Ac production from this source is sporadic [40, 101]. Most recently,a new 229Th generator was developed at Canadian Nuclear Laboratories(Chalk River, ON) that is capable of providing up to 3.7 GBq (100 mCi) of225Ac per year [102]. Overall, the accepted global annual production from229Th is 63 GBq (1.7 Ci) [35, 49, 103–105].While a key advantage of this production method is an 225Ac productfree of other actinium isotopes, 63 GBq (1.7 Ci) is insufficient to meet thecurrent global demand for researchers. This supply will be even more inad-equate should any 225Ac-radiopharmaceuticals receive clinical approval and32increased use [34]. From research into fundamental 225Ac chemistry to themost promising clinical trials (see Section 1.1.5), the development of 225Acradiopharmaceuticals is slowed by the small supply and resulting high costthat makes 225Ac inaccessible to many researchers.1.3.1.2 Leveraging Unique Facilities to Supply 225Ac ResearchDue to the high cost of 225Ac, 225Ac-radiopharmaceutical developmentat TRIUMF started by leveraging the Isotope Separator and Accelerator(ISAC) Facility [106]. This is discussed in detail in Chapter 3. Commis-sioned in 2000, ISAC produces beams of rare isotopes for experiments pri-marily studying nuclear structure and nuclear astrophysics. Irradiation ofuranium or thorium targets with protons at 480 MeV results in the pro-duction of a number of isotopes that are extracted into a heterogeneous ionbeam. Isotope Separation On-Line (ISOL) mass-separates these nuclides toproduce an isobarically homogeneous ion beam [107]. Isolation of mass 225produces an ion beam containing 225Ra and 225Ac that is directed onto analuminum target in which the isotopes are deposited at a depth of 20 nm(as determined by SRIM [108]). Etching of the aluminum post-implantationfollowed by separation of 225Ra and 225Ac on a solid phase extraction (DGA)resin provides both a primary 225Ac fraction for immediate studies, as wellas a number of subsequent 225Ac batches isolated through the decay of225Ra. When eluted at the peak 225Ac activity (after 17.4 days of grow-in)a 225Ra/225Ac generator theoretically produces 225Ac with an activity equalto 44.4% of the 225Ra activity present at the previous elution1, as shown inFigures 1.5 and 1.6. Further details on 225Ac production at ISAC can befound in Chapter 3.Since 2015, 225Ac production at ISAC has enabled radiolabeling and pre-clinical studies at TRIUMF. Though ISOL provides isotopically pure 225Acsources, yields remain insignificant compared to quantities available from229Th generators. At TRIUMF, the maximum measured ISAC beam inten-sities of 1.3× 108 ions/s for 225Ac and 1.6× 108 ions/s for 225Ra could the-oretically produce up to 370 MBq (10 mCi) of 225Ac per month2. However,ISAC does not operate as a dedicated medical isotope production facilityand 225Ac production occurs within the overarching context of the labo-ratory’s research program. Total 225Ac production for 2016 was only 44.411 MBq of 225Ra produces 11−0.444 − 1 = 0.80 MBq of 225Ac from the generator if itis eluted every 17.4 days. Calculations in this section convert 225Ra production values to225Ac production values using this conversion factor.33Figure 1.8: Decay schematic showing the decay and generator-based pro-duction pathways for 225Ac. Gamma emissions useful for quantification of225Ac are shown in red.34MBq (1.2 mCi). ISOL methods have also been applied at ISOLDE (CERN,Geneva) to produce 225Ac for radiopharmaceutical development [109].1.3.2 The need for new 225Ac production methodsEstimates of current demand for 225Ac are less than 185 GBq (5 Ci) per year,however this is likely significantly tempered by both supply constraints andcost. While predicting future demand is difficult, it can be estimated togrow by about 200 to 400 GBq per year (about 5 to 10 Ci per year) foreach 225Ac-based therapy that is approved for clinical use3. Should effortsto develop 213Bi-radiopharmaceuticals also increase, 225Ac demands will beeven higher.As will be shown in Chapter 3, facilities like ISAC can facilitate radio-pharmaceutical development by providing access to medical isotopes that areotherwise challenging to obtain. However, their application will likely remainlimited to medical isotopes in the development stages. Even with potentialproposed upgrades to the MEDICIS facility that could enable monthly pro-duction of up to 1.7 GBq (45 mCi) of 225Ac [109], and potential upgrades toISAC that could increase yields by a factor of ∼10004, these facilities are notexpected to meet existing 225Ac demand and could not supply enough 225Acto support wide-spread use of a clinically approved therapy. Such facilitiesinstead have value as research enablers whose utility comes from their abilityto provide quick access to a range of high-purity medical isotopes so thatthe feasibility of a given isotope’s applications can be explored before havingto build dedicated large-scale isotope-specific production infrastructure.While harnessing untapped 229Th supplies has the potential to moresignificantly impact 225Ac availability, in the long term this may also be in-adequate if multiple 225Ac-radiopharmaceuticals become clinically approved.Due to the high costs and security issues regarding the storage of 233U, in2005 the U.S. Congress ordered the Department of Energy (DOE) to ceaseextraction of 229Th from 233U stockpiles and to instead begin down-blending2For three 10-day implantations, 225Ac yield = 3× [1.3× 108(1− e−λ225Ac×10d) + 0.8×1.6× 10∗(1− e−λ225Ra×10d) = 370 MBq (10 mCi)2While no specific monthly production estimate is explicitly stated by Dos SantosAugusto et al [109], the reported estimated activity from one target is 28 MBq (0.75 mCi)from targets exchanged on a “weekly basis”, which is 112 MBq (3 mCi) monthly.3Assuming four rounds of 1 µCi/kg doses [29] for 10 000 patients (each 75 kg) per yearper therapy, and one half-life for processing and transport.410× from increasing proton beam current from 10 to 100 µA, 6× from increasingtarget thickness from 10 to 60 g/cm2, 2× more efficient beam extraction, and 8.39× fromreplacing uranium carbide targets with thorium targets [110].35(dilution with 238U to a non-weaponizable 233U concentration) and perma-nent disposal of the two tonnes of stockpiled 233U [39]. Petitions to recover229Th before 233U disposition were denied [101] until recently in 2019. Fromthe high- and intermediate-purity 233U sources within the inventory [111],this unused material represents the loss of 32.6 g (∼260 GBq or 7 Ci) of229Th or a potential 1.5 TBq (40.5 Ci) of annual 225Ac production. Otherestimates suggest this is a loss of 37 g (∼8 Ci) of 229Th [37] and suggest a lossof 2.2 TBq (60 Ci) of annual 225Ac production [101]. Without new 229Thsources, 225Ac production from current DOE 229Th generators could increaseby only 20% if the current milking schedule is optimized for 225Ac produc-tion instead of unit cost [34]. Quantities of additional 229Th-containing 233Usources that may exist in other countries (ex. Russia) remain unknown.Without the existence of significant additional 229Th generators, the useof 225Ac or 213Bi in multiple approved therapies will require the developmentof new 225Ac production methods. The remainder of this section aims topresent a comprehensive list of alternative 225Ac production options. Thepotential of each method to meet projected 225Ac demand and the practicalchallenges associated with each method will be discussed. Possible produc-tion methods proposed in the literature are summarized in Table 1.2, whileTable 1.3 summarizes other nuclear reactions capable of producing 225Acbut that are considered impractical at this time. When not derived fromoriginal sources, details of calculations are provided in footnotes.1.3.3 Nuclear reactions for radionuclide productionThis section aims to introduce general nuclear reaction concepts that arerelevant to medical radionuclide production. Reactions used for medical ra-dionuclide production typically involve the bombardment of a target made ofnaturally occurring stable (or very long-lived) nuclei with particles contain-ing few nucleons, such as neutrons, protons, deuterons, or alpha particles;photonuclear interactions (first mentioned in Section 1.2.1) can also be usedto remove nucleons from a target nucleus. These reactions all generallyresult in the production of a residual nucleus (either the radionuclide of in-terest, or its parent) and other emitted particles. A general description ofnuclear reactions can be written asprojectile + target nucleus→ residual nucleus + emitted particle(s) (1.12)which can also be written as a T (P ,E)R reaction, where T denotes thetarget nucleus at rest (KET = 0), P denotes the projectile particle, R the36residual nucleus, and E the sum of the emitted particle(s).An example reaction is5α+ 14N = 17O + p (1.13)which is also written as 14N(α,p)17O.Nuclear reactions are governed by a number of conservation laws, im-portantly, conservation of mass-energy and conservation of momentum (fora more complete discussion of conserved quantities in nuclear reactions, thereader is referred to the text by Schieck [113]). Nuclear reactions that re-sult in the formation of new nuclei are inelastic (Q 6= 0) and can either beexoergic (Q > 0) or endoergic (Q < 0), where the Q-value is the differencebetween the total mass energy of the reactants and the total mass energy ofthe products, i.e.Q =[(mP +mT )− (mR +mE)]c2 (1.14)where mi is the mass of particle i. By conservation of energy, Q can alsobe expressed as the change in kinetic energy during the reaction, i.e.Q = (KER + KEE)− (KEP + KET ) (1.15)Kinetically, reactions are possible provided that Q + KEP > 0 in thereference frame of the reaction’s center of mass. Endoergic reactions, there-fore, can only occur if enough kinetic energy is provided by the projectile.This threshold energy, εs, is described byKEP ≥ εs = −QmP +mTmT(1.16)in the lab frame (εs > Q because some kinetic energy will always beassociated with the center of mass, meaning that not all of KEP is availablefor the reaction).While the threshold energy described by Equation 1.16 is a necessaryrequirement for a reaction to occur, it is not a sufficient requirement withrespect to the projectile energy. For both endoergic and exoergic reactions,other thresholds arise from the repulsive potential the projectile may have toovercome in order to enter the target nucleus. While the complete potentialexperienced by the incoming projectile is the sum of the attractive nuclearpotential, repulsive Coulomb potential, and the effective potential resulting5This reaction is the first nuclear reaction that was observed by Rutherford in 1919[112–114]37from centrifugal forces, in the context of barriers and threshold energies, wewill here consider only the Coulomb potential (for more, see the texts byLoveland et al [115] or Konya et al [114]).The Coulomb barrier experienced by a projectile approaching the targetis described byVC =ZPZT q2RP +RT(1.17)where Zi and Ri is the proton number and radius of each particle, respec-tively. Neutrons experience no Coulomb barrier and the threshold energy ofexoergic neutron reactions approaches zero and can be on the order of eV.However, charged projectiles must have sufficient kinetic energy to overcomethe Coulomb barrier and enter the nucleus in order for reactions to occur.Once sufficient conditions for a reaction to occur are met, the probabil-ity that it will occur is described by the reaction’s cross section, σ, a keyenergy dependent observable of nuclear reactions. Given a flux of projectileparticles, Φ, incident on a target containing NT target nuclei, the reactionrate per unit time, φ = σNTΦ. Often, multiple reactions are possible fora given target and projectile, and the total cross section that describes theprobability the these particles will interact is given by the sum of cross sec-tions for all possible elastic or inelastic reactions, and can also be thoughtof as the effective cross sectional area of a single target atom. An additionaldiscussion of cross sections is provided in Section 6.2.1.Once a projectile enters the target nucleus, various models can be usedto describe the interactions that take place, depending on the reactants andenergy of the reaction (again, for more see the textbook by Schieck [113]).The most relevant model for medical nuclide production is the compoundnucleus reaction model. In this model, the projectile enters the target nu-cleus and forms a compound nucleus, a short-lived reaction intermediate.The projectile’s kinetic energy is distributed among the other nucleons ofthe compound nucleus and the compound nucleus is then modelled as a hotFermi gas. The excited compound nucleus then decays by emitting nucleons,which can be modelled as evaporation of nucleons from the Fermi gas: theemitted particles exhibit a Maxwellian energy distribution with a minimumenergy equal to the height of the exit barrier (roughly equal to the Coulombbarrier). The result of the interaction is the residual nucleus, R, and theemission of particles, E. The residual nucleus may also be in an excitedstate, and can decay by gamma emission. The cross section for compoundnuclei reactions can be described as the product of the compound nucleusformation cross section and the probability that the compound nucleus will38decay through a given exit channel. An important assumption of this modelis that the mode of compound nucleus decay is independent of how thenucleus was formed.A noticeable trend described by this model is the energy dependence ofthe cross section for potential reaction exit channels. Considering neutronemission, as the projectile energy increases from the threshold energy, thecross section for evaporation of a single neutron increases until it becomeskinetically possible for emission of two neutrons to occur. As energy furtherincreases, this two-neutron emission will become dominant over the one-neutron emission exit channel and the cross section for this two-neutronprocess will further increase until the evaporation of three neutrons becomeskinetically possible, and so on.However, as projectile energy increases beyond approximately some tensof MeV per nucleon, the nuclear reactions are no longer described by thecompound nucleus model because projectiles begin to interact with individ-ual nucleons within the target nucleus, instead of with the target nucleusas a whole. This is explained by the decrease in the particle’s de Brogliewavelength with energy (λ ∝ KE−12P ). For example, a 10 MeV proton hasa wavelength (λ ≈ 10−12cm) approximately equal to the size of a nucleus,while a 1000 MeV (λ ≈ 10−14cm) proton has a wavelength smaller thanthe typical inter-nucleon spacing within a nucleus. The consequence of thisis that the 10 MeV proton will interact with the entire nucleus – the com-pound nucleus process – while the 1000 MeV proton will undergo a series oftwo-body projectile-nucleon interactions as it passes through the nucleus –the spallation process.This series of projectile-nucleon interactions is called an intranuclear cas-cade, and is only the first step in the spallation process. The intranuclearcascade results in the high-energy ejection of several nucleons from the nu-cleus (a number that increases with projectile energy), and leaves behinda highly excited nucleus. The remaining energy deposited in the nucleusis distributed evenly among the nucleons, and the excited nucleus decaysby evaporation. The evaporation process is similar to that described previ-ously for the compound nucleus process, however, a greater number of exitchannels will be available after the more energetic intranuclear cascade, in-cluding potential emission of protons, low-energy neutrons, alpha particles,light nuclear fragments, deuterons, etc. For heavy target nuclei, the high-energy fission of the excited nucleus can also occur in competition with theevaporation process. This high-energy fission process differs from the typicallow-energy neutron-induced fission process in that the fission product mass39distribution becomes more symmetric with increases in incident particle en-ergy, diminishing nuclear shell effects that make an asymmetric distributionmore kinetically favorable in low incident projectile energies. A variety ofapproaches are used to model the intranuclear cascade, evaporation, andhigh-energy fission processes of spallation reactions [116].This concludes a brief introduction to the physical processes typicallyinvolved in the production of medical radionuclides. For a more detaileddiscussion, the reader is directed to the following references [113–116]. Theremainder of Section 1.3 will discuss how nuclear reactions can be used for225Ac production.1.3.4 Potential alternative 225Ac production methods1.3.4.1 Potential for 225Ac Production in Nuclear ReactorsWhile the majority of medical isotopes today are sourced from nuclear reac-tors [117], the potential for reactor-based 225Ac production is limited. Theparent isotope, 225Ra, can be produced in reactors via the 226Ra(n,2n)225Rareaction, however, this reaction would require an intense source of high(>6.4 MeV) neutrons found only near the tail end of a typical breeder re-actor neutron energy spectrum. Given that significantly more lower energyneutrons would be present, these irradiations would be dominated by theco-production of 227Ac, a long-lived (t1/2 = 21.8 y) and highly toxic ac-tinium isotope, the presence of which in significant quantities may preventthe clinical approval of a pharmaceutical. To the best of our knowledge, thismethod has not been investigated experimentally or thoroughly modelled.However, rough estimates suggest this method could produce MBq to GBq(µCi to mCi) amounts of 225Ac per month per gram of 226Ra target materialat a single reactor facility6.The potential to increase 229Th stocks using reactors has also been inves-tigated [120, 121]. Results suggest the irradiation of 226Ra targets at a singlereactor could produce 100 MBq (2.7 mCi) of 229Th per month per gram of226Ra target material [120]. Other results have suggested this value maybe closer to 59 MBq (1.6 mCi) [121]. While larger specific yields were seenwhen using 228Ra and 227Ac target materials (352 and 600 MBq (9.5 and16.2 mCi) of 229Th per month per gram, respectively), these isotopes cannot6Assuming two 15-day irradiations per month, 1 gram 226Ra target, average cross-section of 2 barns over the 6.4 to 16.4 MeV range [118], and average neutron flux of1× 1012 n/s/cm2 over the same energy range [119] produces 52 GBq (1.4 Ci) of 225Ra or44 GBq (1.2) Ci of 225Ac per month.40be supplied in sufficient quantities [120]. The 228Th(n,γ)229Th reaction isimpractical for the same reason. For example, 2.5 thousand tonnes of nat-ural thorium would have to be processed to produce a single gram of 228Ra(t1/2 = 5.8 y), which could potentially be used to slowly generate228Th(t1/2 = 1.9 y). However, given the challenges and costs associated withsafely handling large 226Ra sources (see Section 1.3.4.4) and the resultinglow 225Ra or 229Th yields, reactor production of sufficient 225Ac quantitiesmay not be practical.1.3.4.2 Potential for 225Ac Production Using Electron Accelera-torsThe use of the 226Ra (γ,n)225Ra reaction for 225Ac production has beenexplored experimentally [122] and theoretically [123]. These works have ex-plored irradiating old radium needles on electron linear accelerators (linacs)found in many cancer centres. These linacs typically use electron beamsincident on tungsten targets to produce bremsstrahlung x-rays for externalbeam radiation therapy. Experimental results measured the production of2.44 MBq (66 µCi) of 225Ac after a single-hour irradiation by 18 MV x-raysof a 20 mg of 226Ra source located 12.5 cm from the tungsten target andwith incident electron beam of 26 µA average current [122]. This scales to apotential 48 GBq (1.3 Ci) of 225Ac per month for a 1 g 226Ra source, whichcould be potentially increased by irradiation parameter optimization. Thismethod has the advantage of producing 225Ac without contamination fromother actinium isotopes. While co-production of 224Ra occurs for photonsabove 12 MeV, this should not impact the desired 225Ra/225Ac generatoras 224Ra (t1/2 = 3.7 d) decays to inert220Rn and does not result in theproduction of any Ac isotopes.While many medical linacs capable of this 225Ac production method mayexist, these facilities are used for patient care and, to our knowledge, noneare currently equipped with the infrastructure required for safe large-scaleisotope production and processing. Again, the 48 GBq (1.3 Ci) of 225Acper month would likely be cost prohibitive given the challenges (see Section1.3.4.4) associated with a 1 g 226Ra target. It has been estimated that linac-based 225Ac production could be increased by up to a factor of 16, althoughaccompanied by an increase in target mass [124].Given this low yield, sufficient 225Ac production via the 226Ra(γ,n)225Rareaction would require the use of a facility with significantly higher elec-tron beam current. Though none are dedicated medical isotope productionfacilities, some such facilities exist for which 225Ac production values deter-41mined by scaling experimental medical linac irradiation results by electronbeam current can be found in Table 1.2. In addition, TRIUMF’s plannedAdvanced Rare IsotopE Laboratory (ARIEL) facility will use a 50 MeV, 10mA electron beam to produce intense high-energy x-rays for radioisotopeproduction by photofission [106]. While the ARIEL electron target is in-tended for operation as an ISOL facility for fundamental research – not amedical isotope production facility – scaling experimental results for 225Raproduction on medical linacs to account for the higher current and differ-ent irradiation geometry suggests ARIEL could theoretically produce up to74 TBq (2000 Ci) of 225Ac per month from a 1 g 226Ra target. However,how an isotope production target could survive a 500 kW beam is anotherunsolved problem. Other lower current electron accelerators, such as theexisting 50 MeV, 10 µA ALTO electron accelerator (Orsay, France) [125],could theoretically produce up to 56 GBq (1.5 Ci) per month.1.3.4.3 Potential for 225Ac Production using Low Energy ProtonAcceleratorsThe promising use of the 226Ra(p,2n)225Ac reaction to produce 225Ac on low-energy proton accelerators was first demonstrated in 2005 by Apostolidis etal [126]. This reaction has a high (710 mb) cross-section peak at 16.8 MeVand could thus be performed on the many low energy cyclotrons already inuse worldwide for medical isotope production. An estimated >550 of thesecyclotrons have an energy over 16 MeV, some of which operate at up to 500µA [127]. Another advantage of this approach is that it would not coproduce227Ac. While the (p,n) reaction is expected to produce some 226Ac (t1/2 =29.4 h), measurements of co-production of 226Ac have not been reportedfrom experiments found in the literature [126]. A simple Fluka [128, 129]simulation approximating the Apostolidis et al experiment suggests an 226Acactivity at end of bombardment (EOB) equal to ∼11% the 225Ac activity.However, unlike with 227Ac contaminants, the ratio of expected 226Ac to225Ac activity would decrease over time due to the differences in half-lives.The co-production of 225Ra via the 226Ra(p,pn)225Ra reaction is expectedto be negligible at the optimal energies required for direct 225Ac production[130].Given the high cross-section, large scale production of 225Ac via the(p,2n) reaction would be capable of meeting long-term demand for 225Acwith only a single production site. Combining available cross-section data[126] with stopping power for 226Ra [108] suggests a single 20 MeV, 500 µAproton beam incident on a 226Ra target (∼1 g) could produce a theoretical42maximum of 4 TBq (108 Ci) of 225Ac per month7.The use of low energy proton irradiation of 232Th to produce 229Pa, whichdecays to 229Th, has also been explored [131]. The peak measured cross-section for this 232Th(p,4n)229Pa reaction is 162 mb for a proton energyof 29.8 MeV. However, yields for this production method are low, with apotential to produce only 7.4 MBq (0.2 mCi) of 229Th per month on a 50MeV, 500 µA cyclotron.1.3.4.4 Challenges Associated with 226Ra TargetsMost alternative 225Ac production methods discussed so far have involvedthe use of 226Ra as a target material. Since irradiations for radionuclide pro-duction typically require targets containing macroscopic quantities (>mg)of target material, a stable or naturally occurring and long-lived target ma-terial is typically required. The closest such nuclide to 225Ac, 226Ra is oneof only a few options – spallation reactions on naturally occurring 232Thand 238U being the only other possibilities for large scale 225Ac production.Other potential target materials such as 230Th, 228Th, 228Ac, and 228Ra arenot available in large enough quantities to be of practical use.Despite its potential, the use of 226Ra targets poses significant challengesdue to the availability of the nuclide and safety hazards that complicate thetarget manufacturing, irradiation, processing, and recycling. Part of the238U decay chain, 226Ra ultimately decays to stable 206Pb and is typicallyfound in equilibrium with most isotopes in its decay chain. 226Ra was thefirst radioactive isotope discovered and was produced in large quantities fromthe 1920s for use in a number of medical and industrial applications untilproduction stopped in 1960 [132]. Due to its high radiotoxicity, reactivitywith water and air, and decay to the noble alpha-emitting 222Rn gas, 226Rasources typically contained radium salts encapsulated in platinum [133]. Theinternal production of helium from the five alpha decays in the 226Ra chaincaused most of these sources to rupture, after which 222Rn gases are releasedand 226Ra salts can leak out. Even when sealed, the gamma rays emittedby 226Ra progeny present external radiation hazards, with a dose rate of 8.17Activity produced by a target completely stopping the incident proton beam can becalculated using energy-dependent values for stopping power, S(E), and cross-section,σ(E), using the following equation: A(t) = ρφ(1 − e−λt) ∫ 0E0σ(E)dES(E), given target densityρ, proton fluence φ and initial energy E0, irradiation time time t, and product isotopedecay constant λ. For this equation, a 226Ra target density of 5 g/cm2 was assumed, aswell as an irradiation schedule of three 10-day irradiations to get a monthly productionvalue. The integral was performed using fitted data in MATLAB.43mSv/h at 1 m from a 37 GBq (1 Ci, 1 g) 226Ra source without shielding.The high energies of some of these gamma rays can also present shieldingchallenges.While the use of 226Ra sources declined after the health effects of ra-diation exposure became known and safer reactor-based isotopes becameavailable, many 226Ra sources remained in storage – primarily in hospitals– for decades. The hazards associated with the presence of 226Ra sourceslead many governments to push for the elimination of 226Ra inventories andin 1996 the International Atomic Energy Agency (IAEA) established guide-lines for the disposal of 226Ra sources in long term geological repositories[133]. This limits the availability of large 226Ra quantities, with the IAEAestimating only a few kilograms of 226Ra exist among these sources world-wide [133]. Typical medical sources contained <100 mg of 226Ra, with asome industrial sources containing up to 1000 mg quantities. For this rea-son, calculations in Table 1.2 assume 1 g as a reasonable upper limit on thesize of potential 226Ra targets.New 226Ra sources could be extracted from the waste of current uraniummining operations. Approximately 50 thousand tonnes of uranium ore ismined each year [134], from which 226Ra is separated and disposed of aswaste. With potential to extract 257 mg of 226Ra from each tonne of U3O8[123], this amounts to about 12.85 kg of 226Ra waste per year.Whether obtained using old sources or through uranium mine tailings,the manufacturing of 226Ra targets for 225Ac production would require in-frastructure beyond what is typically used to make medical isotope pro-duction targets. 226Ra regulatory and safety issues – particularly thoseassociated with 222Rn – would also require additional infrastructure dur-ing the target irradiation, processing, and the necessary recycling of irra-diated 226Ra material. While 226Ra targets have the greatest potential for225Ac production per gram of target material, difficulties and costs associ-ated with these targets is a significant disadvantage of the 226Ra(p,2n)225Acand 226Ra(γ,n)225Ra production methods.1.3.4.5 Potential for 225Ac Production via High-Energy ProtonSpallation of ThoriumAn alternative 225Ac production method that avoids the use of 226Ra targetsinvolves the irradiation of natural thorium targets with protons above ap-proximately 70 MeV. This 232Th(p,x)225Ac reaction produces 225Ac througha number of reaction pathways, though the total cross-section peaks ∼40times lower than for 226Ra(p,2n)225Ac production. Thorium metal is the44preferred chemical form for post-irradiation processing of the target, and iso-lation of MBq to GBq (µCi to mCi) quantities of 225Ac from irradiated tho-rium metal has been demonstrated by both American and Russian researchgroups at Brookhaven National Laboratory (BNL, Brookhaven, NY), LosAlamos National Lab (LANL, Los Alamos, NM), and the Institute for Nu-clear Research of the Russian Academy of Sciences (INR) [35, 101, 104, 135–142]. Unlike 226Ra (3.7×1010 Bq/g, or 1 Ci/g), 232Th (4.1×103 Bq/g, 110nCi/g) is not prohibitively radioactive, poses fewer radiological hazards andis readily available as a target material. Tens of kilograms are known toexist in stockpiles within a number of countries, and more thorium metalis able to be produced in bulk quantities from thorium oxide or thoriumnitrate, hundreds of tonnes of which are produced annually worldwide asa by-product of rare-earth mining [134]. This availability means recyclingof irradiated 232Th target material may not be necessary. Another advan-tage of this method is that facilities already exist with demonstrated abilityto perform target fabrication, irradiation, and processing. Examples of ac-celerator facilities capable of producing large amounts of 225Ac via protonspallation are listed in Table 1.2.While spallation of naturally occurring 238U will also produce 225Ac,232Th irradiation is preferred for a number of reasons. The 238U(p,x)225Acreaction cross-section is ∼10 times lower (as modelled using Fluka), anddue to the higher density and lower melting point of uranium, thoriumtargets could more safely handle the higher heat load induced by higherproton beam currents. The co-production of fissile 239Pu and 235U is alsoavoided by 232Th irradiation.The spallation of thorium produces a number of radionuclides other than225Ac. While this may provide opportunity for recovery of other usefulmedical radionuclides, it also complicates target processing by requiring theseparation of dozens of elements. Concerns also exist in the field that theamount of 227Ac co-produced from thorium spallation will prevent its useas a method for clinical-grade 225Ac production. An 227Ac to 225Ac activityratio of 0.1-0.3% is typically found in irradiated targets at end of bom-bardment [136, 138–141, 143]. However, potential exists for current targetprocessing methods to be modified to produce 225Ac quantities that are freeof 227Ac by isolation of an radium-actinium generator [2]. Most methodsalready isolate radium from the irradiated thorium matrix, and if this isdone days after EOB, only 228Ra, 226Ra, 225Ra, 224Ra, and 223Ra will bepresent because of the length of their half-lives (t1/2 = 5.7 y, 1600 y, 14.9d, and 3.6 d, respectively), and 223Ra (t1/2 = 11.4 d). Of these,228Raand 225Ra beta-decay to actinium isotopes, while the others alpha-decay to45radon isotopes. Use of this mixture as a radium-actinium generator willproduce 225Ac free of 227Ac. While 228Ac (t1/2 = 6.2 h) will be present after225Ra/225Ac separation, the ratio of 228Ac to 225Ac activity (∼0.88% at thetime of optimal 225Ac elution [2]) will decrease with time. After sufficient228Ac decay, 225Ac could then be removed from the 228Th (t1/2 = 1.9 y)produced by 228Ac decay to obtain a final 225Ac product with significantlyreduced radioactive impurities when compared to the directly produce 225Acfraction. While the total 225Ac yield from this method will be reduced bya factor of about 10, it does not prevent the use of the directly-produced,227Ac-containing batch of 225Ac from being used for research or for use in225Ac/213Bi generators.Only a few existing accelerators can produce proton beams with a cur-rent and energy sufficient for large-scale 225Ac production. A list of some ofthese facilities is given in Table 1.2 along with estimates of the maximumamount of 225Ac each could produce per month. These values only includedirectly produced 225Ac and exclude 225Ac produced from 225Ra generatorsthat would increase production for each by roughly 10% to 20%. Withoutknowing details of each institutions’s target irradiation facilities, all are com-pared based on their maximal yield estimates that assume a target stationcapable of handling a thorium target thick enough to completely stop theproton beam (the same assumption was made for 226Ra (p,2n)225Ac maxi-mal yields)8. As a result, practical yields will be lower. For example, whileTRIUMF’s 500 MeV, 120 µA beam could theoretically produce 11.2 TBq(304 Ci) of 225Ac per month, 3 TBq (82 Ci) of monthly 225Ac productionis a more practical limit given the existing target station’s size and coolingcapacity. Similarly, practical estimates reported for production at BNL andLANL are 165 GBq (4.5 Ci) per month [142].8Calculated using the equation in Footnote 7, using a target density of 11.72 g/cm2and three 10-day irradiations. Thorium stopping power was obtained from SRIM [108],thorium spallation cross-sections were obtained from EXFOR [144].46Table 1.2: Summary of current and potential 225Ac production methods. Production values for current sourceslist current production levels, while values for potential sources list estimates of maximum possible production atsample of existing and operational facilities that have dedicated stations for large-scale medical isotope production.Details of calculations or references to cited values can be found in the text. Values listed for 226Ra targets assumea target mass of 1 g.ProductionMethodFacility CapabilitiesMonthly 225AcProduction [GBq(Ci)]CurrentSources229Th generatorORNL 0.704 g (150 mCi) of 229Th 2.2 (0.06)ITU 0.215 g (46 mCi) of 229Th 1.1 (0.03)IPPE 0.704 g (150 mCi) of 229Th 2.2 (0.06)PotentialFutureSources232Th(p,x)225AcTRIUMF 500 MeV, 120 µA 11266.5 (304.05)BNL 200 MeV, 173 µA 2675.84 (72.32)INR 160 MeV, 120 µA 1002.0 (27.08)Arronax 70 MeV, 2×375 µA 462.1 (12.49)LANL 100 MeV, 250 µA 12.00iThemba LABS 66 MeV, 250 µA 127.7 (3.45)226Ra(p,2n)225Ac20 MeV, 500 µA cyclotron 3983.1 (107.65)15 MeV, 500 µA cyclotron 1157.4 (31.28)ISOLTRIUMF (existing) 0.37 (0.01)TRIUMF (potential upgrades) 190.6 (5.15)226Ra(γ,n)225Ramedical linac 18 MeV, 26 µA 48.1 (1.3)ALTO 50 MeV, 10 µA 55.5 (1.5)226Ra(n,2n)225Ra fast breeder reactor ∼37 (1)47Table 1.3: Other methods for 225Ac production.ProductionMethodComments226Ra(p,pn)225RaYields insignificant compared to 226Ra(p, n)225Ac pro-duction (105× less according to Fluka simulation)232Th(p,4n)229Pa Low cross-sectionNatU(p,x)225AcProduces approx. 10× less 225Ac and 225Ra comparedto thorium spallation, creates fissile 239Pu and 235U,can handle less beam current than thorium spallationtargets232Th(n,γ)233U Would take decades for 229Th to build up230Th(γ,n)229Th 230Th not available in sufficient quantitiesReactor productionof 229ThPotential target materials 228Ac, 228Ra, 228Th, and230Th not available in sufficient quantities. Productionyields from 226Ra irradiation (110 MBq/month/g, or 3mCi/month/g) too low considering cost and difficultyof 226Ra source production.1.4 Thesis OutlineThe initial motivations for the research presented in this thesis were toinvestigate if multi-nuclide imaging of the 225Ac decay chain could be usedto quantify individual biodistributions of the decay chain’s nuclides, thuspotentially providing a more complete understanding of the decay chain’spharmacokinetics during preclinical 225Ac-radiopharmaceutical evaluation.At that time, due to its scarcity and cost, the only potential readily-availablesource of 225Ac was TRIUMF’s ISAC facility (Section 1.3.1.2). Therefore,the development of 225Ac production and collection at ISAC was also agoal of this work. Specifically, these efforts can be framed by the followingresearch questions:(1) 225Ac production at ISAC: How can 225Ac be produced at ISAC?How much 225Ac can be produced? Can this 225Ac be used for pre-clinical 225Ac-radiopharmaceutical development?(2) Feasibility of 225Ac decay chain imaging: Can available preclini-cal imaging instruments be used to individually quantify distributionsof 225Ac progeny nuclides, 221Fr and 213Bi? What is the performance48of the instrumentation for creating separate 221Fr and 213Bi imagesfrom simultaneously acquired data?(3) Preclinical 225Ac decay chain imaging: Can these multi-nuclideimaging methods be used to individually image dynamic 221Fr and213Bi biodistributions in a preclinical model?Questions (1) and (2) are addressed in Chapters 3 and 4, respectively.However, during the course of this work, it became evident that address-ing question (3) would require greater quantities of 225Ac than what couldbe produced at ISAC. This obstacle motivated a change in research focustowards new methods of 225Ac production using alternative TRIUMF facil-ities. This new focus, centering on 225Ac production using TRIUMF’s 500MeV Isotope Production Facility (IPF), forms the majority of the researchpresented herein. These new research questions include:(4) IPF targetry: What are the appropriate design requirements for athorium-based 225Ac production target at TRIUMF’s IPF? What doesa target design that meets these requirements look like? What arethe proton beam parameters that will allow this target to be safelyirradiated? How much 225Ac and 225Ra can be produced in thesetargets at IPF?(5) 232Th(p,x) radionuclide production: What other radionuclidesare co-produced in 225Ac production targets at IPF? How accurateare Monte Carlo methods for estimating the resulting radioactive in-ventory? What are the 232Th(p,x) cross sections for 225Ac and 225Raproduction, and for the production of other relevant radionuclides?(6) Chemical separation of 225Ac from IPF targets: How can exist-ing radiochemical separation methods for isolation of Ac from protonirradiated thorium be modified such that they can be applied for IPFtargets, using TRIUMF’s radiochemistry facilities? Can the produc-tion of 225Ra during thorium irradiation be used to chemically iso-late a generator-produced Ac product with fewer long-lived impurities(specifically, 227Ac) than the directly-produced Ac product? And, howdoes the quality of these two Ac products compare to each other?Questions (4), (5), and (6) are addressed by Chapters 5, 6, and 7, respec-tively. Each of the research chapters in this thesis (Chapters 3 through 7)have been published in peer-reviewed journals in some similar form to how49they appear herein. Therefore, each chapter is structured to read as a stan-dalone paper and includes background information and methods specific tothat chapter. General methods that are employed in multiple research chap-ters are introduced in Chapter 2. Finally, Chapter 8 provides a summaryand overall perspective on these research chapters as a whole.502 Methods Used for RadioactivityQuantification and EstimationThe quantification of radioactivity is the principle measurement used togenerate the majority of the data presented in this thesis and is used inevery research chapter (Chapters 3 through 7). While measurement methodsthat are specific to each chapter are described therein, Chapter 2 describesthese radioactivity quantification techniques in general, focusing on aspect ofthe methods that are applicable to all chapters. The measurement methodspresented include gamma spectroscopy (Section 2.1) and alpha spectroscopy(Section 2.2). Section 2.3 then introduces Fluka simulations, a methodused for estimating the radioactive inventories of irradiated materials insituations where empirical measurements (gamma or alpha spectroscopy)are impossible or impractical.2.1 Gamma SpectroscopyGamma spectroscopy was essential throughout the work presented in thisthesis and comprises the majority of the data that is presented, especiallyfor Chapters 6 and 7. Therefore, a thorough description of this techniqueand how it was applied to the research is warranted.Section 2.1 describes the methods and procedures used to set up, cali-brate, commission, and maintain the TRIUMF Life Sciences Division’s High-Purity germanium (HPGe) detector, located in the RCR1 lab, which wasthe gamma-ray spectroscopy workhorse used throughout all chapters of thisthesis. The aims of this section are to:1. Document calibration procedures, operating parameters, and initialperformance that may need to be referenced during the detector’s life-time2. Demonstrate the detector’s ability to reliably perform accurate quan-51titative assays of radioactive samples, as well as the limitations of suchmeasurements3. Provide a reference manual for the many user-created files that areregularly referenced and required for use of the detectorIn fulfillment of these objectives, the basic functioning of the detector isoutlined, followed by the steps taken for its setup and calibration. The useand location of key files is also described. Experiments used to validate theaccuracy of the detector are also presented.2.1.1 BackgroundHPGe gamma spectroscopy detectors permit precise, high energy resolution(<1 keV), quantitative measurements of radioactive samples. Gamma raysthat interact and deposit energy within the detector’s semi-conducting ger-manium crystal elevate electrons into the conduction band. A high (kV)electric potential accelerates these electrons towards a collecting cathode,creating an electronic pulse with an integrated charge directly proportionalto the energy deposited by the gamma ray. This electronic pulse is ampli-fied before being set to a multi-channel analyzer (MCA), which records theintegral of the amplified pulse in a histogram. This histogram is referred toas a gamma ray spectrum.Detectors and samples being measured are typically placed within a thicklead shielding well with a heavy movable lid in order to eliminate signalfrom other nearby radiation sources. Due to the small conduction bandgap of germanium, the crystal must be cooled by liquid nitrogen wheneverthe high voltage is applied in order to prevent catastrophic damage to thedetector. Therefore, the detector is thermally connected by a thick rodto a dewar filled with liquid nitrogen that sits below the shielding well.Since the positioning of samples relative to the detector significantly affectsmeasurements, a 3D printed sample holder is used to provide reproducibledetector-sample configurations.The Genie 2000 software suite (version 3.4, Canberra Industries Inc.) wasused to acquire and analyze gamma ray spectra. Two other similar detectorsystems exist at TRIUMF and are maintained by the Radiation ProtectionGroup (RPG), also operated using the Genie 2000 software suite.Setup, calibration, commissioning, and routine use of these detectorsrequires the creation of a number of critical files that must be referencedduring data acquisition and analysis, including:52• MCA Interface Definition (MID) files, which configure the MCAparameters• Energy Calibration files, which define the energy range of eachMCA channel as well as the expected shape (FWHM and low-tail) ofgamma peaks• Peak-to-Total Calibration files, which describe ratio of the numberof counts in a photopeak to the number of counts in the Comptoncontinuum as a function of photopeak energy, required for use of theGenie 2000 Cascade Correction algorithm• Geometry files, which describe detector-sample geometries for theGenie 2000 Cascade Correction algorithm• Efficiency Calibration files, which describe counting efficiency as afunction of energy for a given detector-sample geometry• Background Spectra files, which account for radiation sourceswithin the detector shielding well• Library files, which define radionuclides and their gamma emissionsand are used to identify nuclides within a spectrum• Certificate files, which define calibration sources• Analysis Sequence files, which define customizable automated al-gorithms for analyzing spectra• Calibration Spectra files, the raw data used for calibrating thedetector• and of course, data files themselvesSection 2.1 aims to record the creation of these files, and demonstratethat they work both individually and together to permit reliable and quan-titatively accurate assays of radioactive samples.Mixed calibration sources containing 133Ba (t1/2 = 10.6 y) and152Eu(t1/2 = 13.5 y) were used for calibrations. These sources were providedby Stuart Hunt & Associates (Mississauga, ON) and have activity con-centrations traceable to the National Institute of Standards and Technol-ogy (NIST). All values describing physical properties of nuclides (half-lives,gamma ray energies etc.) are taken from the NuDat database maintainedby Brookhaven National Laboratory [83].532.1.1.1 Hardware SetupThe following settings were used when setting up the high voltage unit andamplifier:• Potential: -3500 V• Coarse gain: 100• Fine gain: 6.26• Pulse shaping: 2 µsThe 2 µs pulse shaping was selected as the value that provided the bestenergy resolution (see Appendix A.1). This parameter defines the timeinterval over which pulses are integrated in the detector during detection ofevents.The file GAMMA.mid defines the the MCA (serial #04049755) parame-ters and is used by the Genie 2000 Acquisition and Analysis software tocommunicate with the detector.2.1.2 Energy and shape calibrationEnergy-channel and peak shape calibrations are performed simultaneouslyin Genie 2000. Since spectra are stored in the MCA as number of countsper MCA channel, it is necessary to perform an energy calibration so thatspecific energy ranges can be assigned to each of the 8192 channels. Shapecalibration, including both peak width and low-tail calibrations, providesuseful information when performing fits to measured data, as expected peakwidths can be used to restrain fits in multiplets (overlapping peaks), or canindicate if a peak may be a multiplet.To perform these calibrations, a spectrum was acquired using a source(R-01107a) containing 152Eu (1.5050 ± 0.04515 kBq) and 133Ba (1.5147 ±0.0454 kBq) in a 20 mL vial, positioned at approximately 20 cm above thedetector end cap for a 24 hour data acquisition. The analysis sequenceenerCal is used to analyze spectra before performing an energy and shapecalibration. This analysis sequence initiates the Genie 2000 Interactive PeakFit Tool, and it is critical that the user uses this tool to ensure peaks usedin the calibrations have high-quality fits. The fits used in this calibrationare illustrated in Appendix A.2. The energy and shape calibrations are theninitiated using the certificate file energyCalibration.ctf. These fits werethen used to perform the energy, FWHM, and low-tail calibrations described54in Sections 2.1.2.1, 2.1.2.2, and 2.1.2.3. Data in these sections are from acalibration performed on 2016-09-24.2.1.2.1 Energy CalibrationTable 2.1 shows the values used to perform the energy calibration using a3rd-order polynomial fit. An energy calibration is shown in Figure 2.1 andindicates the energy response is highly linear over the full range of 0.4 to2001.0 keV.Table 2.1: Gamma peaks used by the energyCalibration.ctf certificatefile along with values from an energy calibration performed on 2016-09-24.Peak centroid values were determined using Genie 2000’s Interactive PeakFit Tool. These values are plotted in Figure 2.1.Centroid Channel Energy [keV] Nuclide216.93 ± 0.02 53.1622 ± 0.0006 133Ba331.11 ± 0.01 80.9979 ± 0.0011 133Ba498.19 ± 0.01 121.7817 ± 0.0003 152Eu1131.08 ± 0.01 276.3989 ± 0.0012 133Ba1239.35 ± 0.01 302.8508 ± 0.0005 133Ba1408.90 ± 0.01 344.2785 ± 0.0012 152Eu1456.92 ± 0.01 356.0129 ± 0.0007 133Ba1570.83 ± 0.01 383.8485 ± 0.0012 133Ba3187.68 ± 0.02 778.9045 ± 0.0024 152Eu3945.18 ± 0.02 964.057 ± 0.005 152Eu4443.30 ± 0.02 1085.837 ± 0.010 152Eu4550.76 ± 0.01 1112.076 ± 0.003 152Eu5762.27 ± 0.03 1408.013 ± 0.003 152Eu2.1.2.2 Peak Width CalibrationThe width of gamma peaks on HPGe detectors is known to be energy de-pendent. Calibration of the peak FWHM values provides useful informationwhen performing fits to measured data, as expected peak widths can beused to restrain fits in multiplets, or can indicate if multiple gamma raysare present within a peak. Values used for the 2016-09-24 calibration areshown in Table 2.2.Unlike the energy calibration, Genie 2000 provides no flexibility in theequation used to fit the shape calibration data. The following equation is55Figure 2.1: Energy calibration curve from 2016-09-24. The uncertainties foreach data point are listed in Table 2.1.used by Genie 2000 for the FWHM calibration:FWHM = a+ b ∗ E0.5 (2.1)where E is the energy of the peak. The poor suitability of this equation isshown in Figure 2.2. While an accurate width calibration is not essentialto the analysis of spectra, the user should keep this in mind when usingcalibration-based FWHM values during any analysis with Genie 2000. Alinear fit to this data is much more appropriate, as shown in Figure 2.2. Atable of predicted FWHM values based off of a linear calibration curve isgiven in Appendix A.3.The exception to predictable peak widths are annihilation photons,which appear broader than peaks from gamma rays emitted directly bya nucleus, as shown in Figure 2.2. This is a result of the underlying energydistribution of annihilation photons, which occurs since not all positronsannihilate at rest.56Figure 2.2: Peak width calibration curves determined by Genie 2000 andby a linear fit. The poor agreement of the Genie 2000 calibration curveis evident. This calibration was performed on 2016-09-24. Verification ofthe calibration was performed on 2016-12-05 using an number of differentradionuclides. The broader nature of annihilation photons is also shown.Table 2.2: Peak shape calibration values determined during an energy cali-bration on 2016-09-24. The resulting width and tail calibrations are shownin Figures 2.2 and 2.3, respectively.energy [keV] FWHM [keV] low tail [keV]53.16 0.813 ± 0.002 0.125 ± 0.00781.00 0.833 ± 0.001 0.168 ± 0.010121.78 0.877 ± 0.001 0.227 ± 0.010276.40 1.040 ± 0.001 0.232 ± 0.012302.85 1.067 ± 0.001 0.310 ± 0.032344.28 1.106 ± 0.001 0.315 ± 0.034356.01 1.121 ± 0.001 0.335 ± 0.017383.85 1.153 ± 0.002 0.291 ± 0.029778.90 1.526 ± 0.001 0.327 ± 0.020964.06 1.680 ± 0.002 0.330 ± 0.0151085.8 1.800 ± 0.002 0.398 ± 0.0271112.08 1.807 ± 0.002 0.376 ± 0.0151408.01 2.085 ± 0.002 0.437 ± 0.01757Figure 2.3: Peak low-tail values and the calibration curve determined byGenie 2000 using a linear fit. Values and uncertainties are determined byGenie 2000. This calibration was performed on 2016-09-24.2.1.2.3 Peak Low-Tail CalibrationPeaks measured with HPGe detectors are known to exhibit a low-energytail that slightly skews the otherwise Gaussian-shaped peak towards lowerenergies. The result is peaks that are not symmetrical. For more informationon the definition of the low-tail, the reader is referred to p. 252 of Genie2000 Customization Tools Manual [145]. The size of the low tail is alsoenergy dependent and is calibrated along with the FWHM during shapecalibrations. Genie 2000 uses a linear fit for the low-tail calibration. Thoughcalibration of this feature has little affect on results, values from a calibrationperformed on 2016-09-24 are shown in Table 2.2 and are plotted in Figure2.3.2.1.3 Background spectraIt is especially important during long (>12 hour) data acquisitions or whenassaying samples containing low (∼mBq) levels of radioactivity that thebackground radiation environment be taken into account during the analy-sis. Regular assessment of the background is also required to monitor thedetector for radioactive contamination that may affect future measurements.Background correction during data analysis in Genie 2000 is performedby referencing a previously acquired and analyzed background spectrum.The background spectrum should be acquired over a minimum of 24 hourswith the sample holder to be used in future measurements empty but in-58side the detector well (in case the sample holder becomes contaminated).The peaks within the background spectrum must be located and their ar-eas determined before the spectrum can be used for background correction.The area of peaks found in the background spectrum are subtracted fromany overlapping peaks in the spectrum being analyzed. No subtraction ofthe Compton scatter continuum is performed – this is done by the peakarea algorithms – so only photopeaks can affect the background. Photonsthat make it through the shielding well as scatter will only contribute tothe continuum and will not affect the background. Therefore, backgroundgamma-radiation with potential to affect measurements will originate frominside the detector well.Even if the interior well of the detector is free of user-generated contam-inants, a number of peaks will still be present in background spectra fromthe decay of the naturally occurring, long-lived radionuclides 40K, 232Th ,235U, 238U, and their progeny. The library file BACKGROUND.NLB listed in Ap-pendix A.4 contains a list of gamma lines that may be seen in a backgroundspectrum because of these nuclides. The presence of these radionuclidesis not significant enough for these peaks to become detectable during dataacquisitions shorter than a couple of hours.It is recommended that a ≥24-hour background spectrum be acquiredweekly on the detector (preferably over the weekend) to check for contamina-tion and to provide up-to-date information for accurate background correc-tion. Table 2.3 lists peaks typically seen in 24-hour background acquisitionson the RCR1 detector, based on five acquisitions during the fall of 2016.A comparison of these peaks with background spectra acquired from othersimilar detectors on the TRIUMF site is also provided.After acquisition of the background spectrum, analysis should be per-formed using the user-defined BACKGROUND sequence. Due to the low signal-to-noise ratio expected in background spectra, this sequence uses a low-sensitivity peak search algorithm to locate peaks at 4-sigma above the con-tinuum. The peaks are then compared to gamma lines from the naturallyoccurring radioisotopes listed above using the library in Appendix A.4. Anypeaks listed as unidentified that are not found in Table 2.3 should be furtherinvestigated as a possible source of detector contamination.59Table 2.3: Peaks (>20 keV) seen in typical 24-hour background acquisitionon the detector in TRIUMF’s RCR1 lab, including a comparison with otherdetectors at TRIUMF and the naturally-occurring source of the peaks.energy [keV] seen on other detectors? origin46.54 X 210Pb53.4 X unknown55.6 unknown63.29 X 232Thx-rays (70-100 keV) X multiple sources139.6 X unknown143.76 X possibly 235U185.71 X 235U198.4 X unknown238.63 X 212Pb511.00 X multiple sources583.19 X 208Tl609.32 X 214Bi911.8 X unknown1120.29 214Bi1460.82 X 40K602.1.4 Peak-to-total calibration and cascade correction2.1.4.1 Cascade Summing EffectsMost nuclear decays result in the emission of multiple gamma rays, typicallyseparated by mere picoseconds or nanoseconds. Compared to the resolvingtime of the detector (2 µs) these emissions are effectively simultaneous. Ifone or more of these gamma from a single decay interact with the detector,the sum total of energy deposited in the crystal is recorded instead of theenergies of the two (or more) individual gamma rays. These gamma lines aresaid to be subjected to Cascade Summing Effects. For a detailed overviewof the theory of Cascade Summing and Correction, the reader is referred toAppendix D of the Genie 2000 Customization Tools Manual [145]. A briefexample from that document is summarized below.In transition to the daughter nucleus ground state, the nucleus can tran-sition through simultaneous emission of γ1 and γ2 or through emission ofγ3, where the energy, Eγ3 , of γ3 is equal to Eγ3 = Eγ1 + Eγ2 . If γ1 andγ2 both interact with the detector, then the total energy recorded by thedetector will be equal to γ3. A measurement of the activity of the parent nu-clide based on γ1 or γ2 will therefore be subject to cascade summing losses,while a measurement based on γ3 will be subject to cascade summing gains.Similar effects occur when x-rays or annihilation photons are also present.Since it is also possible for either of γ1 or γ2 to deposit only part oftheir energy in the detector crystal, correction of cascade summing effectsrequires determination of the total efficiency of the detector as a functionof energy, in addition to the peak efficiency. These values are typicallyexpressed as a peak-to-total ratio, defined as the number of counts in thephotopeak over the number of counts in the entire spectrum, assuming thatthere is only one peak in the spectrum. A peak-to-total ratio calibrationis used by patented Genie 2000 algorithms to correct for cascade summingeffects. These algorithms also require a geometry file made using the Genie2000 Geometry Composer that describes the detector-sample geometry inquestion.Nuclear decay and emissions data containing information needed to per-form cascade correction for a given isotope is stored in the Genie 2000 TrueCascade Summing Library. This library is non-editable and radionuclidesnot found in the library cannot be corrected for cascades. A list of these nu-clides is provided in Appendix A.5. For more information about the library,the reader is referred to the Genie 200 documentation [146].61Table 2.4: Spectra used for the peak-to-total calibration, including the ori-gins of calibration sources used.energy [keV] nuclide side peaks [keV]40.0 225Ra n/a59.4 241Am n/a122.0 57Co 136.8511.0 64Cu 1345.8661.9 137Cs n/a909.7 89Zr 511.02.1.4.2 Peak-to-Total Calibration for Cascade CorrectionPeak-to-total ratios must be measured using spectra acquired for single-nuclide sources that are free of cascade summing effects. Table 2.4 liststhe sources used. This makes sourcing of the calibration sources diffi-cult: only three suitable sources (Table 2.4) were available on site at TRI-UMF. Fortunately, the regular production of short-lived isotopes at theTR-13 and the ISAC Implantation Station (IIS) provided access to theother three sources. The geometry-dependence of peak-to-total ratios isknown to be negligible, so the geometries of spectra used for the calibrationwas not kept consistent. Spectra used in the calibration are located in theCAMFILES\DetectorMaintenance\PTcal directory.The spectra in Table 2.4 were first analyzed with the user-defined p2tcalanalysis sequence, which performs peak location and nuclide identificationfor only the peaks listed in Table 2.4. Any other located peaks were deletedfrom the analysis. Since 57Co, 64Cu, and 89Zr spectra each have a secondphotopeak that will also contribute to the total number of counts in the spec-trum, these ‘side peaks’ were also included in the analysis. Genie 2000 usesan iterative algorithm to correct for the presence of these additional peaksduring the peak-to-total calibration. Low-energy noise and x-ray peaks wereremoved by using an extrapolation channel of 140 (34.3 keV). Nuclide iden-tification via p2tcal is performed using the library PTCAL.nlb, an editablelibrary provided by the Genie 2000 installation that must be located in theCAMFILES directory in order for peak-to-total calibration to be performed.This library had to be edited so that 64Cu, 89Zr, and 225Ra could be includedin the calibration. A copy of this updated library is listed in Appendix A.6.The results of this calibration are shown in Figure 2.4. A spline fit witha cross-over energy of 122 keV was used, as recommended by the Genie 2000Operations Manual [147]. It is likely that this calibration could be improved62Figure 2.4: Peak-to-Total Calibration performed 2016-12-23. Figure showsthe calculated calibration curve as well as the values (including error bars)measured during the calibration.over time as more sources are made available during work from within theLife Sciences group.2.1.5 Efficiency calibrationSince the probability of detecting a gamma ray depends on its energy,an energy-efficiency calibration is required for quantitative gamma spec-troscopy. The peak efficiency, defined for a given gamma ray as the numberof gamma rays of that energy detected over the number emitted, is de-termined by the source-to-detector distance (SDD), the source shape, thematerials between the source and the detector, and the energy-dependentprobability of the gamma ray stopping within the detector crystal. Togetherthese features are referred to as a geometry, and an efficiency calibrationmust be performed for each geometry for which quantitative spectroscopy isdesired. While the efficiency decreases at higher energies due to decreasedprobability of interacting with the detector, it also decreases with low en-ergies as the probability of being attenuated before reaching the detectorincreases.The geometry discussed in this section is a 20 mL vial (containing a 20mL volume) positioned approximately 20 cm above the detector cap. Thisis the greatest SDD that will allow the 20 mL vial to fit inside the closedshielding well of the detector.63Table 2.5: Expected and measured ratios of individual peak areas withinmultiplets used in the efficiency calibration, as determined using the Inter-active Peak Fit Tool.peaks inmultiplet [keV]measured peakarea ratio(high/low)expected ratio(high/low)nuclide30.63, 30.97 2.11 ± 0.05 1.83 ± 0.08 133Ba39.52, 40.12 1.90 ± 0.02 1.79 ± 0.06 152Eu79.61, 81.00 12.15 ± 0.18 12.42 ± 0.26 133Ba2.1.5.1 Efficiency Calibration for Cascade-Free, Low SensitivityGeometriesA 20 mL calibration source (R-01107a), containing (30.05 ± 3.0%) kBq of133Ba and (30.23 ± 3.0%) kBq of 152Eu, was positioned approximately 20cm from the surface of the detector using the sample holder shown in Figure2.5. A spectrum was acquired for 12 hours on 2016-09-22. The analysissequence effiCal was used to locate peaks in the spectrum and initiate theInteractive Peak Fit Tool. The Sum/Non-linear LSQ Fit algorithm [145] wasused to determine the areas of all singlet and multiplet peaks. Unlike theenergy calibration, multiplet peaks were used for the efficiency calibrationto provide additional data points in the low-energy, high-slope regions of theefficiency calibration curve. To ensure quality multiplet fits, care was takento ensure that the fit resulted in individual peaks with nearly equal FWHMsand that the ratios of individual peak areas matched the expected branchingratios of peaks within the multiplet as closely as possible. Measured andexpected peak area ratios for peaks in all relevant multiplets are shown inTable 2.5. The fits for all peaks used in efficiency calibration are shown inAppendix A.7.With all peak areas determined, the efficiency calibration was performedusing the certificate file R01107a.ctf. Care was taken to ensure the correctpeak area from within each multiplet was selected by Genie 2000 duringthis step of the process, and manually corrected if necessary. Efficiencyvalues determined for each peak are shown in Table 2.6. A spline fit with acrossover energy of 81 keV was used to determine the efficiency calibrationcurve from these data points, as shown in Figure 2.6.This calibration is stored in the calibration file effiCal 20mL 20cm.cal.64Table 2.6: Measured efficiency values for all peaks used to determine thecalibration curve shown in Figure 2.6.Energy [keV] Measured Efficiency Uncertainty [%]30.63 0.00140 4.4139.52 0.00188 3.8853.16 0.0022 3.7279.61 0.00231 3.8381.00 0.00226 3.14121.78 0.00215 3.06223.24 0.00144 3.62244.70 0.00131 3.09302.85 0.00105 3.11344.28 0.00091 3.11356.01 0.00089 3.00383.85 0.00081 3.14411.12 0.00076 3.22778.90 0.00040 3.17867.38 0.00036 3.771085.84 0.00030 3.181089.74 0.00030 3.451112.08 0.00029 3.191299.14 0.00026 4.371408.01 0.00023 3.0965Figure 2.5: 3D printed sample holders used to reproducibly position 20 mLvials at nominal sample-to-detector distances of 5, 10, 15, and 20 cm (left)and 0 cm (right).Figure 2.6: Efficiency calibration curve determined for a 20 mL vial withapproximately 20 cm SDD. The 133Ba and 152Eu peaks used to fit the curveare also shown. A spline fit with 81 keV crossover is used, dividing the curveinto a low and a high energy fit.66 5DDQG$FGHFD\YVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRS5DDQG$FGHFD\YVYJ 0H9њ0H9њ 0H9њ0H9 ћ0H9ћ0H9њ0H9ћ0H9њNH9SKRWRQ  $F  G)UP$WPV3RXV 7OP 3EK %LVWDEOHNH9SKRWRQ   NH9ћ5D G%LPNH9SKRWRQ  Figure 2.7: 225Ra decay chain, including gamma emissions with high branch-ing ratios.2.1.5.2 Validation of Efficiency CalibrationAn accurate efficiency calibration curve is essential for accurate quantitativegamma spectroscopy. Errors in this calibration are likely to be greatest inthe low-energy region where the slope of the curve is high. Unfortunately,many isotopes – such as 225Ra – can only be quantified using a single low-energy peak.Radioactive decay chains provide a useful way of validating the shape ofthe efficiency calibration curve, since they can contain a number of differentisotopes with known activities at a given point in time. Since these separateisotopes may be quantified via gamma rays of different energies, only anefficiency calibration with correct shape will measure the expected relativeamounts of each isotope in the decay chain.The 225Ra decay chain is shown in Figure 2.7. A 20 mL sample contain-ing 225Ra (t1/2 = 14.9 days) was used to validate the efficiency calibrationdescribed in Section 2.1.5.1. At t = 0 the sample contained 225Ra and onlynegligible amounts of 213Bi. The sample was counted periodically every fewdays so as to observe the grow-in of the decay products. 225Ra, 221Fr, and213Bi activities were measured using 40, 218, and 440 keV gamma lines,respectively. As can be seen from Figure 2.8, the measured activity con-centrations match calculated values predicted from the first data point att = 0. This implies that the relative shape of the efficiency calibration curveis accurate, at least in the 40, 218, and 440 keV regions. Small errors in thecalibration curve shape may exist in the energy region near the peak of theefficiency curve.An independent test of the efficiency calibration was performed using aseparate 20 mL calibration source (R-01119) provided by RPG. This source’sradioactivity is NIST-traceable, containing (1.82 ± 0.06) kBq of 133Ba and(36.79 ± 1.29) kBq of 152Eu. When this source was counted on the RCR167Figure 2.8: Gamma spectroscopy measurements of the 225Ra decay chain ofthe same sample over time. Dotted lines represent calculated 225Ra , 221Fr, and 213Bi activity concentrations predicted from the first data point att = 116h, and assuming zero 225Ac at t = 0, as is usually observed.detector for 16 hours, (1.79 ± 0.02) kBq of 133Ba and (37.11 ± 0.23) kBqof 152Eu were measured, consistent with values determined by the sourcemanufacturer.2.1.5.3 Efficiency Calibration for Cascade-Prone, High Sensitiv-ity GeometriesWhile decreasing SDD results in higher sensitivities and faster measure-ments of low-activity samples, coincidence summing effects (Section 2.1.4)are also increased. This section describes the effect of coincidence summingon gamma spectroscopy results and provides documentation for an efficiencycalibration of a 20 mL vial, 0 cm SDD geometry.Coincidence summing effects were shown to be negligible for the 20 cmSDD geometry described in Section 2.1.5.1. While an approximately 20-foldincrease in counting efficiency is observed when SDD is decreased to 0 cm,as will be shown, coincidence summing effects make these measurementsless reliable even when using Genie 2000’s Cascade Correction algorithm.Since the 133Ba and 152Eu calibration nuclides have significant cascades,both the efficiency calibration for the geometry and measurements acquiredwith these geometries must be corrected for cascades.The geometry discussed in this section is a 20 mL vial (containing a 20mL volume) positioned approximately 0 cm above the detector cap usingthe sample holder shown in Figure 2.5.68Efficiency Calibration with and without Cascade CorrectionA 20 mL calibration source (R-01107b), containing (1.505 ± 3.0%) kBq of133Ba and (1.515 ± 3.0%) kBq of 152Eu, was positioned approximately 0 cmfrom the surface of the detector using the sample holder shown in Figure2.5. A spectrum was acquired for 24 hours on 2016-09-25. The analysissequence effiCal was used to locate peaks in the spectrum and initiate theInteractive Peak Fit Tool. The Sum/Non-linear LSQ Fit algorithm [145]was used to determine the areas of all singlet and multiplet peaks.With all peak areas determined, the efficiency calibration was performedusing the certificate file R01107b.ctf. Care was taken to ensure the correctpeak area from within each multiplet was selected by Genie 2000 duringthis step of the process, and manually corrected if necessary. The efficiencycalibration was performed both with and without cascade correction of the133Ba and 152Eu peaks, creating two efficiency calibrations. For cascadecorrection, the peak-to-total calibration described in Section 2.1.4 was used,as was the geometry file 20mL 0cm.geo. Efficiency values determined foreach peak with and without cascade correction are shown in Table 2.7. Somecascade-corrected values were rejected as the cascade correction resultedin some data points appearing as significant outliers. A spline fit with acrossover energy of 81 keV was used to determine the efficiency calibrationcurves from these data points, as shown in Figure 2.9.These calibrations are stored in the calibration fileseffiCal 20mL 0cm noCC.cal and effiCal 20mL 0cm withCC.cal.Test of Cascade-Corrected Efficiency Using Cascade-Free IsotopesThe cascade-corrected efficiency calibration can be validated by comparingmeasurements of cascade-free radionuclides acquired at 0 cm SDD and at20 cm SDD (where cascade effects are negligible). Table 2.8 shows results ofsuch measurements. Since most of the 133Ba and 152Eu peaks used for thelow energy efficiency curve are not subject to cascades, measurements below81 keV are expected to change little if the efficiency calibration is determinedwith or without cascade correction. However, for the high energy efficiencycurve (>81 keV) 133Ba and 152Eu cascades should affect the efficiency cali-bration. Though Table 2.8 contains few data points, both these effects areare evident. Results for the cascade-prone geometry are determined bothusing an efficiency calibration that corrects for 133Ba and 152Eu cascades,and an efficiency calibration performed without cascade correction. Bothcascade-corrected and uncorrected results are consistent with the cascade-69Table 2.7: Measured efficiency values for all peaks used to determine thecalibration curves shown in Figure 2.9.energy[keV]without cascadecorrectionwith cascadecorrectionmeasuredefficiencyuncertainty[%]measuredefficiencyuncertainty[%]30.63 0.04491 4.30 0.04491 4.3039.52 0.05493 3.85 0.05493 3.8553.16 0.05828 3.45 0.06870 4.1379.61 0.06736 3.58 0.07830 4.1581.00 0.06801 3.14 0.07871 3.75121.78 0.05975 3.06 - -244.70 0.03041 3.09 0.03977 4.69276.40 0.02731 3.12 - -302.85 0.02579 3.09 - -356.01 0.02274 3.00 - -411.12 0.01913 3.13 0.02430 4.47443.96 0.01809 3.08 0.02477 5.09778.90 0.01095 3.10 0.01257 3.651085.84 0.00839 3.11 0.00827 3.121089.74 0.00821 3.23 0.00933 3.701299.14 0.00671 3.73 0.00772 4.221408.01 0.00563 3.06 0.00601 3.2070Figure 2.9: Efficiency calibration curves determined for a 20 mL vial withapproximately 0 cm SDD, determined both with (green) and without (blue)cascade correction. The 133Ba and 152Eu peaks used to fit the curves arealso shown. A spline fit with 81 keV crossover is used, dividing the curveinto a low and a high energy fit.free geometry for the 40 keV region, where 133Ba and 152Eu cascades havelittle effect on the efficiency. However, for higher energy regions only thecascade-corrected 0 cm SDD geometry agrees with measurements from the20 cm geometry.2.1.6 Effect of cascade summing on nuclides with cascadesThe nuclides with the most significant cascades that are also readily avail-able include 225Ac, 221Fr, and 213Bi. Table 2.9 includes measurements ofTable 2.8: Measurements of cascade-free isotopes determined using acascade-negligible geometry (20 cm SDD) and a cascade-prone geometry(0 cm SDD).activity [a.u.]20 cm SDD 0 cm SDDnuclideenergy[keV]no cascade effectsno cascadecorrectionwith cascadecorrection89Zr511 4.13 ± 0.12 5.03 ± 0.11 4.02 ± 0.14909 4.40 ± 0.09 5.02 ± 0.11 4.59 ± 0.11225Ra 40 1.90 ± 0.08 2.01 ± 0.05 1.85 ± 0.0571Table 2.9: Radioactivity composition of a 20 mL sample containing isotopeswith significant cascades, measured using a cascade-negligible geometry (20cm SDD) and a cascade-prone geometry (0 cm SDD). The decay chain con-taining 225Ac, 221Fr, and 213Bi was in transient equilibrium at the times ofmeasurement.activity [a.u.]20 cm SDD 0 cm SDDno cascade effectsno cascadecorrectionwith cascadecorrection225Ac 1.02 ± 0.09 1.59 ± 0.04 1.18 ± 0.05221Fr 1.08 ± 0.04 1.54 ± 0.04 0.97 ± 0.05213Bi 1.03 ± 0.03 1.25 ± 0.02 0.81 ± 0.02these isotopes using the efficiencies determined in Section 2.1.5.3 both withand without cascade correction determined, as well as with the 20 cm SDDefficiency determined in Section 2.1.5.1 for which cascade summing effectshave been shown to be negligible. The measurements in Table 2.9 were ac-quired from a single sample containing 225Ac and its progeny isotopes intransient equilibrium (see Figure 2.7). Results for the cascade-prone geom-etry are determined both using an efficiency calibration that corrects for133Ba and 152Eu cascades, and an efficiency calibration performed withoutcascade correction. Cascade correction was performed only on the efficiency,not on the measurements of 225Ac, 221Fr, and 213Bi , since these nuclidesare not found in the Cascade Summing Library.Since the decay chain is in equilibrium, 225Ac, 221Fr, and 213Bi activitiesshould be equal, as seen when using the cascade-negligible geometry (20cm SDD). Since none of the 225Ac, 221Fr, and 213Bi isotopes are found inthe Genie 2000 Cascade Summing Library (Appendix A.5), they cannotbe corrected for cascade summing effects, even when using an efficiencycreated using cascade correction. Therefore, measurements of these isotopesmade using efficiencies that did not include cascade correction will be doublyprone to cascade summing effects – this is evident in Table 2.9 as the valuesdetermined with cascade corrected efficiencies are in closer agreement tothose determined with the cascade-negligible efficiency.The values in Table 2.9 demonstrate that if cascade correction is notapplied to the efficiency calibration nor to measurements of nuclides withsignificant cascades, errors of over 50% can exist in the results.72 XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ           HQHUJ\>NH9@FRXQWV           HQHUJ\>NH9@FRXQWVFigure 2.10: Gamma ray spectrum of the 225Ac decay chain in equilibrium,shown with both a linear (top) and log (bottom) y-axis.2.1.7 Efficiencies calibrations for additional geometriesThe purchase of separate stock solutions of 133Ba and 152Eu (100 kBq each)allows for the creation of additional calibration sources for geometries thatmay be desired in the future. A list of calibration sources made from thesesolutions is listed in Appendix A.8.2.1.8 Gamma spectroscopy for 225Ac quantificationA gamma spectrum of the 225Ac decay chain in equilibrium is shown inFigure 2.10. However, as discussed in Section 1.2.4, the equilibrium ornon-equilibrium state of the 225Ac decay chain must be considered whenapplying decay correction during the spectrum analysis. Most often, 225Acis best quantified via the 218 keV peak of 221Fr under conditions where225Ac/221Fr equilibrium can be assumed.732.1.9 SummaryResults from Section 2.1.5.1 demonstrate the reliability of this detector toaccurately quantify radionuclides for geometries where cascade summingeffects are negligible. Unfortunately, these geometries have a low efficiency,implying that higher activity samples must be used if fast counting is desired.For samples containing very low activities, it would be desirable to havereliable geometries with higher efficiency.The 0 cm SDD efficiency calibration discussed in Section 2.1.5.3 is sub-ject to cascade summing effects from 133Ba and 152Eu. Though results inTable 2.8 suggest the cascade corrected efficiency calibration may be ade-quate for cascade-free radionuclides, the number of measurements in thistable are insufficient to be definitive. The ability of Genie 2000 to correctfor measurements of radionuclides with cascades has not be validated onthis detector, since no appropriate samples have been available yet. Thoughpapers exist in the literature demonstrating the reliability of the Genie 2000Cascade Correction Algorithm to correct for cascade effects [148, 149], thisalgorithm relies on user-created files (peak-to-total calibration and geome-try descriptions) and its performance should therefore be checked for eachdetector. It is likely that improvements could be made to the peak-to-totalcalibration (Section 2.1.4) by adding additional data points using additionalcascade-free nuclides.Even with proper setup of the cascade correction, cascading radionu-clides not present in the Cascade Summing Library (Appendix A.5), such as225Ac, 221Fr, and 213Bi, cannot be corrected for cascade summing, as shownin Table 2.9. This library is not user editable and is defined by the manu-facturer. Thus reliable measurements of these nuclides must be performedwith geometries for which cascade summing effects are negligible.2.2 Alpha SpectroscopyAlpha-particle spectroscopy is another technique that can quantify radioac-tivity and identify radionuclides via the detection of emitted radiation. How-ever, fundamental differences between how gamma-rays and alpha-rays in-teract with matter lead to marked differences in how these two techniqueswork and for what applications they can be applied. Alpha spectroscopyhas a obvious advantage for detection and quantification of alpha-emittingradionuclides that do not emit sufficient gammas or x-rays to be detectedby gamma spectroscopy. However, alpha spectroscopy sample preparationrequirements are more time consuming and can introduce additional sources74of uncertainty that make gamma spectroscopy options more favorable whenavailable, as is the case for 225Ac and this work. However, the use of alphaspectroscopy to verify the absence of other alpha-emitters is prudent, if notessential, when producing therapeutic alpha-emitting nuclides. This sectionwill introduce alpha spectroscopy, provide some comparison to gamma spec-troscopy, and describe how alpha spectroscopy was used (and why it oftenwas not used) in the work described in this thesis.Challenges and limitations of alpha spectroscopy arise from the sam-ple preparation requirements. Unlike gamma rays and x-rays that interactstochasticlly with matter, alpha particles lose energy continuously as theypass through matter (see Section 1.1.3). This means any material betweenthe radiation source and the alpha particle detector will degrade the alphaparticle energy, resulting in loss of energy resolution in the alpha particlespectrum that can be significant enough to render the spectrum useless. Thehigh alpha particle LET means this effect is significant even for materialswith very low density (such as air) or materials that are only microme-tres thick (such as a material used to contain or seal the alpha radiationsource). This means that alpha spectroscopy sources cannot be sealed ra-diation sources, nor can they be in the liquid form in which most samplesoriginate.The preparation of alpha spectroscopy sources from liquid samples iscommonly done by microprecipitation and filtration of the radioactivity fromthe solution. This technique is described in detail in Appendix B, but willbe summarized briefly here. A small (µg quantity) cerium carrier is added tothe sample and then mixed with concentrated hydrofluoric acid, resulting inthe precipitation of cerium fluoride from the solution; most alpha-emittingelements (except gaseous radon) coprecipitate with the cerium fluoride. Thesolution is then passed through a 100 nm thick filter, depositing the alpharadiation source on the top of the filter. The filter is then placed inside thevacuum chamber of the alpha spectrometer, which is then pumped down toremove air from between the source and the detector.Detectors used in alpha spectroscopy are most commonly surface bar-rier detectors, consisting of a p-n semiconductor. A reverse bias appliedto the semiconductor creates a depletion region without free charges thatfaces the radiation source. Alpha particles that enter the depletion regionlose energy by creating electron-hole pairs. The bias voltage causes thesefree electrons to move towards one side of the semiconductor, creating acharged pulse signal that is proportional to the amount of energy depositedin the detector. Much of this is similar to what was described for gammaspectroscopy in Section 2.1, however, because alpha particles can be fully75Figure 2.11: An example alpha particle energy spectrum collected from asample containing 225Ac and its progeny in equilibrium.stopped within a small amount of material, unlike gamma spectroscopy de-tectors, the efficiency of an alpha spectrometer is independent of incidentparticle energy.An example 225Ac alpha spectrum is shown in Figure 2.11. The alphaspectrum appears more simple than the gamma spectrum (Figure 2.10),with clear distinct peaks associated with the nuclides in the decay chain:the 8.4 MeV 213Po peak, the 7.1 MeV 217At peak, two 221Fr peaks at 6.3and 6.1 MeV, and two overlapping 225Ac peaks at 5.83 and 5.79 MeV. Theabsence of a background below and between the peaks means peak areascan be determined by the total counts without any baseline subtraction.Appendix B describes the collection and analysis of 225Ac spectra. Thismethod is able to determine 225Ac activity to within <5% of values de-termined by gamma spectroscopy. However, alpha spectroscopy was notused for 225Ac quantification throughout this work. Gamma spectroscopyis favourable for 225Ac quantification, where available, because the samplepreparation and spectrum acquisition are much faster. Gamma spectroscopyis also inherently more safe, since gamma spectroscopy samples can be sealedwithout interfering with the measurement. The steps (precipitation, filtra-tion, etc.) involved in alpha spectroscopy also introduce additional sourcesof uncertainties and potential for losses of activity that could go uncounted.While internal standards are often used to account for such losses when76measuring quantities of different nuclides, for Ac there is no such suitablenuclide other than 225Ac.2.3 FLUKA Simulations2.3.1 An Introduction to FlukaWhile gamma spectroscopy (Section 2.1) and and alpha spectroscopy (Sec-tion 2.2) provide empirical radioactivity measurements, situations can arisewhere such measurements are impractical or incapable of providing a de-sired radioactivity measurement. For example, a nuclide of interest may notemit sufficient gamma rays or alpha particles for it to be counted, or maybe present in quantities too small to detect (because of a radioactivity valuethat is small either in absolute value or small compared to other nuclides inthe sample that create interferences in the spectrum). The sample may alsohave a form factor that prohibits accurate measurements (ex. the sampleis too large to fit into the detector, or a geometry for which an accuratecalibration source is unavailable) or have a total activity that is too high tocount. Situations may also arise where the number of radionuclides to beanalyzed is prohibitively laborious.All of these above situations – especially the latter – can arise in thecase of radioactive samples produced by the high-energy proton irradiationsthat are a central component of this work. Fortunately, high-energy particletransport codes are able to model such irradiations and provide estimatesof the resulting radioactive inventory. Such codes combine various physicsmodels with Monte Carlo methods to simulate the interactions of primaryand secondary particles with targets and surrounding materials during anirradiation. Fluka is one such high-energy transport code with applicationsin radiation shielding and facility design, dosimetry, detector and targetdesign, medicine, and radionuclide production [128, 129].A number of publications have demonstrated the accuracy of the resultsthat Fluka can provide in such applications [150–159]. An assessment ofFluka’s performance for estimating radioactive inventories from the 438MeV proton irradiation of thorium was one of the primary objectives ofChapter 6, and shows that the estimated activities are generally accurateto within a factor of 2 for most nuclides. Chapter 6 (Section 6.2.7) alsocontains the most complete description within this thesis of the necessaryFluka input and settings required for accurate radioactivation simulations.Fluka is capable of modelling a variety of different particle interac-tions over a broad range of energies. For spallation reactions (described in77Section 1.3.3), the specific physics models used to model intranuclear cas-cades, evaporation, and high-energy fission are described comprehensivelyelsewhere [116, 128].Fluka was used in a number of ways throughout the efforts that re-sulted in this thesis. Most importantly, Fluka’s predictions of radioactiveinventories enabled essential experiment planning by predicting the viabilityof the 225Ac production approaches and the radiation safety hazards thatresult. Such pre-experimental safety assessments are crucial for determiningthe appropriate level of radiation safety precautions that must be taken andfor securing necessary internal safety approvals. An example of such safetyassessments is provided in Appendices C and D. Appendix C also containsan example list of the full Fluka-estimated radioactive inventory producedby the proton irradiation of thorium at approximately 450 MeV, as well as adescription of the models used to quantify radiation hazards resulting fromthe irradiation, including internal and external dose estimates. A shorterexample of a question Fluka was used to answer during the planning ofthis work is provided in Section 2.3.2.2.3.2 An example Fluka studyThe purpose of this section is to provide an example of how Fluka radioac-tivity estimates were used in the planning of the work that lead to this thesis.These previously published conference proceedings consider the irradiationof a thorium oxide prototype target and compare the expected impuritiesin thorium-spallation-derived Ac products produced both directly and bythe decay of Ra isotopes [2]. The thorium oxide prototype target describedwas later irradiated at TRIUMF and demonstrated by gamma spectroscopymeasurements that 225Ac production at TRIUMF’s IPF facility was viable.While not an ideal target material for routine production, the thorium ox-ide was irradiated as the first prototype because it was readily availableat the time, while procurement of the thorium metal took many months.The conclusion of this Fluka study that the spallation production of suf-ficient 225Ac quantities without the presence of 227Ac was possible at thetime contributed to the decision to further pursue this production methodat TRIUMF (see Chapters 5 through 7).BackgroundThere has been increasing interest in leveraging TRIUMF’s existing infras-tructure to produce a large-scale supply of alpha-emitting isotopes useful78for targeted radioimmunotherapy. Nuclides of interest include 225Ra, 224Ra,223Ra, 225Ac, and 213Bi [15]. The decay chain containing 225Ra, 225Ac, and213Bi (Figure 1.1) is of particular and current focus. The current annualglobal supply of 225Ac is less than 1.7 Ci, and desire for new sources isstrong [160]. Los Alamos, Oak Ridge, and Brookhaven National Laborato-ries have recently demonstrated the feasibility of accelerator-production of225Ac via proton irradiation of thorium above 100 MeV [140]. To this end,TRIUMF’s 500 MeV Isotope Production Facility (IPF) could be consideredan ideal facility for regular and potent production given the energy (454MeV), intensity (up to 120 µA), and reliable operation of available beam.Here we present the initial design of a thorium target that aims to testIPF production of 225Ac , starting at a low level (1130 µA*h) and producingmCi amounts of 225Ac. Included are simulations of expected target produc-tion and radiochemical yields for isolated 225Ra and 225Ac products. Theproposed radiochemical procedure produces 225Ac both directly and indi-rectly via a 225Ra generator, the latter containing a significantly reducedfraction of the long-lived and toxic 227Ac within the final product.Materials and MethodsTarget DesignThe target was designed to combine the IPF target facility and TRIUMF’sexisting materials and methods for thorium target manufacturing, previouslyestablished for the production of radioactive ion beams at ISAC. To adaptthe ISAC ThO2 foils to fit within the current encapsulated IPF target design,a centering ring assembly is used to hold an encapsulated tantalum targetcontaining 1 g of ThO2. Additional infrastructure used in the target will bemanufactured from Inconel-based alloys. Figure 2.12 provides an overview ofthis target assembly. The target is housed in a carriage where it is submergedin water flowing at a rate of 14.25 L/min.Fluka SimulationFluka was used to estimate the radioactive inventory in the irradiatedtarget at end of bombardment (EOB), and one day, one week, and onemonth after EOB. A 454 MeV proton beam with 90 µA current, and widthsin the x- and y-directions of 1.35 and 1.38 cm FWHM, respectively, wassimulated for an irradiation lasting 12.56 h. The target was defined asshown in Figure 2.12. A neutron energy cut-off of 10−5 eV and a proton79Figure 2.12: Models of the thorium oxide target design made in Fluka(top) and in SolidWorks (bottom).cut-off of 100 keV was used.Potential Radiochemical SeparationWhile known methods exist for the dissolution of the proposed ThO2 targetmaterial [161], possible redesigns of the target using thorium metal maybe required to facilitate easier radiochemical separation. This should notsignificantly affect Fluka results if the same amount of thorium is used.While several methods for separating 225Ac from irradiated thorium metalcan be found in the literature [104, 139, 141], the method described by Alievet al is one of the more simple methods that separates Ra and Ac, and hasalso been tested at the mCi level [143]. The method involves the followingsteps:1. Dissolution of irradiated thorium using a 50 mL solution containing 880M HNO3 and 0.004 M HF.2. Extraction of Th, Pa, Cd, Zr, Nb products with a solution of HDEHPacid in toluene (final volume 100-150 mL).3. Separation of Ac and rare earth metals from the remaining products(including Ra) using DGA resin and N,N,N‘,N‘tetroctyldiglioclamideas an extracting phase, and eluting Ac and rare earth elements in 3mL 0.01 M HNO3.4. Separation of Ac from the rare earth metals using TRU resinwith octyl(phenyl)-N,N-disobutylcarbomoylmethylphosphine oxidedissolved in tributylphosphate as an extracting phase and eluting pureAc in 30 mL of 3 M HNO3.Aliev et al report retention of >99% for Ac and Ra up to step 3, andfinal Ac yield of 85%. The separation of 225Ra and 225Ac by DGA resin hasbe replicated recently at TRIUMF with >98% yields.One drawback of spallation-production of 225Ac is the co-production ofother Ac isotopes, most notably the long-lived 227Ac (t1/2 = 21.8 y). Otherpotential contaminants are 228Ac (t1/2 = 6.2 h) and226Ac (t1/2 = 26.4h). In order to create an 225Ac product without these contaminants thatis suitable for medical use, we consider producing 225Ac both directly andvia a co-produced 225Ra generator. Waiting until one week after EOB toperform the target dissolution will permit the decay of the 227Ac parentisotope, 227Ra (t1/2 = 42 min), and other short-lived products. The firstAc/Ra separation is then performed, isolating all Ac isotopes present inthe target one week after EOB. The separated Ra fraction forms a 225Acgenerator, that another 17.5 days later will yield a second batch of generator-produced 225Ac with significantly reduced 227Ac content. 228Ac and 226Accontaminants from 228Ra and 226Ra in the generator are short-lived and willdecay much faster than 225Ac.Reported yields form the radiochemical separation process were com-bined with the Fluka estimation to predict the composition of both directlyproduced and generator-produced 225Ac products.ResultsRelevant Fluka simulation results showing the activities of selected Ra andAc isotopes in the target at EOB and one week EOB are shown in Table 2.10.The yields and impurities for final 225Ac products predicted by Fluka and81Table 2.10: Fluka estimation indicating the radioactive inventory of thethorium target immediately and one week after a 1130 µA*h irradiation at90 µA.at EOB EOB + 1 weekActivity [Bq] Uncertainty [%] Activity [Bq] Uncertainty [%]230Ra 2.50E+07 15.9 0 -228Ra 1.94E+04 7.9 1.95E+04 7.9227Ra 1.39E+08 6.6 2.84E-03 0.8226Ra 1.59E+02 4.5 3.05E+02 2.6225Ra 6.87E+06 4.8 4.96E+06 4.8224Ra 1.37E+08 1.8 5.14E+07 1.6223Ra 1.54E+07 3.4 2.48E+07 1.7228Ac 1.04E+09 2.1 1.95E+04 7.9227Ac 9.09E+04 1.9 9.14E+04 1.9226Ac 4.18E+08 2.0 7.96E+06 2.0225Ac 7.70E+07 1.7 4.97E+07 1.7224Ac 1.56E+09 2.0 3.29E+03 8.3Table 2.11: Predicted amount of 225Ac produced when the Ra/Ac separa-tion is performed 1 week after EOB. Impurities of other actinium isotopesare expressed as a percent of the 225Ac activity. Due to their short half-lives,228Ac and 226Ac percent impurities decrease with time.Time since Ra/Ac isolation 0 days 1 day 5 days225Ac [MBq] 42.2 39.4 29.9228Ac/225Ac [%] 0.039 0.003 0.000227Ac/225Ac [%] 0.185 0.198 0.261226Ac/225Ac [%] 16.020 9.740 1.33082Table 2.12: Predicted amount of 225Ac and impurities (expressed as ac-tivity ratios) produced when the radium fraction (initially separated fromactinium in Table 2) is used as an 225Ac generator. 227Ac impurity is signif-icantly reduced from Table 1 due to the short half-life of its parent 227Ra.226Ac impurities are effectively removed since no radium isotopes decay to226Ac. 228Ac impurities decrease with time after the Ac is removed from thegenerator.Time since Ra/Ac isolation 0 days 2 days225Ac [MBq] 42.2 39.4228Ac/225Ac [%] 0.882 0.003227Ac/225Ac [%] 9.95E-9 1.14E-8226Ac/225Ac [%] 0 0the chemical procedure described are shown in Table 2.11 (directly produced225Ac) and Table 2.12 (225Ac produced via 225Ra decay). These resultsassume that the target was left to decay for one week before processingbegan – likely necessary given the current infrastructure for removing theirradiated target from the beamline.After one week of decay, the target is dissolved and the Ra and Acisotopes are chemically isolated. At this time, 42.22 MBq (1.14 mCi) of225Ac is available. The 4.96 MBq (0.13 mCi) of isolated 225Ra forms agenerator that produces 2.20 MBq (0.06 mCi) of 225Ac 17.5 days later. Asseen in Tables 2.10 and 2.11, the lower yield for the generator produced225Ac comes with the benefit of higher purity.ConclusionSimulated yields suggest production of considerable 225Ac quantities free ofsignificant 227Ac contaminants can be produced at an existing and under-utilized TRIUMF facility. A low-level irradiation of 1130 µA*h on a 1 gThO2 target is expected to demonstrate this by directly producing 42.22MBq (1.14 mCi) of 225Ac containing 80 kBq of 227Ac, and indirectly pro-ducing 2.20 MBq (0.06 mCi) of 227Ac via a 225Ra generator isolated oneweek after EOB. The generator-produced 225Ac fraction should contain <1Bq of 227Ac.833 225Ac Production at TRIUMF’sISAC Facility3.1 Background225Ac was first produced at TRIUMF using the ISAC Facility’s isotope sep-aration on-line (ISOL) technique. This effort provided a source of 225Acfor use in a number of experiments [3, 4, 162–165], including the 225Acimaging studies described in Chapter 4. However, the small and infrequentquantities of 225Ac available from ISAC were insufficient to reliably progressthese studies into 225Ac applications requiring larger amounts of radioactiv-ity; this motivated the desire to focus the rest of this thesis on alternativemethods for 225Ac production (Chapters 5, 6, and 7). Despite the smallquantity of 225Ac produced, the work presented in this chapter describesTRIUMF’s first efforts to produce 225Ac. These efforts allowed TRIUMF togain valuable experience working with 225Ac before addressing more complextargetry (Chapter 5) and radiochemistry (Chapter 7) challenges associatedwith 225Ac production via thorium irradiation.3.2 Methods Used for 225Ac Production at ISACIon beams of 225Ra and 225Ac were created using the ISOL technique atTRIUMF’s ISAC facility [106]. Detailed descriptions of the collection ofradioactivity from these beams is described elsewhere [1, 3, 164–167]. TheISAC facility produces radioactive ion beams by irradiating a uranium car-bide target with 9.8 µA of 480 MeV protons, resulting in spallation andhigh-energy fission reactions that produce most nuclides lighter than 238U,including 225Ra and 225Ac. Simultaneous ionization of the target under vac-uum using surface or resonant laser ionization ionizes the target materialand the nuclear reaction products into a secondary particle beam that is ac-celerated to 30-40 keV and passed through a high-resolution mass separator84p+480 MeV 10 µAtarget stationuranium targetionization & extractionheterogeneous ion beammass separator magnetto implantation stationto yield station225Ra & 225Ac ion beamFigure 3.1: Beamlines at TRIUMF’s ISAC facility that are relevant for225Ra and 225Ac production.before being delivered to various experiments. A diagram of this process isshown in Figure 3.1.For 225Ac production, selection of mass A=225 results in a beam con-taining 225Fr, 225Ra, and 225Ac, which is then directed towards an aluminumtarget into which the radioactive ion beam is directed. Ions that hit the tar-get interact as charged particles moving through a medium and slow downuntil reaching an expected range within the material (see Section 1.1.3) thatcan be calculated using SRIM [108]. The aluminum implantation target ishoused within a chamber that can be detached from the beamline; the targetand implantation chamber are shown in Figure 3.2. After implantation, thealuminum target containing the implanted radioactivity was removed fromthe beamline and moved to a radiochemistry lab. The 225Ra and 225Acwas retrieved from the aluminum material by etching the surface of the alu-minum with HCl (0.1 M) to obtain a final solution containing 225Ra and225Ac in approximately 0.5 mL. The etching of the aluminum target surfaceis facilitated by a small cavity (approximately 1 mm deep) on the target’ssurface (see Figure 3.2).The purification of 225Ac from 225Ra was adapted from previously re-ported methods for isolation of 225Ac [36, 104, 168, 169]. The recovered225Ra/225Ac solution (0.1 M HCl, approximately 0.5 mL) was diluted to85Figure 3.2: Solid model of the ISAC implantation chamber for collection ofradioactive ion beams. The inset photograph in the top left corner showsthe aluminum target used for 225Ra and 225Ac ion beam collection.4 M HNO3 (5 mL), and passed through a DGA column (35-40 mg DGAbranched resin in a 6 mm diameter reservoir, preconditioned with H2O (2mL), 0.5 M HNO3 (2 mL), and 4 M HNO3 (2 mL). Under these conditions,Ac binds to the DGA while Ra passes through. The loaded DGA columnwas then washed with 4 M HNO3 (4 mL). After air drying the column, the225Ac was eluted from the resin using 0.05 M HNO3 (0.5 mL). The load frac-tion containing 225Ra was collected and retained for use as an 225Ra/225Acgenerator. A diagram of this process is shown in Figure 3.3.The chemical purity of the 225Ac product was assessed via inductivelycoupled plasma optical emission spectrometry (ICP-OES) and inductivelycoupled plasma mass spectrometry (ICP-MS) to quantify the presence of anystable cations that may compete with 225Ac in radiolabeling reactions. Sam-ples of both the initial solution containing 225Ra and 225Ac (before separa-tion via DGA) and the final purified 225Ac solution were analyzed for elemen-tal composition using an Agilent 7700 ICP-MS. All samples were preparedby drying on a hotplate, treated with concentrated HNO3 and then againdried to convert all salts into the nitrate form. Samples were then dilutedwith a 1% HNO3, 0.05% HF solution containing 10 ppb indium as an internalstandard. Standard solutions were prepared from both mixed and single-element standards purchased from Inorganic Ventures (Christiansburg, VA,USA). Elements assayed included: Be, Al, Ca, Sc, Ti, Cr, Mn, Fe, Co, Ni,Cu, Zn, Ga, Sr, Y, Zr, Nb, Mo, Sn, W, and Pb.86DGA branched (35-40 mg)1 2 31 - load 225Ra/225Ac,~5 mL 4 M HNO32 - wash 4 M HNO3, 4 mL 3 - elute 0.05 M HNO3 0.5 mL 225RaIIresidual 225RaII225AcIIIwait for 225Ac grow-inFigure 3.3: 225Ra/225Ac radiochemical separation methods used for purifi-cation of ISOL-produced 225Ac.3.3 Results from 225Ac Production at ISACMass A=225, singly-charged (+1) ion beams produced at TRIUMF’s ISACfacility contained 225Ra and 225Ac intensities between 4.0 × 106-1.6 × 108and 3.8 × 106-1.3 × 108 ions/s, respectively, depending on the state of theextraction electrode and the availability of the laser ionisation source [106].225Fr was also present but decayed rapidly to 225Ra. For durations between13.3 and 80.7 h, the 40 keV ions beams were implanted into an aluminumdisk to depth of 10-35 nm as determined by SRIM (see Figure 3.4) [108].Etching of the radioactivity from the aluminum target post-implantationwith 500 µL of 0.1 M HCl resulted in 0.2 to 7.5 MBq of 225Ra and 0.16 to18.0 MBq of 225Ac. A summary of the production runs is shown in Table3.1.Single-column purification of 225Ac from 225Ra on the DGA column reli-ably yielded a pure 225Ac product, free from parent isotope 225Ra and withisolation yields >90% as determined by gamma ray spectroscopy. A secondelution with an additional 0.5 mL of 0.05 M HNO3 was typically able torecover the remaining 225Ac. The overall purification yield of Ac from thetarget solution was >98%. Example results from a single separation areshown in Figure 3.5, based on gamma ray spectra similar to those shown inFigures 3.6, 3.7, and 3.8.87Figure 3.4: SRIM simulation results showing the depth distribution of 40keV 225Ra+ ions incident on an aluminum surface.Figure 3.5: Representative elution profile for 225Ra/225Ac separation onDGA branched resin in nitric acid media.88 XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ           HQHUJ\>NH9@FRXQWV           HQHUJ\>NH9@FRXQWVFigure 3.6: Representative gamma ray spectrum of a sample containingboth 225Ra and 225Ac, before purification using the procedure shown in Fig-ure 3.3. The spectrum is shown with both a linear (top) and log (bottom)y-axis. Evident is the 40 keV peak used for 225Ra quantification, as well asthe 218 keV 221Fr peak and the 440 keV 213Bi peak that can be used for225Ac quantification under decay chain equilibrium conditions (see Section1.2.4). The less detectable 100 keV peak of 225Ac can be used for directquantification provided there are enough counts in the peak to provide asufficient signal to noise ratio. However, as shown in the figure, this 100 keVpeak is located in the energy region with highest background signal (Comp-ton scatter) and near many other potentially overlapping peaks, making itless desirable for 225Ac quantification.89 XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ           HQHUJ\>NH9@FRXQWV          HQHUJ\>NH9@FRXQWVFigure 3.7: Gamma ray spectrum of a sample containing 225Ra and un-detectable quantities of 225Ac (fraction 1 of the procedure shown in Figure3.3). The spectrum is shown with both a linear (top) and log (bottom)y-axis. Evident is the 40 keV peak used for 225Ra quantification. Smallamounts of 213Bi are often seen in this fraction as evident from the small440 keV peak. However, the absence of 218 keV 221Fr peak indicates thatthis 213Bi does not result from the decay of 225Ac within the purified 225Rafraction.90 XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ           HQHUJ\>NH9@FRXQWV           HQHUJ\>NH9@FRXQWVFigure 3.8: Gamma ray spectrum of a sample containing 225Ac and inde-tectable quantities 225Ra (fraction 3 of the procedure shown in Figure 3.3).The spectrum is shown with both a linear (top) and log (bottom) y-axis.91Table 3.1: Summary of 225Ra and 225Ac production runs at ISAC, TRI-UMF’s ISOL facility. aEE = extraction electrode; bLIS = laser ionizationsource. The values of 225Ra and 225Ac radioactivity produced have uncer-tainties between 3-5%.implantation parameters beam intensity [ions/s] production [MBq]date time [h] EEa LISb 225Ra 225Ac 225Ra 225AcDec ’15 13.3 off off 3.20E+07 3.80E+06 0.19 0.16Apr ’16 44.8 off on 4.00E+06 1.00E+07 0.99 1.4May ’16 48.9 off on - - 1.13 1.35Aug ’16 21.6 on on 1.60E+08 5.70E+07 7.1 10.5Dec ’16 45 on on 9.30E+07 1.30E+08 6.8 18Apr ’17 80.7 off on 9.00E+07 2.80E+06 7.5 1.7Sept ’18 40 on off 1.00E+08 1.60E+07 8.6 9.4To quantify the amount of stable metal impurities present in the 225Acproduct that could compete with 225Ac during radiolabeling reactions, thechemical purity of the 225Ac was assessed via ICP-OES and ICP-MS. Modestvalues of aluminum with (7709 ± 1281) and (10175 ± 872) ppb or (3.9 ± 0.6)µg and (5.1 ± 0.4) were present in the first and second eluates, respectively,compared to 166,000 ppb (830 µg) present in the load fraction (see Table3.2). The 200-fold decrease of Al in the eluate 1 compared to the initial loadsolution suggests that the DGA resin does a satisfactory job of removingexcess AlIII from the 225AcIII product with a separation factor of ∼102.However, an additional washing step may further decrease the amount ofmetal impurities, which may in turn positively impact radiolabeling yields.Calcium, iron, copper, nickel, and zinc were found in the 225Ac product(elute 1) with amounts of (1392 ± 208), (203 ± 20), (47 ± 12), (19 ± 6),and (137 ± 21) ppb, respectively. If one assumes the entire solution of eluate1 (0.5 mL) were to contain 10 MBq of 225Ac, the non-radioactive impuritieswould account for (6970 ± 1158) atoms of aluminum, (847 ± 127) atoms ofcalcium, (88 ± 9) atoms of iron, (51 ± 8) atoms of zinc, (8 ± 2) atoms ofnickel, and (18 ± 5) atoms of copper per atom of actinium. Of concern arethe high metal:AcIII ratios of AlIII, FeIII, and CaII in the 225Ac eluate, sincethe gold standard in actinium chelation, DOTA, also has a strong affinityfor these metals [170].92Table 3.2: Trace metal content in ppb (µg/L) determined by ICP-MS (n=2, average ± standard deviation).Values denoted with (*) were determined by ICP-OES (n=1).Be Al Ca* Sc Ti Cr MnLoad 0.055 ± 0.002 166000* 47.4 ± 0.8 0.07 ± 0.02 15 ± 1 46 ± 11 66 ± 11Wash 0.018 ± 0.001 14000* 63 ± 8 0.061 ± 0.003 15 ± 1 11 ± 3 15 ± 4Elute 1 0.06 ± 0.02 7709 ± 1281 1392 ± 208 0.5 ± 0.1 77 ± 11 14.9 ± 0.3 4.37 ± 0.02Elute 2 0.07 ± 0.02 10175 ± 872 745 ± 24 0.9 ± 0.3 101 ± 8 62 ± 63 7 ± 3Fe Co Ni Cu Zn Ga SrLoad 274 ± 45 0.11 ± 0.02 18 ± 15 32 ± 11 57 ± 25 3.1 ± 0.6 1.13 ± 0.1Wash 94 ± 3 0.04 ± 0.01 76 ± 94 12 ± 5 36 ± 5 0.86 ± 0.03 1.69 ± 0.02Elute 1 202 ± 20 0.10 ± 0.02 19 ± 6 47 ± 12 137 ± 21 1.8 ± 0.5 20 ± 1Elute 2 427 ± 192 0.6 ± 0.7 37 ± 17 46 ± 4 134 ± 23 2.1 ± 0.4 11.5 ± 0.6Y Zr Nb Mo Sn W PbLoad 0.19 ± 0.01 7.8 ± 0.7 <dl 0.90 ± 0.05 0.73 ± 0.04 1.0 ± 0.1 2.2 ± 0.6Wash 0.32 ± 0.01 7.8 ± 0.8 0.022 ± 0.001 1.226 ± 0.004 0.31 ± 0.01 0.6 ± 0.3 8 ± 2Elute 1 3.6 ± 0.2 40 ± 5 0.21 ± 0.04 5.8 ± 0.8 0.94 ± 0.01 9 ± 5 132 ± 27Elute 2 3.6 ± 0.3 41 ± 5 0.3 ± 0.1 8.3 ± 1.5 0.9 ± 0.2 12 ± 6 19 ± 1933.4 SummaryMass A = 225 ion beams containing 225Ra and 225Ac at TRIUMF’s ISACfacility were successfully used to produce 225Ac (up to 18.0 MBq). The225Ac produced was sufficient for use in a number of preclinical experiments[3, 162, 163], and enabled the imaging studies detailed in Chapter 4.However, the small and infrequent quantities of 225Ac available fromISAC were not sufficient to progress the imaging studies of Chapter 4, andas described in Section 1.3.2, were not sufficient to support development of225Ac-TAT beyond the preclinical stages. This motivated the transition ofthe focus of this thesis towards developing an alternative production methodthat is described further in Chapters 5, 6, and 7.944 Multi-Nuclide SPECT of the225Ac Decay Chain4.1 BackgroundDue to the high cytotoxicity and short range of alpha radiation, targetedinternal radiation therapy using alpha-emitters can potentially treat aggres-sive cancers by destroying small or single-cell metastases with minimal harmto healthy tissue [171]. The 225Ac decay chain (Fig. 1.8) has considerablepotential for use in this therapy due to the relatively long 225Ac half-life(t1/2 = 9.9 d) followed by four alpha-emissions [172]. Physical properties ofthe 225Ac decay chain are summarized in Section 1.2.2.The advantage gained from multiple alpha-particles is offset by the chal-lenge of retaining both 225Ac and its progeny at the target, as the migrationof the daughter products from the target following 225Ac decay reduces ther-apeutic effect and increases toxicity to non-target and excretion organs [100].While used in a small number of clinical studies (see Section 1.1.5), the dif-ficulty of targeting cells with the entire decay chain remains a concern for225Ac pharmaceutical development and is an active area of research [173–176]. As an example from preclinical trials, some targeting vectors exhibitrenal toxicity due to 213Bi uptake that limits the amount of 225Ac that canbe administered [177, 178].Performance evaluation of 225Ac pharmaceuticals must therefore sepa-rately assess the biodistributions of each alpha-emission in the 225Ac decaychain and the resulting integrated dose to various tissues. Determining thisin preclinical studies is currently a challenge since quantitative ex vivo as-sessment is limited by the short half-lives of 225Ac progeny isotopes, 221Fr(t1/2 = 4.8 min) and213Bi (t1/2 = 45.6 min).While quantitative SPECT imaging could assess the pharmacokineticsof radiopharmaceuticals in vivo, there are currently no established imaging-based methods capable of separately yet simultaneously imaging the multiple95radionuclides in the 225Ac decay chain. While SPECT images of 213Bi alonehave been acquired with a VECTor microSPECT/PET/CT system, neither225Ac nor 221Fr were present [179]. Qualitative 221Fr SPECT images havebeen reported in two preclinical cases, as have qualitative clinical imagesof 213Bi alone [29, 50, 55, 173, 176]. While other imaging modalities suchas alpha-cameras [180] or Cherenkov imaging [181] have also been used toimage the biodistributions of the 225Ac decay chain or other alpha-emittingmedical isotopes, quantitative SPECT has a distinct advantage over thesemethods. Though alpha-camera spatial resolution is on the order of tensof microns and is superior to SPECT, alpha-cameras are limited to ex vivoplanar imaging. Advantages of SPECT over Cherenkov imaging of the 225Acdecay chain include higher sensitivity, the ability to produce quantitative and4D biodistriutions, and the potential to use photon energy discriminationto distinguish between different components of the 225Ac decay chain.This chapter describes first steps taken towards developing quantita-tive preclinical imaging tests of 225Ac radiopharmaceuticals via dual-isotopeSPECT imaging of 225Ac progeny 221Fr (218 keV) and 213Bi (440 keV) usinga VECTor microSPECT/PET/CT system. To the best of our knowledge,we present the first simultaneously acquired quantitative 221Fr and 213Bi im-ages. This study is limited by the small amount of 225Ac that was availableat the time. Performance assessment of VECTor for simultaneously imaging221Fr and 213Bi is presented, and the ability to separately image dynamic221Fr and 213Bi activity distributions is demonstrated. If used in vivo, thistechnique could provide invaluable information for evaluating the safety andefficacy of 225Ac radiopharmaceuticals under development by assessing thebiodistribution of multiple 225Ac decay chain components over time. Ulti-mately, this could facilitate faster development of 225Ac pharmaceuticals atthe preclinical stage, by determining which pharmaceuticals are best suitedfor larger preclinical therapy studies or clinical trials.4.2 Materials and Methods4.2.1 Relevant physical properties, production, and quantifi-cation of 225Ac225Ac decays to stable 209Bi via two beta and four alpha decays (see Section1.2.2). The alpha-emitting portion of the decay chain effectively encom-passes 225Ac through 213Bi, since 213Po decay occurs microseconds after213Bi decay. Only 221Fr and 213Bi can be imaged, via their 218 keV (11.4%)and 440 keV (25.9%) gamma emissions, respectively. Other gamma emis-96sions are present with branching ratios less than 3% relative to 225Ac decays.While many of these isotopes emit x-rays in the 80 to 100 keV range, thesephotons cannot provide images representing activity distributions of specificisotopes. As detailed in Section 1.2.1, the short half-lifes of 225Ac progenyrelative to the parent causes the decay chain to establish transient equilib-rium.All work presented in this chapter was done using 225Ac produced atTRIUMF’s ISAC Facility (see Chapter 3). A total of (3.8 ± 0.30) MBqof 225Ac was available for imaging, free of other radioactive contaminants.The radioactive composition of all samples was determined via gamma spec-troscopy using the Genie 2000 software package and a high-purity germa-nium detector (see Section 2.1). 225Ac quantities were determined indirectlyvia measurement of 221Fr and 213Bi once transient equilibrium was estab-lished. These measurements were experimentally determined to have anuncertainty of 8%.4.2.2 Data acquisition and image reconstructionThe Versatile Emission Computed Tomography (VECTor) imaging platform(MILabs, Utrecht, Nederlands) is a small-animal, multi-modality scannercapable of quantitatively imaging single photons over a wide energy range(both SPECT and PET isotopes) [182]. The imaging platform combinesa CT scanner and a SPECT system with three flat panel NaI detectorsin a triangular arrangement. Within the NaI panels is an interchangeablecylindrical collimator containing rings of clustered pinholes. Collimator in-terchangeability provides versatility, with collimators of varying resolution,sensitivity, and diameter optimized for different photon energies and appli-cations. The field of view is limited to a small region inside the collimatorthat is visible to all pinholes. Larger volumes are imaged by stepping thebed through multiple bed positions within the collimator.VECTor uses a 350 keV threshold to distinguish between both high(PET-like, i.e. 511 keV) and low (99mTc-like, i.e. 140 keV) energy photons.Given the difficulties in obtaining large 225Ac quantities, and since simulta-neous 221Fr (218 keV) and 213Bi (440 keV) imaging involves both these highand low energy ranges, two collimators were selected as potential candidatesfor imaging with VECTor: the ultra-high sensitivity (UHS) collimator [183],and the high-energy ultra-high resolution (HEUHR) collimator [184]. TheUHS collimator performs optimally at lower energies and provides highersensitivity favourable for low-activity imaging. In contrast, the HEUHRcollimator offers higher spatial resolution and improved performance over97a broad energy range. When imaging with 140 keV, the collimators yielda sensitivity of approximately 12500 cps/MBq (UHS) and 3000 cps/MBq(HEUHR), and spatial resolutions of 1 and 0.55 mm, respectively. In thisstudy, we characterize VECTor’s ability to simultaneously image 221Fr and213Bi for both HEUHR and UHS collimators.Despite the low activity available for imaging, the 9.9 day 225Ac half-lifepermits long data acquisitions, providing sufficient counts for image recon-struction. However, such long acquisitions prohibit in vivo imaging. Thecollimator, duration, bed positions, and counts acquired for each acquisitionis reported in Table 4.1. Unless otherwise stated, all data were acquired withthe decay chain in equilibrium. Data acquired in list mode were sorted into512 energy bins of 3.86 keV width; resulting spectra are shown in Fig. 4.1.The system’s energy resolution is 9.3% for 140 keV and 8.6% for 511 keV.Two images were reconstructed from each data acquisition: one from datacollected in the 218 keV photopeak (221Fr) and another from the data in the440 keV peak (213Bi). Different system matrices are used to reconstruct lowenergy (221Fr) and high energy (213Bi) images. A system matrix optimizedfor 140 keV is used when reconstructing events from energy peaks below350 keV, while for energies above 350 keV a system matrix calculated for511 keV photons is used. Data were corrected for decay, and images with0.4 mm wide cubic voxels were reconstructed using energy windows of 15%width, 4 subsets, and 25 iterations using VECTor’s pixel-based ordered sub-set expectation maximization (POSEM) iterative reconstruction algorithm[185]. This combination of subsets and iterations was chosen based on op-timization of contrast-to-noise ratio (CNR) for resolution phantom images(see Section 4.2.4). The number of MLEM-equivalent iterations (numberof POSEM subsets times number of iterations) was first determined. 100MLEM-equivalent iterations was selected as this number yielded the opti-mal CNR for most images when using different isotope (221Fr vs 213Bi) andcollimator (UHS vs HEUHR) combinations. Keeping this number fixed,the number of subsets was varied. Compared to a single-subset reconstruc-tion, no significant differences were observed when data were divided into 4subsets. Therefore, 4 subsets and 25 iterations was chosen as the best opti-mization of image quality and reconstruction time. Background and scattercorrection is performed by the VECTor image reconstruction software, inthis case using a triple energy window method with a high and low energybackground window of a 3% width. Co-registration of emission images andthe subsequently acquired CT images enabled attenuation correction of theSPECT images. To enable quantitative SPECT reconstruction, calibrationfactors for each collimator and photopeak were determined from images of98Figure 4.1: Energy spectra, normalized by acquisition time, acquired by theVECTor scanner for both HEUHR (red) and UHS (green) collimators witha comparison to a background spectrum (grey) acquired with no collimatoror activity present. Spectra were acquired using a uniform source containing1.05 MBq (28.3 µCi) of 225Ac. The energy regions used to reconstruct the221Fr and 213Bi are shown in blue and red, respectively. The adjacent greyregions indicate the energy windows defined for background and scattercorrection.a uniform syringe containing (1.05 ± 0.08) MBq of 225Ac reconstructedfrom a 12-hour acquisition. The reconstructed images were analyzed usingMATLAB (v. 2015b).4.2.3 Image contrast and noiseImage contrast and uniformity were assessed using a cylindrical acrylic phan-tom similar to the NEMA NU-4 micro-PET image quality phantom [186].The phantom contains one high activity concentration insert (‘hot’ region)and one activity-free insert (‘cold’ region), both submerged in a low activityconcentration background (‘warm’ region). These inserts permit contrastmeasurements similar to in vivo conditions, where a small high activity re-gion may be present within a uniform low activity background. The insert-free portion of the warm region was used to measure noise characteristicsand the uniformity of the system’s response. The hot and warm regions werefilled with 225Ac concentrations of (1.56 ± 0.12) MBq/mL and (0.33 ± 0.03)MBq/mL, respectively. For contrast and uniformity measurements only, a 1mm Gaussian filter was applied to the reconstructed images. Contrast mea-surements were performed using cylindrical ROIs defined within CT imagesand centred over the hot, warm, and cold regions using diameters equal to99Table 4.1: Activities used, acquisition durations, and counts acquired ineach photopeak for all imaging experiments. Values for dynamic scans listthe number of counts in the first frame.PhantomTotalActivity[MBq]BedPosi-tionsColli-matorTimeperBedPosi-tion[min]Counts[mil-lions]Contrast,Noise,Uniformity2.77 ± 0.22 36HEUHR 40221Fr 4.34213Bi 8.37UHS 40221Fr 27.30213Bi 101.07Resolution 1.79 ± 0.14 18HEUHR 80221Fr 5.23213Bi 9.53UHS 40221Fr 15.98213Bi 43.25Cation column0.24 ± 0.02 1 HEUHR 60221Fr 0.15213Bi 0.2310080% of the physical diameter of each volume (ROI placement is visualizedin Fig. 4.2a). Definitions of contrast recovery as defined by the NEMA NU2-2007 standard were used [187]. Contrast recovery between the hot andwarm regions was therefore defined as:CRh−w =Ih/Iw − 1ah/aw − 1 ∗ 100% (4.1)and contrast recovery between the warm and cold (activity-free) regionswas defined as:CRw−c = (1− IcIw) ∗ 100% (4.2)where Ih, Iw, and Ic represent mean activity concentrations measuredwithin the hot, warm and cold ROIs, and ah and ac represent activity concen-trations independently determined by gamma spectroscopy. Profiles acrossthe hot and cold regions were also measured on a single image plane.Image uniformity can be assessed using radial profiles through uniformregions containing high activity concentrations. Due to the low activityconcentration within our phantom and the resulting noise, images were av-eraged over 4 mm in the axial direction before measuring radial uniformityprofiles.Within this uniform region of the phantom, image noise was also assessedusing two metrics. To assess the variability in the response to a uniform ra-dioactivity concentration, noise was assessed by measuring the coefficient ofvariation (COV) within the warm ROI across 45 (7.6 mm) adjacent planes.In a method similar to that described by Tong et al [188], background vari-ability was measured using 9 ROIs located within the uniform region of thephantom and having diameters equal to those of the hot and cold inserts.The placement of these ROIs is shown in Fig. 4.2b, and was done using5 non-adjacent image slices 2 mm apart for a total of 45 ROIs. The coef-ficient of variation of ROI mean values was taken as the final measure ofbackground variability.4.2.4 Image resolution and limit of detectionAn acrylic phantom containing groups of cylindrical holes of diameters 1.70,1.50, 1.30, 1.10, 0.95, and 0.85 mm was used to assess the ability to resolvesmall objects that may be present in future in vivo studies. All but the 0.85mm holes were filled with (4.66 ± 0.37) MBq/mL of 225Ac. Attempts to getas much of the available activity as possible into the phantom resulted inthe smallest holes not filling with the solution. The resulting images were101Figure 4.2: (a) SPECT cross section of the phantom’s contrast region, withgreen circles indicating the location of ROIs used to determine contrast mea-surements, and the red line showing the location of the measured profiles.(b) SPECT cross section of the phantom’s uniform region, with blue circleindicating the location of the ROI used for the ‘warm’ region, and greencircles indicating the ROIs used for noise measurements.analyzed by measuring inter-rod contrast as defined by Walker et al [189].This metric measures inter-rod contrast between ROIs centered inside andin between rods of a given size. ROIs were defined using known dimensionsof the phantom and positioned using CT images. The ideal value for thismetric is 100%, with 20% defined as the minimum threshold for resolvability.To assess the ability to accurately quantify the activity concentrationwithin small objects, the recovery coefficient (RC) was measured for eachrod using ROIs with diameters 80% of the physical rod diameter. The RChas an ideal value of one and is defined as:RC =hdho(4.3)where ho is the known activity concentration and hd is the apparent activityconcentration within the ROI.To parameterize the quantitative accuracy of images at lower activityconcentrations, inter-rod contrast and RC measurements were repeated forimages reconstructed using 20%, 5%, and 1% of the total counts, simulatingdata acquired with activity concentrations of 0.93, 0.23, and 0.05 MBq/mL.102Figure 4.3: 221Fr and 213Bi images of the contrast phantom acquired withboth the HEUHR and UHS collimators and filtered with a 1mm 3D Gaussianfilter.4.2.5 Dynamic imaging of differing 221Fr and 213Bi distribu-tionsTo demonstrate the ability to image dynamic 221Fr and 213Bi activity distri-butions that are not co-localized, a cation exchange chromatography columntypically used to isolate 213Bi from the 225Ac parent was imaged. Describedby Morgenstern et al [49], this procedure uses AG MP-50 cation exchangeresin, loaded with 225Ac in 4 M HNO3.225Ac binds to the resin, along withmost of the 213Bi. Once the 213Bi and 225Ac regain equilibrium, 213Bi iseluted in a solution of 0.1 M NaI and 0.1 M HNO3.225Ac remains boundto the resin as does 221Fr.For the imaging study, (0.30 ± 0.02) MBq of 225Ac was loaded onto theresin (AG-MP 50 resin, column volume 100 µL), and the 213Bi was eluted ina 200 µL volume that was left in the column, but outside the resin volume.After the elution, the 213Bi is no longer in equilibrium with 225Ac: in theresin a deficiency of 213Bi exists relative to 225Ac; in the eluate an excess of213Bi and no 225Ac is present. The expected result is a decay of 213Bi in theeluate, and a growth of 213Bi in the resin as equilibrium is re-established.Beginning at 20 minutes post-elution, a series of six 1-hour data acqui-sitions were performed at the interface between the resin and the eluate.After image reconstruction, the total amount of 221Fr and 213Bi within theresin and the eluate was evaluated as a function of time.103Figure 4.4: Profiles through contrast phantom images in the uniform region(a) and the contrast region (b). The ideal profile (solid grey) showing theknown activity concentration and associated error (dashed grey) has beenfiltered with the same Gaussian filter applied to the images. Profiles from221Fr images are shown in blue, and profiles from 213Bi images in red.4.3 Results4.3.1 Image contrast and noiseTable 4.2 contains contrast recovery and noise measurements acquired fromthe contrast phantom. Contrast recovery is highest for the HEUHR collima-tor, with contrast recovery values of 83-85% for the high activity concentra-tion region, compared to 73-77% for the UHS collimator. However, contrastrecovery between the cold and warm regions is reduced due to the non-zerobackground observed in the cold region and outside the phantom, a typicalresult caused by the difficulty of the image reconstruction to converge withinlow-activity regions.For HEUHR images, the measured activity concentration within the hotregion is within 9% of the expected values independently determined viagamma spectroscopy (Section 4.2.1). This error is reduced to 2% for theUHS images. However, measured activity concentrations in the low activity(warm) region differ from real values by less than 19%, with the exceptionof the UHS 213Bi images in which an activity concentration 67% of the idealvalue is measured. Profiles through the contrast inserts are shown in Fig.4.4.These observations are visually supported by images of the contrastphantom (Fig. 4.3). Each collimator appears visually to perform best inits nominal energy range. The HEUHR collimator can better distinguishthe phantom from background in 213Bi images, while the 221Fr images ex-104hibit lower frequency noise and a higher background. In comparison, theUHS collimator produces 221Fr images that better distinguish the phantomfrom background when compared to 213Bi images.Figure 4.5: 221Fr and 213Bi images of the resolution phantom acquired withboth the HEUHR and UHS collimators105Table 4.2: Image quality results from images of the contrast phantom, including the ideal values expected from aperfect image.collimator imagehot regionmean [% ofideal value]warm regionmean [% ofideal value]contrastrecoveryhot-warm [%]contrastrecoverywarm-cold [%]noise[%]backgroundvariability[%]HEUHR221Fr 91 89 84.5 66.5 15 7213Bi 106 118.7 83 86.8 25 8UHS221Fr 99 81.5 77 75.3 17 7213Bi 102 67.0 73 68.7 29 15ideal value 100 100 100 100 0 0106Figure 4.6: Profiles through rods of 0.95 mm diameter (left), 1.30 mm diam-eter (centre), and 1.70 mm diameter (right). The apparent activity withineach rod can be compared to the known value of (0.13 ±0.01) mCi/mL.Profiles from 221Fr images are shown in blue, and profiles from 213Bi imagesin red.4.3.2 Image resolution and limit of detectionImages of the resolution phantom are shown in Fig. 4.5. The HEUHR col-limator clearly resolves all rods for both 221Fr and 213Bi images, while theUHS collimator resolves none of the rods in the 213Bi images, and only somefor 221Fr. This is supported by inter-rod contrast measurements shown inFig. 4.7 - the HEUHR collimator has inter-rod contrast values >35% for allrods in both 221Fr and 213Bi images while many UHS inter-rod contrast val-ues are near or below zero, implying that more activity in the reconstructedimage is seen between the rods than within them. The UHS collimator re-solves rods only in 221Fr images for diameters ≥1.3 mm. As the activityconcentration is decreased (by reconstructing with fewer counts) the resolv-ability of rods remains unchanged above 0.23 MBq/mL.While the rods may be resolvable, the activity concentration measuredwithin them is not necessarily accurately estimated. Table 4.3 shows recov-ery coefficients for all resolved rods. RC values range between 0.55 and 0.97for the largest rods and decrease with rod diameter. This is also seen in theprofiles shown in Fig. 4.6. RC values change little for activity concentrations≥0.23 MBq/mL.4.3.3 Dynamic imaging of 221Fr and 213Bi distributionsSPECT and CT images of the cation exchange column after 213Bi elutionare shown in Fig. 4.8. While the 221Fr images appear unchanged over time,changes in the 213Bi activity distribution are visually apparent: a decreasing107Figure 4.7: Inter-rod contrast measurements from the resolution phantomimages.Table 4.3: Recovery coefficients measured within resolvable rods of the reso-lution phantom. Omitted values denote rods that are not resolved (inter-rodcontrast <0.2).rod diameter [mm]collimator image 0.95 1.10 1.30 1.50 1.70HEUHR221Fr 0.50 0.57 0.63 0.68 0.73213Bi 0.37 0.49 0.69 0.86 0.97UHS221Fr - - 0.31 0.44 0.55213Bi - - - - -108Figure 4.8: 221Fr and 213Bi SPECT images (left) of the cation exchangecolumn acquired with the HEUHR collimator at multiple one-hour intervalsafter elution. Times for each image indicate the start time of the imageframe. The CT image (right) corresponds to the same region of the phantomas the SPECT images. The black outlines in the 221Fr SPECT image att = 260 min indicate the boundaries of the volumes used to determine thetotal activities within the eluate and resin, plotted in Fig. 4.9. A non-uniform distribution of activity in the resin is also observed.amount of 213Bi in the eluate and an increasing amount in the resin.The total activity within the resin and eluate over time is shown in Fig.4.9. The curve fit to the 213Bi resin activity measurements was calculatedusing the solutions to Equations 1 to 3, with the initial amount of 225Ac and221Fr determined from the average of the last two 213Bi data points, and theinitial amount of 213Bi determined by linear extrapolation of the first twopoints to t = 0. The shape of this curve agrees well with the remaining datapoints, and both 221Fr and 213Bi transient equilibrium values differ by only5.5%. Within the eluate, an exponential fit to 213Bi activities has a half-lifeof 39.8 min, with 95% confidence bounds of 31.3 and 54.6 min. Consideringthe small number of data points, this fit compares well to the 213Bi half-lifeof 45.6 min.4.4 DiscussionThese results demonstrate the ability to quantitatively image the 225Ac de-cay chain via simultaneous 221Fr and 213Bi SPECT. Given the results in inSections 4.3.1 and 4.3.2, it is clear that a high-energy collimator such as theHEUHR is required to perform this technique. With the HEUHR collima-tor, spatial resolution of ≤0.85 mm and quantitative accuracy within 9%is achieved. Many of the imaging results of these phantom studies are alsoconsistent with similar VECTor phantom studies in the literature. VECTor109Figure 4.9: Plots of the total 221Fr and 213Bi activity within the resin (left)and the eluate (right) obtained from images of the cation exchange column.Background values (measured outside the column volume) have been sub-tracted.studies using the UHS collimator, similar resolution phantoms and otherlow-energy single-photon emitters (99mTc ) report resolution (1 mm) com-parable to results for our low-energy single-photon emitter, 221Fr images[182]. These isotopes have comparable energies (218 vs 140 keV). For theHEUHR collimator, other studies report resolvability for rods <0.55 mmwith 140 keV and <0.75 mm for 511 keV, comparable to our results for221Fr and 213Bi.Studies by de Swart et al have characterized VECTor’s ability to im-age 213Bi using a similar high energy collimator but without the presenceof 225Ac or 221Fr [179]. When using comparable amounts of activity, theauthors report resolvability for rods ≥0.90 mm in 213Bi images, as well asinter-rod contrast comparable to our HEUHR 213Bi results (≥0.95 mm).The recovery coefficients within large volumes reported by de Swart et alare consistent with those given in Table 3 for 213Bi and – accounting for thelower branching ratio – for 221Fr as well.The better performance of the tungsten HEUHR collimator is expectedsince – unlike the lead UHS collimator – it is designed for higher energies.With the UHS collimator, the higher energy (440 keV) 213Bi photons (andthe resulting scatter) are more capable of penetrating parts of the collimatorthan the lower energy (218 keV) 221Fr photons. Not so for the HEUHRcollimator, as illustrated in Table 4.1 by the number of counts acquired foreach image: the average ratio of 213Bi counts to 221Fr counts is 1.75 forthe HEUHR collimator and 3.13 for the UHS collimator - approximately1.80 is expected, accounting for the relative branching ratios and detection110probabilities by the 9.5 mm thick NaI detector.While a high energy collimator is needed to provide 221Fr and 213Biimages of acceptable quality, the HEUHR 213Bi images in this study presentartefacts not seen in other images. These ring-like artefacts are possiblya Gibbs artefact [190] or are possibly indicative of a slight system matrixinaccuracy. These artefacts can be seen in the profiles through the hotregion of the HEUHR 213Bi contrast image, shown in Fig. 4.4 and in thehigh-activity regions of the 213Bi images in Fig. 4.8 (the ring-like artefactis viewed from the side in this figure). The cause of these artefacts is likelyattributable to the fact that the system matrix provided by the manufacturerand used to reconstruct the images is calculated for 511 keV photons anddoes not perfectly reconstruct the 440 keV images. However, a similar effectis not observed for the 221Fr (218 keV) images, for which a 140 keV systemmatrix is used.Difficulties in obtaining enough 225Ac is a challenge faced by other re-searchers involved in 225Ac studies due to the cost and limited supply of thisisotope. While other methods of supplying 225Ac are under development,and TRIUMF expects to increase 225Ac production in the near future, invivo studies are not possible with the amount of 225Ac presently available.Though increased activity would improve image quality, the long data acqui-sitions used here provide a total number of counts for image reconstruction(see Table 4.1) that is comparable to the number of counts for a typical invivo study at our centre, usually ∼106 to 107. Note that while the cation ex-change column study only had 105 counts, this is compensated by the smallimage volume – only one bed position was used. More activity is neededfor in vivo imaging due to the requirements to image a larger volume andreduce acquisition time to durations suitable for animal care. For mice,the number of bed positions may double and acquisition time may need tooccur ten times faster. These factors combined suggest approximately 20times more activity will be required to obtain in vivo images of comparablequality.As seen in the contrast phantom image results, the accuracy of the im-ages will also depend on the activity concentration (i.e. an in vivo imagewhere all activity in concentrated in a small volume may not be directlycompared to an image where the same amount of activity is spread out overa larger volume). Results from the resolution phantom images indicate ac-tivity concentrations ≥0.23 MBq/mL will result in acceptable image quality.This result implies that therapeutic amounts of 225Ac (typically about 0.05MBq/kg [29]) are likely not imageable in live subjects as a single VECTorbed position can only image a ∼1 mL volume. However, imaging with higher111activities (≥10 MBq) could still provide a test of 225Ac pharmaceutical per-formance by assessing the biodistribution of the decay chain in terms ofpercent uptake and retention in target and non-target organs. Imaging of213Bi-radiopharmaceutical biodistributions (without the presence of 225Acor 221Fr) may be more feasible due to the higher 213Bi maximum tolerableactivity, as has been previously demonstrated [179].These preliminary results demonstrate the feasibility of simultane-ously imaging 221Fr and 213Bi activity distributions. While other mi-croSPECT/CT systems could in principle perform this imaging technique,these results demonstrate a high-energy, high-performance collimator isneeded to provide quantitative images of acceptable quality. The contrastphantom studies indicate that activity concentrations can be accurately de-termined within high activity regions of sufficient size, while resolution phan-tom studies show the ability to resolve mouse-organ-sized objects. The accu-racy of 221Fr activity concentration estimates indicates that down-scatteringfrom 213Bi does not affect the ability to quantitatively image 221Fr, a re-sult consistent with other studies that suggest the VECTor reconstructionsoftware can correct for these effects [182]. While images will benefit fromincreased activity, this method is feasible and warrants further study in vivo.This imaging technique shows potential to resolve a challenge commonlyencountered in 225Ac pharmaceutical research: easily assessing the biodis-tribution of 225Ac progeny isotopes over time. Referring to the decay chainin Fig. 1.8, imaging of 221Fr will indicate the location of alpha-emissionsfrom 221Fr as well as from 217At, due to the latter’s rapid decay. Similarly,213Bi images will be co-localized with alpha-emissions from both 213Bi and213Po. Since 225Ac itself cannot be directly imaged, the location of 225Acalpha-emissions could be determined by euthanizing the animal and repeat-ing the imaging after the decay of any 221Fr that is not co-localized with225Ac.The information made available through this technique would be of sig-nificant importance to 225Ac radiopharmaceutical development. Providinga complete picture of the 225Ac decay chain’s pharmacokinetics over timewould measure the fraction of 225Ac progeny isotopes maintained at thetarget site and could resolve persisting concerns within the field regardingthe safety of serial alpha-emitting radionuclides like 225Ac. As an example,in situations where an 225Ac radiopharmaceutical is seen to result in renaltoxicity due to 213Bi, time-dependent biodistribution data made availableby this technique could distinguish between: i) toxicity due to free 213Bithat is co-injected with the radiopharmaceutical; toxicity due to 213Bi thatis generated by 225Ac within the body before 225Ac uptake at the tumour;112and iii) toxicity due to 213Bi generated by 225Ac at the tumour that has thenmigrated elsewhere. Given the short 213Bi half-life, if either i) or ii) were thecase then the toxic effects could be potentially reduced by administration ofan agent that temporarily blocks 213Bi uptake in the kidneys, increasing theamount of 225Ac that could safely be administered. Ultimately, this tech-nique could provide a useful test of new 225Ac pharmaceuticals developedat TRIUMF or elsewhere, and help identify the pharmaceuticals best suitedfor therapeutic preclinical and clinical trials.4.5 SummaryThis chapter demonstrated that a microSPECT/CT system equipped witha high energy collimator is capable of simultaneously and quantitativelyimaging dynamic 221Fr and 213Bi activity distributions resulting from thedecay of 225Ac.However, larger quantities of 225Ac are required for in vivo imaging. Asdescribed in Section 1.4, the inability of TRIUMF’s ISAC Facility to reliablyproduce such quantities was the primary motivation for pivoting the focusof this thesis towards alternative 225Ac production at TRIUMF’s IPF, asdetailed in Chapters 5, 6, and 7.1135 Thorium Target Design and Ir-radiation5.1 BackgroundOf potential alternative accelerator-based 225Ac-production methods (seeSection 1.3), the proton-induced spallation of thorium at TRIUMF’s 500MeV Isotope Production Facility has potential to produce significant quan-tities of 225Ac [1]. As discussed in detail in Chapter 7, the co-production of225Ra during the spallation process is also of interest, as 225Ra can serve asa generator of additional 225Ac.To make 225Ac via thorium spallation at TRIUMF, thorium targets arebombarded with 480 MeV protons at a beam current of up to 100 µA.During the irradiation the thorium is hermetically sealed within a targetcapsule. For safe and reliable operation it is crucial that this hermetic sealaround the thorium is at all times able to withstand any thermally-inducedmechanical stresses resulting from the large power deposition into the targetfrom the proton beam (see Section 1.1.3), since such a “target failure” couldenable the release of gaseous and volatile radionuclides co-produced withinthe thorium during the spallation process. Careful modelling and design ofnew targets must therefore be done to ensure safe and successful irradiations.This chapter introduces the design of a new target system for 225Acproduction through proton-induced thorium spallation at the TRIUMF 500MeV Isotope Production Facility (IPF). The input and assumption for themodeling are described and discussed, and modeling results and initial op-erational experiences are presented.1145.2 Materials and Methods5.2.1 TRIUMF’s 500 MeV Isotope Production FacilityTRIUMF’s 500 MeV Isotope Production Facility (IPF) was first conceivedin 1978, and modelled after a similar facility at Brookhaven National Lab-oratory [191]. Historically, IPF has been primarily used for the irradiationof molybdenum targets for the production 82Sr/82Rb generators, as well asoccasional CsCl and KCl targets. However, the facility has received littleuse in recent years despite routinely receiving proton beam. IPF is locatednear the end of beamline 1A (BL1A), the main beamline of TRIUMF’s 500MeV cyclotron [192]. With the exception of TRIUMF’s Thermal NeutronFacility [193] – which is downstream at the BL1A beam dump – the major-ity of BL1A users are located upstream from IPF and are not affected byits operations. Typical beam parameters for IPF are described in Section5.2.2.IPF consists of a 30 cm diameter, 8 m tall column of cooling water.The target station is located in the bottom of the water column at beamlevel. Above the water column, a shielded transfer hot cell is used to bringtargets in or out of the facility and to move them in or out of the beam.Within the transfer cell, targets are inserted into one of six cassettes whichare lowered into the cooling water column and down to target station by achain drive. A total of 12 targets can be simultaneously irradiated at IPF– each cassette can hold a pair of up to 8 mm thick targets, separated bya 2.5 mm gap (see Figure 5.1b). When isotope production targets are notin use, helium gas targets are inserted to displace cooling water from thebeam path, minimizing heat loads on the IPF cooling water heat exchanger.During irradiation, targets are submerged in the water column and housedin one of six cassettes through which recirculating cooling water is pumped(see Figures 5.1a and 5.1b). The cooling water flow of 114 L/min is routedthrough the station’s 8 water circuits, six of which each feed individualcassettes. The two remaining water circuits are used for radial cooling of thetarget station’s entrance and exit windows. Flow rates through individualcassettes are estimated to be between 7.2 and 23.4 L/min, depending onthe location of the cassette. Cooling water temperature typically measures25-28 ◦C at the target.A typical IPF target is shown in Figure 5.1c: two Inconel R© 600 windows(0.127 mm thickness) are welded to either side of a ring-shaped stainlesssteel target frame (10.1 cm diameter, 8.4 mm thickness), sealing within the8.2 mm thick, 7.6 cm diameter puck of target material (ex. a puck of molyb-115Figure 5.1: a) IPF target station at beam level, with six cassettes insertedinto the beam. The arrows indicate cooling water flow direction. (b) AnIPF cassette holding two targets. (c) A typical IPF target.116denum dioxide or potassium chloride salt) [191]). As shown in Figure 5.1,the targets interface with other IPF components in three ways: alignmentgrooves on the bottom of the frame fix the orientation of the target withinthe cassette; a thermocouple hole at the bottom of the target has a thermo-couple inserted in it during irradiation to monitor target temperature; anda tapped hole in the side of the frame allows targets to be securely picked upand manipulated by a threaded rod. More details regarding the IPF facilityand its targets are provided by Burgerjon et al [191].5.2.2 Proton beam parametersFor 6-7 months per year, BL1A typically operates with 100-110 µA of 480MeV protons at extraction from the TRIUMF main cyclotron, with theability to increase this up to 170 µA. Before reaching IPF, beam losses occurdue to two beryllium muon production targets (T1 and T2). Depending onthe thickness of these targets, the proton beam reaching IPF can have anenergy between 451 and 472 MeV and a current that is reduced by 15-40%to 60-94 µA under typical operating conditions. The beam profile at IPFis measured by a multi-wire scanner located 2 m before IPF. The Gaussianbeam typically has a 2σ width between 25 and 35 mm in the horizontal andvertical directions, depending on the beam tune and thickness of the T1 andT2 targets.Due to the variability in the beam conditions at IPF and the desire todesign an 225Ac production target that is compatible with all BL1A oper-ating conditions, multiple operational cases are considered when modellingirradiations of the thorium targets. A symmetrical Gaussian beam shape isassumed, with 2σ beam widths between 15 and 40 mm. Currents between60 and 120 µA are also considered. Beam energy is fixed at 454 MeV (thelowest estimated beam energy at IPF), since at 454-470 MeV a <4% changein beam energy negligibly affects isotope production rates and heat loads onthe target as both cross-sections and stopping powers are relatively flat inthis energy range [108, 118]5.2.3 Thorium target5.2.3.1 Design considerationsSince safe and reliable 225Ac production requires the hermetic seal of thetarget to withstand any stresses caused by thermal changes in the targetthat result from the proton beam, the target design must also maximize117heat transfer from the thorium to the cooling water through the hermeticseal.Post-irradiation processing of the target also requires that the thoriumbe dissolved. While a previous IPF thorium target prototype utilized ThO2[2], this is not suitable for routine 225Ac production, due to the insolublenature of ThO2 [194]. Thorium metal was chosen as the target materialas it can be readily dissolved post-irradiation. The metal also has otheradvantageous properties such as a high melting point and high density.While the high density of thorium metal provides greater scaleability formaximizing 225Ac production if simultaneous irradiation of larger thoriumquantities are desired, current needs only require the irradiation of thinthorium foils <1 mm in thickness. Therefore, the 8 mm wide hermetictarget casing used for decades at IPF had to be modified in this targetdesign.5.2.3.2 Mechanical assemblyThe thorium target consists of an stainless steel 316 (SS316) outer framethat interfaces with IPF cassettes, and the thorium target material that issealed within the frame by two Inconel R© 718 windows (0.127 mm thickness).Currently, the thorium metal target material consists of a 60 mm diameter,0.25 mm thick foil, purchased from IBI Labs (International Bio-AnalyticalIndustries, Inc., Boca Raton, FL).Sealing of the thorium within the target is done in two stages. First,the thorium is sealed within a target sub-assembly that consists of a thininner welding ring (1 mm thick, 76 mm diameter), to which both windowsare electron-beam (EB) welded (Figure 5.2a). The sub-assembly is then EBwelded to the target frame (Figure 5.2b). A photo of the finished target isshown in Figure 5.2c.Relevant material properties for the thorium, SS316, and Inconel R© 718components of the target assembly are shown in Table 5.1. Yield and ul-timate strength values for Inconel R© 718 were obtained from the materialscertification provided by the manufacturer (American Special Metals, CoralSprings, FL). Material composition by mass for each target component isprovided in Table 5.2.All material properties used for modelling of the target were obtainedeither directly from the manufacturer, or the Knovel Engineering Data andTechnical Reference Database [195]. Thorium material properties were alsoobtained from the ASM International databases [196].118Figure 5.2: a) Target sub-assembly, including the thorium foil, welding ring,and entrance and exit windows. Note the location of EB welds that bindthe windows to the welding ring, sealing the thorium within. (b) Weldingof the sub-assembly to the target frame. (c) Photo of the thorium target.Note the inward deflection of the Inconel R© 718 window.Table 5.1: Base properties at room temperature for target components.Property Inconel R© 718 thorium SS 316Density (g/cm3) 8.19 11.72 8.0Young’s Modulus (GPa) 199 72.4 193Thermal expansion (µm/mK) 13 11.1 16.3Poisson’s ratio 0.3 0.27 0.28Yield strength (MPa) 460 144 290Ultimate strength (MPa) 895 219 580Melting Point (K) 1533 2028 1673Thermal conductivity (W/m2K) 11.1 13.86 14.6119Table 5.2: Elemental composition of alloys used in IPF targets. Values arefrom supplier certificates of analysis unless otherwise stated.Composition (% mass)Material Cu Cr Fe Mn Si C S Mo NiInconel R©7180.3 17 23.6 0.35 0.35 0.08 0.015 3.3 55SS 316 - 16 70 0.5 0.25 0.083 0.083 2 11thorium >99.5% by ICP-MS analysis5.2.3.3 Areal contact at thorium-window interfaceContact between the thorium foil and the target assembly window is animportant factor when considering how effectively the target will be cooledduring irradiation, as the majority of power deposited in the target assemblyis expected to be removed to the cooling water via heat transfer over thisbarrier.As shown in Figure 5.2a, before the thorium is sealed within the sub-assembly, a 0.125 mm gap exists between the thorium and each window.Sealing of the foil under the vacuum provided by the EB welding chamberresults in a first mode deflection of the target windows: atmospheric pressureacts on the sealed, evacuated sub-assembly, forcing the windows to bendinwards (visible in Figure 5.2c). This ensures contact between the thoriumand windows at the center of the target where heat loads from the protonbeam are highest.In order to measure the area for which the thorium and windows are incontact, the thickness of a manufactured sub-assembly was measured using aprofilometer (Nanovea ST400). Shown in Figure 5.3, this indicates that theinner 49.8 mm of the thorium foil contacts the windows, as defined by thepoints where the windows stop deflecting inwards. These 49.8 mm represent83.0% of the 60 mm thorium foil diameter, or 68.9% of the surface area. Asecond profile (not shown), made perpendicular to the one in Figure 9, alsoindicated 48.2 mm of contact (80.4% of the diameter).For simulations of thorium target temperatures during irradiation, aconservative 45 mm wide contact region (75% of the diameter, and 56.3% ofthe surface area) is assumed. However, it should be noted that the amountof contact during the irradiation is expected to increase from measurementsshown in Figure 5.3: while the profile measurement was done at atmosphere,additional pressure on the target windows will be present during irradiation120Figure 5.3: Plot of the thorium target sub-assembly thickness. Measurementof the inward deflection of the window, as also seen in Figure 5.2c, indicatesthe region for which the thorium and windows are in contact. The expectedthickness in the centre of the sub-assembly (assuming contact of the thoriumwith both windows) is 504 µm.due to the depth of the target in the cooling water column (8 m below thewater surface).5.2.3.4 Thermal contact resistance at thorium-window interfaceIn addition to the contact area between the thorium and windows, the ther-mal contact resistance at this interface is also an important factor whenconsidering how effectively the target will be cooled during irradiation. Thegreatest predictors of contact resistance are contact pressure, surface rough-ness, hardness, and yield strength. Thorium is soft and has a polished finish,so the contact resistance would likely be small. While limited data exists forthorium contact resistance measurements, comparisons can be made to simi-lar materials. Several copper and aluminum alloys have similar properties tothat of thorium, however, since aluminum values for contact resistance arehigher it is more conservative to compare the thorium to aluminum (6000 se-ries). The aluminum alloy with the closest material properties to thorium isaluminum 6061-T4 (Table 5.3). Table 5.4 also shows approximated contactresistances for several comparable metals. The aluminum-aluminum contactresistance is the highest of the comparable metals at 0.0005 m2K/W. Figure11 shows a more detailed estimation of Aluminum 6061-T4 stress for thepressure range (0.1-0.2 MPa) the target will operate in. Since both sources121Table 5.3: Comparison of thorium to select aluminum and copper alloys interms of material properties relevant to thermal contact resistance.Material Yield strength (MPa) Brinell hardnessthorium 144 60-90aluminum 6061-T4 146 65-89aluminum 2024-T4 395 120-150aluminum 7075-T6 503 150-191copper 1010 305 105-123Table 5.4: Thermal contact resistances for select materials under vacuumconditions.Interface Thermal contact resistance (m2K/W)iron-aluminum 0.00002copper-copper 0.0001aluminum-aluminum 0.00045stainless-stainless 0.005ceramic-ceramic 0.002show a resistivity of below 0.001 m2K/W the simulations will make the con-servative approximation of 0.001 m2K/W as the target contact resistance.5.2.4 Thermomechanical modelling5.2.4.1 Power depositionEnergy deposited by 454 MeV protons within each target component weresimulated using SRIM [108] and results for each target component inMeV/proton are shown in Table 5.5. These values are then used to createpower distribution profiles for each component that incorporate the beam’scurrent and Gaussian profile. A MATLAB script is used to generate theseprofiles and output them as contours that can be imported directly intoANSYS CFX (version 19.0). ANSYS CFX then interpolates between thesecontours to determine the 3-dimensional power deposition distribution foreach target component. Note that the beam is assumed to have a Gaussian122Table 5.5: Energy deposited in thorium target components by 454 MeVprotons.Component MaterialThickness(mm)Energy deposited(MeV/proton)thorium foil thorium 0.25 0.423entrance window Inconel R© 718 0.127 0.21exit window Inconel R© 718 0.127 0.21target frame SS 316 8.51 8.306welding ring SS 316 0.91 1.466shape symmetrical in the x- and y-directions, with beam width specified bythe 2σ-value of the Gaussian. Since beam current and width may changebetween individual IPF irradiations (see Section 5.2.2), multiple beam widthand current values are considered.5.2.4.2 Thermal modellingANSYS CFX simulations were used to model heat transport within the tar-get during irradiation. Power deposition distributions and cooling water flowsimulations were combined to model the thermal response of an irradiatedand cooled target. Radiative heat transfer was excluded from the thermalsimulations and only conductive heat flow was considered.ANSYS CFX simulations used a κ- turbulence model to represent themixed laminar and turbulent flow conditions present inside the target cas-sette. This model does not deal with issues of flow recovery, unconfinedflows, flow separation or flow reattachment. While flow recovery, flow sepa-ration, and flow reattachment were observed in simulations, the flow rate islow enough for these effects to be negligible. Therefore, the κ- turbulencemodel is a robust, stable, and conservative model to use [197].Properties of inlet cooling water flow across the targets were set to 28◦C, and a total flow rate of 0.120 L/s per cassette was used (correspondingto the lowest calculated value for mass flow rate through a given cassette,as detailed in Section 5.2.1). Due to the absence of flow measurements forindividual cassettes, flow sensitivity checks were conducted to determine theeffects of reduced flow on the simulation results.The numerical accuracy of the solutions was determined based on theapproach described by Celik et al [198]. The technique implements theiterative process of decreasing mesh size and solving the simulation until123temperature, heat transfer, and flow changes are negligible between meshchanges. The Grid Convergence Index is then used to estimate the rate ofconvergence of the solution and truncation errors. Based on this standardcheck, the maximum error in the simulated temperature results was 9 K forthe target windows.5.2.4.3 Mechanical modellingTo evaluate potential damage to the target during irradiation, stresses for thethorium foil and target windows were analyzed using a linear stress-strainmodel. Greater importance was placed on the integrity of the windows thatprovide a hermetic seal around the target during irradiation – damage to thethorium foil alone is not considered a target failure. Use of a linear modelreduces computation time but limits the accuracy of results to cases wheresimulated stresses are below the yield stress of the materials. Therefore,when assessing the potential for target failure, the maximum stress in thetarget windows was, conservatively, compared to the yield stress of Inconel R©718.To further reduce computation time, simulations also assumed temper-ature independence of material properties within the target assembly. Thisintroduces an additional limitation: results will only be accurate withintemperature ranges for which critical material properties are constant. Forthe Inconel R© windows – the components critical when evaluating potentialfor target failure – this can be assumed between 0 and 600 ◦C. The mostcritical Inconel R© 718 properties – the ultimate and yield strengths – dras-tically decrease above 600 ◦C . Note that other Inconel R© 718 propertiessuch as Young’s modulus, Poisson’s ratio, and thermal conductivity are alsotemperature dependent, but are mostly constant over the same 0 to 600◦C range. Due to its rare and radioactive nature, similar material propertytemperature-dependence data is challenging to find for thorium.In addition to thermally-induced stresses in the target caused by the pro-ton beam, the target also experiences stresses caused by atmospheric andhydrostatic pressures. Since the thorium is sealed within the sub-assemblyunder vacuum conditions, 0.1 MPa of atmospheric pressure is exerted on theInconel R© windows after the target is removed from the EB welding cham-ber. The windows experience an additional 0.1 MPa (0.2 MPa total) whensubmerged under 8 m of water in the IPF target station during irradiation.In the centre of the target where the windows press against the thorium,this 0.2 MPa of stress is negligible compared to the stress caused by heatduring irradiation (on order of 102 MPa). Higher stresses are experienced124near the edge of the window in the region where it deflects across the edgeof the welding ring. Since accurate modelling of stresses at such boundariesis challenging, tests of the target’s ability to withstand these pressures wereconducted: after the target was placed in a helium pressure chamber at 0.5MPa for 2 hours, no damage was observed. Based on this result, atmosphericand hydrostatic pressures were neglected when modelling the stresses in thethorium target during irradiation.Mechanical simulation boundary conditions were selected on the perime-ter of the thermal loading region to determine conservative worst casestresses. Similar to methods described in Section 5.2.4.2, various iterationsof mesh size and type were completed to determine the grid independenceof the mechanical solution before final simulations were completed.5.2.5 Yield measurementsAfter test irradiations, the thorium foil was dissolved in 10 M HNO3 + 12.5mM HF and evaporated to a thorium nitrate salt before re-dissolution in80.0 mL of 1 M HNO3, in preparation for the radiochemical separation of225Ac from the target (see Chapter 7). A small portion (<100 µL) of theredissolved target was removed and analyzed by gamma ray spectroscopywith a N-type co-axial HPGe gamma spectrometer from Canberra fittedwith a 0.5 mm beryllium window. The detector was calibrated (energy andefficiency) with a 20 mL 133Ba and 152Eu source. The dead time was lessthan 2%. Additional details regarding gamma spectroscopy methods can befound in Section 2.1.The amount of 225Ra produced was quantified using the 40 keV gammaline of 225Ra, while the amount of 225Ac produced was quantified using the218 keV gamma line of 221Fr (see Section 1.2.4).5.3 Results and Discussion5.3.1 Modelling and sensitivity analysisTable 5.6 shows the power deposited by the proton beam in each targetcomponent and the total sum, accounting for different beam shapes andbeam currents. The beam current was varied from 60 µA to 120 µA and thebeam width from 15 mm to 40 mm to cover all realistic cases. While thetotal deposited power scales with the beam current as expected, variationdue to the beam width are 23% for all beam currents. It should be notedthat as the beam width increases, the total power deposited in the thorium125Table 5.6: Energy deposited in thorium target components by 454 MeVprotons.power deposition in target (W)current(µA)width(mm)thoriument.win-dowexitwin-dowweldingringframe total6015 25.42 12.63 12.63 0 0 50.6820 25.28 12.63 12.63 0.01 0.05 50.6125 24.59 12.63 12.63 0.01 0.88 50.7530 23.16 12.63 12.63 0.17 4.06 52.6435 21.21 12.63 12.63 0.27 10.04 56.7840 19.08 12.61 12.62 0.35 17.63 62.298015 33.89 16.84 16.84 0 0 67.5720 33.71 16.84 16.84 0.02 0.07 67.4825 32.79 16.84 16.84 0.02 1.18 67.6730 30.88 16.84 16.84 0.22 5.41 70.1935 28.28 16.84 16.84 0.36 13.39 75.740 25.44 16.82 16.83 0.46 23.5 83.0510015 42.36 21.05 21.05 0 0 84.4620 42.14 21.05 21.05 0.02 0.09 84.3525 40.99 21.05 21.05 0.02 1.47 84.5830 38.6 21.05 21.05 0.28 6.77 87.7435 35.36 21.05 21.05 0.45 16.74 94.6340 31.8 21.02 21.04 0.58 29.38 103.8212015 50.83 25.26 25.26 0 0 101.3520 50.57 25.26 25.26 0.03 0.11 101.2225 49.19 25.26 25.26 0.03 1.77 101.530 46.32 25.26 25.26 0.33 8.12 105.2935 42.43 25.25 25.25 0.53 20.08 113.5540 38.16 25.22 25.25 0.69 35.26 124.58126foil decreases since some of the proton beam is, undesirably, no longer hittingthe thorium but hits the welding ring and frame instead. As an example,the resulting temperature and thermally induced stress for a 100 µA, 20 mmbeam are shown in Fig. 5.4, along with the cooling water flow profiles for a0.12 L/s cassette flow. The maximum temperature and stress in the windowfollow roughly the beam shape.To summarize, thermal results determined by ANSYS CFX for all beamparameters considered, are shown in Figure 5.5. Similarly, the resultingmaximal stresses on the thorium foil and Inconel R© windows are shown inFigure 5.6. As expected, increases in beam current and decreases in beamwidth result in higher maximum temperatures and stresses on the targetwindows. However, using safety factors defined relative to each material’syield strength, it can be seen that all beams of width >20 mm and <100µA result in safety factors on the target window >1. Window temperaturesalso remain within the region of accuracy (<600 ◦C) as defined in Section5.2.4.3. These limits are well within the range of typical beam parametersat IPF (Section 5.2.2), meaning that 225Ac production at IPF can occurdownstream of experimental users without any alterations to the beam orimpact to other users of the beamline.Some of the assumptions and input parameters to the thermomechan-ical simulations were simplified in order to reduce computation time. Thetemperature-independence of material properties, the linear stress-straincurves used for each material, and the mechanical simulation boundary con-ditions on the windows are examples that limit the accuracy of the simu-lations. However, these are balanced by conservative assumptions such asthe thermal contact resistance value used for the thorium-inconel interface.Combined with conservative stress limits on the hermetic seal of the target(relative to the yield stress of Inconel R© 718 as opposed to the much higherultimate stress), these assumptions provide confidence that these targets canbe irradiated safely under the simulated conditions.To test the sensitivity of the window and thorium foil temperature onthe achieved thermal contact resistance between the thorium foil and thewindow, simulations were carried out varying the resistance from 0.0005m2K/W to 0.003 m2K/W. The window temperature, cooled by the coolingwater, is almost unaffected even for a heat transfer resistance underestimatedby a factor of three. The thorium foil temperature, however, raises from 442K to 506 K, potentially causing damage to the thorium foil.Similarly, we varied the water flow in the cassette holding the targetsfrom the nominal 0.12 kg/s down to 0.006 kg/s. Although the temperaturesof both the window and the thorium foil increase, even at a 95% reduction127Figure 5.4: a) Example of simulated flow streamlines and temperatures; andb) stresses in the target entrance window for a 100 µA, 20 mm beam.Figure 5.5: Maximum simulated temperatures within target window (left)and thorium foil (right) components during irradiations of varying beamcurrent and width.128Figure 5.6: Maximum simulated stresses resulting from temperatures withinwindow (left) and thorium (right) target components during irradiations.Note that increase in thorium foil stresses as beam width increases (from 15to 25 mm) is due to deposition of heat in regions of the thorium that arenot in contact with the window.in water flow, the temperatures only increases by less than 15%. Note that azero flow situation is interlocked by the target thermocouples, which wouldtrip off the proton beam in the absence of cooling water flow.5.3.2 Test irradiationsTwo irradiations of this target design have been completed to date. Bothtargets were irradiated for 36.5 hours with an average beam current of 72.5µA. Beam width was between 28-32 mm in the vertical and 30-35 mm inthe horizontal directions.After allowing targets to decay for 7 days, the thorium foil was removedfrom the target. In both cases, no damage, warping, or significant discol-oration of the foil was observed.The amount of 225Ac and 225Ra produced were measured via gammaspectroscopy. The decay corrected activity at EOB (average ± standarddeviation) was (524 ± 21) MBq (14.2 mCi) and (86 ± 13) MBq (2.3 mCi)for 225Ac and 225Ra , respectively. These correspond to saturation yields of72.5 MBq/µA for 225Ac and 17.6 MBq/µA for 225Ra.While the 225Ac quantities produced so far may be modest, significantscaleability exists for 225Ac production at TRIUMF’s IPF. An increase in129irradiation time to a full 225Ac half-life (9.9 days), would increase productionby a factor of at least 8. The simultaneous irradiation of 12 targets is alsopossible. Combined, these two factors alone suggest 225Ac production at IPFcould be readily scaled to at least 42 GBq (1.1 Ci) every 10 days, withoutrequiring changes to the beam parameters or target design. Further increasesin 225Ac and 225Ra yields could theoretically be achieved by increasing theproton beam current or the thickness of the 0.25 mm thick thorium foil(IPF targets can accommodate targets up to 8 mm thick), however, thesewould require a reassessment of the safety of such an irradiation – using themethodology presented herein – and a potential redesign of the target toprevent target failure.The saturation yields for a 12-target irradiation would increase to 870MBq/µA and 211 MBq/µA for 225Ac and 225Ra, respectively. Previous stud-ies by others for the production of 225Ac via 232Th spallation have reported225Ac saturation yields of 444 MBq/µA at 90 MeV and 1140 MBq/µA at192 MeV [138, 142]. However, these studies do not report yields for 225Raproduction, which is known to be smaller at the reported energies of irra-diation [118, 130, 144]. The 225Ra produced has the potential to not onlyprovide approximately 0.8 MBq of 225Ac per 1 MBq of 225Ra [1], but alsoto provide generator-produced 225Ac with significantly reduced 227Ac im-purities, a long-lived (t1/2 = 21.8 y) alpha-emitting radioisotope with lowregulatory restrictions on waste disposal and accidental intake [2].5.4 SummaryA target system for accelerator-based production of 225Ac from thoriummetal at TRIUMF was presented and discussed. The thermomechanicalresponse of the target to irradiation by the proton beam was thoroughlyevaluated against conservative thresholds for target safety and the targetwas found to be compatible with the existing beam typically received at theirradiation facility.The target system was tested in two irradiations with 72 µA of 450 MeVprotons. After removal from the beam neither the target windows nor thethorium foil showed signs of warping, discoloration or any other signs ofexcessive heat or mechanical stress. With this system (524 ± 21) MBq of225Ac (14.2 mCi) and (86± 13) MBq of 225Ra (2.3 mCi) was produced withina 36 hour irradiation, corresponding to saturation yields of 72.5 MBq/µAfor 225Ac and 17.6 MBq/µA for 225Ra. It is estimated that the simultaneousirradiation of 12 targets over a 240 hour period could produce 42 GBq of130225Ac and 7 GBq of 225Ra without requiring any changes to the target orbeam parameters – further scaleability exists if these parameters would alsobe changed.1316 Measured and Simulated232Th(p,x) Cross Sections6.1 BackgroundNuclear formation cross section data provides valuable information for val-idating nuclear physics models or predicting the amount of a radionuclideproduced during an irradiation, which may have scientific, economic, orsafety-related consequences. For complex geometries, high-energy irradia-tions with multiple reaction pathways, or in the absences of cross sectiondata for a given activation product, incident particle energy, or target mate-rial, high-energy transport codes are often used to estimate residual nuclideproduction. Such codes combine various physics models with Monte Carlomethods to simulate the interactions of primary and secondary particleswith targets and surrounding materials during an irradiation. Experimentalresults are essential for validating such codes for a given application.Fluka is one such high-energy transport code with applications in ra-diation shielding and facility design, dosimetry, detector and target design,medicine, and radionuclide production [128, 129]. A number of publicationshave demonstrated the accuracy of the results that Fluka can provide insuch applications [150–159]. One such application is the production of 225Ac,a nuclide of currently heightened interest for use in targeted alpha therapyof metastatic disease [15–21, 25, 31, 32].Most of the ∼63 GBq global annual 225Ac supply comes from the decayof 229Th (t1/2 = 7600 y) generators, decaying through the225Ac parent iso-tope, 225Ra (t1/2 = 14.9 d) [1, 33, 35, 49, 103–105]. However, such225Acgenerators are not abundant and the limited 225Ac supply has resulted inmany recent efforts to increase 225Ac production via particle accelerators– most notably those of the US Department of Energy’s Isotope Program[101, 104, 135, 138–140, 142, 199]. Of potential alternative accelerator-based225Ac-production methods, the proton-induced spallation of thorium at TRI-132UMF’s 500 MeV Isotope Production Facility also has potential to producesignificant quantities of 225Ac [1, 5].Irradiating materials with high-energy hadrons produces a plethora ofradionuclides that must be considered when the production of a specificnuclide is concerned, and the case of as 225Ac production from thoriumspallation is no exception. In addition to 225Ac itself, other Ac isotopes mustalso be considered as they cannot be chemically separated from the final225Ac product. Of particular concern is 227Ac, which has a high radiotoxicityand 21.8 year half-life. 225Ra production is also a radionuclide of interest, asit can be used to make spallation-produced 225Ac with reduced 227Ac content[2, 200]. Other spallation and fission products resulting from the irradiationmust also be considered, since their quantities may dictate the associatedsafety, licensing, or transport regulations related to 225Ac production.This Chapter presents 38 cross section measurements relevant to 225Acproduction from the 438 MeV proton spallation of thorium. This selection ofavailable data is compared to Fluka simulations that estimate the produc-tion of the hundreds of co-produced nuclides. While other publications havereported cross sections for proton irradiation of thorium below 200 MeV andat 800 MeV [135, 138–140], to the best of my knowledge, the results reportedherein are the first cross section measurements of thorium spallation near438 MeV. Relevant concepts for nuclide production and cross sections areprovided in Section 1.3.3.6.2 Materials and Methods6.2.1 Basic definitions and equationsThe production of a radionuclide during the proton irradiation of a targetmaterial is described by the differential equationdNdt= φ− λNdt (6.1)which has the general solutionA(t) = φ+ Ce−λt (6.2)where φ is the constant production rate of the radionuclide decaying withdecay constant λ and having a quantity of N nuclei or a radioactivity of A =λN at a given time t during the irradiation. The constant C is determinedby A(t = 0).133For a given irradiation, the amount of radioactivity at the end of bom-bardment (EOB) is described byA0 = φF (t) (6.3)where the time function F (t) describes the nuclide’s decay during irra-diation, the irradiation profile, and A(t = 0). In the most simple case of acontinuous irradiation of duration ∆t and A(t = 0) = 0, F (t) = 1 − e−λ∆tandA0 = φ(1− e−λ∆t) (6.4)The production rate φ = σNTΦ depends on the number of target nuclei,NT , the proton flux, Φ, and the energy dependent formation cross section,σ(E), which is characteristic of both the target and product nuclei.If A0 is determined, and if NT and Φ are also well known, cross sectionscan then be calculated from Equation 6.4.However, radionuclides are often produced both directly (described bythe independent cross section σi) and indirectly after the decay of precursornuclei co-produced during the irradiation (described by the cumulative crosssection σc). For a daughter nuclide (d) with immediate precursor (parent)nuclei (p1, p2, ..., pn), these cross sections are related byσcd = σid +n∑i=1νiσcpi (6.5)where νi is the branching ratio with which parent pi decays directly to (d)or (pi−1).When a radionuclide has no precursors, σi and σc are equivalent. Sim-ilarly, the contributions of individual parents to σcd can be neglected if theparent is not produced during the irradiation or if νiσcpi σid.One can also define the total mass cross section, which is the sum ofindependent cross sections for a given mass number. This value, also referredto as the total mass yield, is often used when comparing different nuclearphysics models.These definitions of σi and σc, as well as many of the equations belowfollow from the formulism presented by Titarenko et al. and used in similarpublications [135, 201, 202]. Though conceptually similar to these publica-tions, equations herein are presented differently due to differences in howA0 is measured. Additional considerations are also presented later in thistext for non-continuous irradiations and nuclei with multiple parents. The134latter must especially be considered for high Z (>83) targets such as tho-rium, which produce alpha-decaying nuclei and where product nuclei canhave three or more parents with half-lives differing by orders of magnitude(ex. 225Ac, 224Ra).As similarly described by Titarenko et al., when measuring cross sectionsby the thin target activation method, two general situations arise dependingon whether or not parent nuclei are present at the time of measurement.Given an activity A measured at time tm after EOB, a nuclide withoutprecursors or with all its precursors decayed will decay with a pure expo-nential. In these situations, A0 is determined byA0 = Aeλtm (6.6)Equating Equations 6.4 and 6.6 determines the cross section from themeasured value A and known values of Φ and NT . However, unless thenuclide has no precursors, only σc is measurable since one cannot accountfor contributions from precursor decay. We consider a parent to have fullydecayed after 10 half-lives (i.e. tm > 10 ln 2/λpi)9.If a nuclide’s precursor(s) have not fully decayed by tm, parent contri-butions to the measured nuclide’s decay rate must be accounted for whendetermining A0. For a parent whose own precursors have decayed by tm,the daughter activity at EOB, A0 ≡ D0 can be determined from the mea-sured daughter activity, D, and measured parent activity, P , by replacingEquation 6.6 with:D0 = Deλdtm − νPλdλd − λp(eλdtmeλptm− 1)(6.7)Furthermore, Equation 6.4 must also be modified if ∆t is not shortenough (compared to the parent and daughter half-lives) for parent-daughtercontributions during irradiation to be neglected. In such a situation, theamount of the parent remains described by Equations 6.1 and 6.4, while thedaughter is described during the irradiation bydNddt= νλpNp + φd − λdNd (6.8)which has the general solution9One should also ensure that after 10 parent half-lives, the amount of parent remainingis negligible compared to the amount of the daughter being measured. If the parent is notmeasurable, this can be checked using Fluka, which are at least accurate to an order ofmagnitude.135D0 = νφp − νλdφpλd − λp e−λp∆t + φd + Ce−λd∆t (6.9)For D(t = 0) = P (t = 0) = 0, D0 at EOB is thus given byD0 = νφp(1 +( λdλd − λp − 1)e−λd∆t− λdλd − λp e−λp∆t)+ φd(1− e−λd∆t)(6.10)Combining Equations 6.7 and 6.10 with σi,cp determined from equations6.4 and 6.6, allows one to determine σid. The determination of σcd thenfollows from Equation 6.5.When λp > λd, this approach is limited in situations where a parentcontributes significantly to daughter production between EOB and tm, re-sulting in an erroneously high measurement of the cross section. Titarenkoet al. defines these as supracumulative cross sections, denoted σc∗[201, 202].The maximum possible relative difference between σc∗and σc is given byσc∗ − σcσc∗≤ λdλp − λd (6.11)This difference is always positive since λp > λd. Equation 6.11 impliesthat the errors in the measurement of σc introduced by the supracumulativeeffects can be quite high. However, reported results often do not distinguishbetween σc and σc∗[201–203]. In such situations, care should be taken totry and account for parent decay between EOB and tm or avoid reportingof the cross section altogether. The latter approach is taken in this work:the maximum potential error introduced herein to σc measurements, as de-termined by Equation 6.11 is <3.5% for 224Ra and 127Sb and <1.5% for allother nuclides.A third situation can occur which must also be considered, where anactivation product has multiple parents, only one of which is fully decayed bytm. This is common for alpha-emitting nuclides produced from high Z (>83)targets such as thorium, notably including the three nuclides most relevantfor 225Ac production from 232Th irradiation: 225Ac, 225Ra, and 227Ac. Insuch situations the measured cross section is clearly not independent sinceindirect production through one parent is included. However, it may neitherbe fully cumulative with respect to all parent contributions.136When possible, the cross section – cumulative only with respect to theparent that has decayed by tm – is determined from Equations 6.7 and 6.10as previously described, along with the cumulative cross section for the stillexisting parent. The fully cumulative cross section for the daughter is thendetermined using Equation 6.5. If the existing parent’s cross section cannotbe determined or its contribution to the daughter’s production neglected, σcfor the daughter nuclide cannot be determined. Exceptions to this rule aremade when the existing parent’s contribution to the daughter nuclide’s pro-duction occurs over an long timescale that is irrelevant for most applications(i.e. decades or millennia)10. While this determines a σc value relevant forpractical applications and is similarly done by many other publications, itshould be noted that this results in an underestimate of the true σc values asdetermined by Equation 6.5. Specific examples are provided Section 6.2.6.6.2.2 Accounting for non-continuous irradiationsThe non-continuous nature of the irradiation described in Section 6.2.3 re-quires that the time function of Equation 6.4 be modified to account for themultiple “beam-on” intervals separated by multiple “beam-off” intervals.Assuming, as was the case, that all beam-on intervals use the sameproton flux, we consider the situation where the target is irradiated withthree beam-on intervals, ∆t1, ∆t3, and ∆t5, separated by beam-off intervals∆t2 and ∆t4.At time t1 = ∆t1, a nuclides activity is described byA(t1) = φ(1− e−λ∆t1) (6.12)which is identical to Equation 6.4. By the end of the first beam-off intervalat time t2 = ∆t1 + ∆t2, the activity will have decayed toA(t2) = A(t1)e−λ∆t2 (6.13)Production after the second beam-on interval, at time t3 = ∆t1 + ∆t2 +∆t3, will be described by Equation 6.2, where the constant, C, is determinedby the amount of activity at t2 to be C = φ−A(t2), therefore,A(t3) = φ−(φ−A(t2))e−λ∆t3 (6.14)In a similar manner, the activity at times t4 = ∆t1 + ∆t2 + ∆t3 + ∆t4and t5 = t4 + ∆t5 is described by10Distinctions between such semi-cumulative cross sections and fully cumulative crosssections do not appear to be made in the literature, including the EXFOR database [203].137A(t4) = A(t3)eλ∆t4 (6.15)andA(t5) = φ−(φ−A(t4))e−λ∆t5 (6.16)Combined, Equations 6.12 to 6.16 determine the activity at the end ofthe full irradiation profile, which simplifies toA0 = φ(1−[1−(1− [1− (1− e−λ∆t1)e−λ∆t2]e−λ∆t3)e−λ∆t4]e−λ∆t5)(6.17)The differences to Equation 6.4 introduced by the modified time function(Equation 6.17) can be significant if the nuclide’s half-life is much longerlived than any of the beam-on or beam-off intervals. For example, 226Ac(t1/2 = 29.37 h) production is reduced by 41% when the correct time functionis used (instead of Equation 6.4) to describe the irradiation in Section 6.2.3.In contrast, 227Ac (t1/2 = 21.8 y) is reduced by <0.01%.If parent-daughter corrections are required during irradiation, themethodology in this appendix can also be used to modify the time func-tion of Equation 6.10.6.2.3 Thorium irradiationsCross section data reported in this Chapter was derived from a 2018 irra-diation conducted during the development of TRIUMF’s 225Ac productionprogram [1, 2, 164, 200]. The thorium target consisted of a (0.25 ± 0.01)mm thick, (60.0 ± 0.1) mm diameter thorium-232 metal foil (>99.95% pu-rity, as determined by ICP-MS) hermetically sealed within a (127 ± 6) µmthick Inconel 600 capsule. The use of the Inconel capsule ensures that anyvolatile or gaseous radionuclides produced in the thorium are not releasedinto the cooling water in which the targets are submerged during irradia-tion. Furhter details of the thorium target design are described in Chapter5 and have been reported elsewhere [5]. At 438 MeV the target is “thin”,with <0.5 MeV proton energy lost over the foil thickness. As described inSection 6.2.5, the thin foil of the Inconel capsule can also be used as a beammonitor.The irradiation was conducted at TRIUMF’s 500 MeV Isotope Produc-tion Facility (IPF), located immediately in front of the TRIUMF cyclotron’s138main beam dump [5, 191]. A detailed description of the IPF can be found inChapter 5. The 500 MeV cyclotron currently operates at a typical extrac-tion energy of 480 MeV, which is reduced to 454 MeV at IPF after passingthrough upstream muon production targets. The 454 MeV protons enteringthe IPF are further reduced to (438 ± 2) MeV at the location of the tho-rium foil after passing through target station components and cooling water.Measurements of the beam profile (approximately 1 m from the target) andcurrent (approximately 10 m from the target) indicated an 65.2 µA Gaus-sian beam with full width at half max (FWHM) of 2.5 cm and 3.2 cm in thehorizontal and vertical directions, respectively. The target was irradiatedover the course of 72.9 hours to a nominal integrated current of 2640 µA*h(total beam-on time of 40.5 h) with the aim of producing approximately 555MBq (15 mCi) of 225Ac. Note that Equations 6.4 and 6.10 must be modi-fied to account for the non-continuous nature of the irradiation (see Section6.2.2).After a 7-day cool-down period, the target was removed from the IPFand transferred to a radiochemistry lab where is was processed for 225Acextraction [200]. This 7-day decay period unfortunately limits the measure-ment of activation products to nuclides with half-lives on the order of 1 dayor longer.6.2.4 Gamma spectra acquisition and analysisAfter removal from the target, the thorium foil was dissolved in 10 M HNO3+ 12.5 mM HF, slowly evaporated to a dry thorium nitrate salt, and re-dissolved in a final (86.0 ± 0.2) mL volume of 1 M HNO3. Aliquots ofthis solution were removed and analyzed by gamma ray spectroscopy. Thepreparation of gamma spectroscopy samples by dissolving the thorium wasnecessary to reduce radiation fields emanating from the samples, but un-fortunately limits the analysis to non-volatile elements that are stable inaqueous solution (noble gases and halogens are excluded).The detector used was a N-type co-axial HPGe gamma spectrometerfrom Canberra fitted with a 0.5 mm beryllium window. The detector’s en-ergy, width, and efficiency calibrations were performed using a 152Eu and133Ba source. The geometry of the calibration source and all samples con-sisted of a 20.0 mL dilute HNO3 solution in a scintillation vial positionedat a distance from the detector beyond which cascade-summing effects wereshown to be negligible. More details regarding the gamma spectroscopymethods can be found in Section 2.1.Spectra (dead time <0.6%) were acquired multiple times over a period 7139to 269 days after the end of irradiation, with different nuclides better quanti-fied at different time points depending on the half-life. The resulting spectra(example in Figure 1) were extremely complex – containing on the order of102 often-overlapping lines – and were therefore analyzed using the Genie2000 software package (version 3.4, Canberra Industries). Gaussian curveswere fitted by the user to all peaks (using the Genie 2000 Interactive PeakFitting Tool) and compared against a gamma ray library representing thetop 102 non-volatile, non-gaseous, gamma-emitting radionuclides estimatedby FLUKA to be in the sample at the time of measurement. Only fittedpeaks with >95% significance and a FWHM within 20% of the calibratedpeak width were accepted. Decay correction during data acquisition wasapplied within Genie 2000 and is not included in the equations defined inSection 6.2.1.0 200 400 600 800 1000 1200 1400 1600 1800 2000HQHUJ\>NH9@101102103104105FRXQWV 226Ac 230 keV203Pb 279 keV233Pa 312 keV 225Acd 440 keV103Ru 497 keV 99Mo 740 keV 206Bi 803 keV 206Bi 881 keV223Rad 832 keV 206Po 1032 keV136Cs 1048 keV 206Bi 1719 keV205Bi 1764 keVFigure 6.1: Gamma spectrum acquired of the irradiated thorium sample,7.3 days after EOB, with select gamma lines from Table 6.1 labelled.To prevent erroneous nuclide identification or quantification, the follow-ing acceptance criteria were used for the gamma spectroscopy results:• Multiple gamma lines for an individual nuclide, each providing consis-tent individual measurements of the total radioactivity were required.The interference-corrected weighted mean of these results, as deter-mined by Genie 2000, is then used to quantify the total radioactivityat the time of measurement.• For nuclides providing only a single gamma ray line suitable for quan-tification, measurements at multiple time points were conducted toensure the gamma line was decaying with the expected half-life.Additional care was taken to ensure that gamma lines used for differentnuclides in the library were sufficiently separated (>0.5 FWHM) to avoidfalse identification of a nuclide, especially with respect to mirror nuclei suchas 111In and 111Ag.140Due to its important role in 225Ac production, special attention wasgiven to the quantification of 225Ra. Due to the high slope of the efficiencycurve in the low energy region (<100 keV), 225Ra is challenging to accuratelyquantify via its single 40.0 keV emission, even when it is the only nuclide inthe spectrum. Comparison of 225Ra measurements at 40.0 keV (using a pure225Ra sample produced at TRIUMF’s ISOL facility [3, 164]) to the measuredgrow-in of 221Fr (218 keV) and 213Bi (440 keV) was used to validate theefficiency calibration at 40.0 keV. Still, in the presence of all other thoriumtarget activation production, 225Ra detection becomes impossible due to theamount of low energy emissions (<100 keV) and scatter produced by othernuclides. Chemical separation of the dissolved thorium target was thereforeperformed before 225Ra was measured using previously reported separationschemes [200]; the more easily detectable 223Ra isotope was used to accountfor Ra losses during the process. The the amount of 225Ra measured wasthen confirmed by monitoring the grow-in of 225Ac.Table 6.1 lists all 47 nuclides that were quantified from the gamma rayspectra, including all lines used for quantification. Section 6.2.6 describeshow these values were used to determine cross sections for 38 of these nu-clides.6.2.5 Monitor reactionsThe (127 ± 6) µm thick Inconel 600 foil used to hermetically seal the thoriumduring irradiation was also used to measure the proton flux. While they arenon-standard monitor reactions [204], nickel spallation products from thisnickel-chromium-iron alloy serve as a readily accessible beam monitor with-out requiring modification of the target design to accommodate additionalmonitor foils. The NatNi(p,x)56Co, NatNi(p,x)57Co, and NatNi(p,x)60Co re-actions were chosen since these activation products have negligible interfer-ence from other target elements in the Inconel and are long-lived enoughto be measured once the foil could be safely handled. Cumulative crosssections (37.15 ± 2.51) mb, (66.70 ± 5.69) mb, and (1.97 ± 0.30) mb for56Co, 57Co, and 60Co, respectively, were interpolated from available EXFORdata [144]. Table 6.2 shows the amount of these products at EOB, as mea-sured by gamma spectroscopy (Section 6.2.4) at 270 d after EOB, and thecorresponding current estimate derived using Equation 6.4. The weightedmean current estimate, (70.3 ± 4.4) µA, is larger than the nominal expectedcurrent (Section 6.2.3), 65.2 µA.141Table 6.1: Gamma spectroscopy data derived from analysis of the irradiation thorium samples,including the time of measurement (tm) since end of irradiation, all gamma lines used in theanalysis, and total radioactivity A in the entire thorium foil at the time of measurement.nuclide t1/2 [d] tm [d]energy[keV]activity [Bq]interference-correctedweighted mean [Bq]233Pa 27.0 46.3311.90 (3.766 ± 0.168) x 108(3.907 ± 0.168) x 108340.48 (4.118 ± 0.193) x 108415.76 (4.234 ± 0.257) x 108230Pa 17.4 46.3454.92 (5.102 ± 1.154) x 106(6.114 ± 0.512) x 106951.88 (6.299 ± 0.550) x 106228Thd 698.5 127.4238.63 (1.875 ± 0.100) x 107(1.882 ± 0.093) x 107240.99 (1.800 ± 0.389) x 107583.19 (1.902 ± 0.125) x 107727.33 (1.818 ± 0.284) x 107228Rad 2098.8 269.4338.02 (4.365 ± 0.820) x 105(3.106 ± 0.287) x 105911.02 (2.742 ± 0.341) x 105968.97 (4.104 ± 0.479) x 105227Th 18.7 7.3235.96 (2.348 ± 0.230) x 108(2.310 ± 0.176) x 108256.23 (2.273 ± 0.229) x 108227Acd 7946.8 269.4351.07 (8.362 ± 0.802) x 105(8.468 ± 0.506) x 105401.81 (1.033 ± 0.179) x 106404.85 (9.283 ± 2.696) x 105226Ac 1.2 7.3185.60 (2.637 ± 1.323) x 107(3.283 ± 0.268) x 107230.00 (3.317 ± 0.278) x 107253.50 (3.015 ± 1.382) x 107142225Ra 14.9 7.3 40.00 (7.173 ± 0.430) x 107 (7.173 ± 0.430) x 107225Acd 9.9 7.3218.00 (3.347 ± 0.167) x 108(3.354 ± 0.149) x 108440.45 (3.357 ± 0.155) x 108224Rad 3.7 7.3238.63 (3.168 ± 0.153) x 108(3.166 ± 0.139) x 108240.99 (3.033 ± 0.159) x 108583.19 (3.289 ± 0.164) x 108223Rad 11.4 7.3269.46 (2.010 ± 0.105) x 108(2.157 ± 0.094) x 108271.23 (2.419 ± 0.099) x 108351.07 (2.156 ± 0.126) x 108401.81 (2.179 ± 0.181) x 108404.85 (2.427 ± 0.100) x 108427.08 (2.415 ± 0.307) x 108832.01 (1.931 ± 0.301) x 108207Bi 11515.8 269.4569.70 (8.099 ± 0.412) x 105(7.200 ± 0.353) x 1051063.66 (5.526 ± 0.417) x 105206Bi 6.2 7.3183.98 (3.287 ± 0.181) x 108(2.662 ± 0.114) x 108516.18 (2.486 ± 0.124) x 108803.10 (2.577 ± 0.127) x 108881.01 (2.786 ± 0.135) x 108895.12 (2.710 ± 0.134) x 1081718.70 (2.635 ± 0.447) x 108206Po 8.8 7.3522.47 (3.393 ± 0.190) x 108(2.953 ± 0.132) x 108807.38 (2.998 ± 0.160) x 108980.23 (2.800 ± 0.159) x 1081007.15 (2.520 ± 0.213) x 1081431032.26 (2.904 ± 0.129) x 108205Bi 15.3 7.3703.45 (1.027 ± 0.054) x 108(1.039 ± 0.050) x 108987.66 (1.052 ± 0.060) x 1081764.30 (1.113 ± 0.226) x 108203Pb 2.2 7.3279.20 (4.019 ± 0.189) x 107(4.019 ± 0.189) x 107401.32 (4.043 ± 1.679) x 107201Tl 3.0 7.3135.34 (5.016 ± 1.728) x 107(3.207 ± 0.480) x 107167.43 (3.006 ± 0.495) x 107144Ce 284.9 269.4 133.51 (3.077 ± 1.261) x 106 (3.077 ± 0.174) x 106141Ce 32.5 127.4 145.44 (6.379 ± 0.401) x 106 (6.379 ± 0.401) x 106140Bad 12.8 7.3487.02 (1.298 ± 0.064) x 108(1.336 ± 0.061) x 108815.77 (1.411 ± 0.074) x 108925.19 (1.286 ± 0.101) x 108139Ce 137.6 127.4 165.86 (4.052 ± 0.472) x 106 (4.052 ± 0.472) x 106136Cs 13.0 7.3273.65 (5.259 ± 0.390) x 107(5.825 ± 0.269) x 107818.51 (5.942 ± 0.287) x 1071048.07 (5.740 ± 0.342) x 107134Cs 753.8 46.3604.72 (1.936 ± 0.186) x 106(1.968 ± 0.153) x 106795.86 (2.016 ± 0.222) x 106132Ted 3.2 7.3228.16 (5.891 ± 0.347) x 107(5.993 ± 0.266) x 107772.60 (5.862 ± 0.311) x 107954.55 (6.192 ± 0.449) x 107131Ba 11.5 7.3123.80 (3.014 ± 0.206) x 107(2.807 ± 0.184) x 107373.26 (3.283 ± 0.462) x 107127Sb 3.9 7.3252.40 (1.168 ± 0.113) x 108(1.096 ± 0.051) x 108144473.00 (1.058 ± 0.086) x 108126Sb 12.4 46.3414.70 (1.285 ± 0.117) x 107(1.309 ± 0.064) x 107720.70 (1.338 ± 0.099) x 107856.80 (1.171 ± 0.120) x 107125Sn 9.6 7.3822.48 (8.590 ± 2.558) x 107(6.190 ± 0.679) x 1071067.10 (6.109 ± 0.762) x 1071089.15 (5.274 ± 1.599) x 1072002.13 (9.867 ± 5.005) x 107125Sb 1006.9 269.4380.45 (3.692 ± 0.673) x 106(3.496 ± 0.150) x 106427.87 (3.585 ± 0.163) x 106463.36 (3.429 ± 0.199) x 106600.60 (3.441 ± 0.192) x 106606.71 (3.480 ± 0.349) x 106124Sb 60.2 46.3713.78 (3.604 ± 0.887) x 107(3.989 ± 0.452) x 107968.20 (4.553 ± 0.875) x 1071690.97 (3.899 ± 0.604) x 107122Sb 2.7 7.3564.24 (1.174 ± 0.048) x 108(1.166 ± 0.058) x 108692.65 (8.912 ± 2.009) x 107121mTed 164.2 269.4212.19 (1.723 ± 0.083) x 106(1.827 ± 0.082) x 106507.39 (2.394 ± 0.179) x 106573.13 (1.965 ± 0.110) x 1061102.15 (1.804 ± 0.399) x 106121Te 19.2 46.3507.59 (1.008 ± 0.145) x 107(9.589 ± 0.722) x 106573.14 (9.727 ± 0.817) x 106120mSb 5.8 46.3197.30 (1.861 ± 0.227) x 106(1.409 ± 0.129) x 1061023.30 (1.127 ± 0.212) x 1061451171.70 (1.293 ± 0.192) x 106115Cd 2.2 7.3260.90 (2.671 ± 0.293) x 108(2.488 ± 0.121) x 108492.35 (2.445 ± 0.147) x 108527.90 (2.497 ± 0.134) x 108114mIn 49.5 127.4 190.27 (6.353 ± 0.856) x 106 (6.353 ± 0.856) x 106111Ag 7.5 46.3245.40 (3.603 ± 0.850) x 107(3.671 ± 0.380) x 107342.13 (3.685 ± 0.413) x 107111In 2.8 7.3 171.28 (1.043 ± 0.072) x 107 (1.043 ± 0.072) x 107110mAg 249.8 46.3657.76 (1.022 ± 0.058) x 107(9.648 ± 0.494) x 106677.62 (9.569 ± 1.783) x 106706.68 (8.791 ± 1.203) x 1061384.29 (8.928 ± 0.618 x 106106Rud 371.8 269.4 621.93 (2.300 ± 0.127) x 107 (2.300 ± 0.127) x 107105Rh 1.5 7.3306.10 (3.389 ± 0.164) x 108(2.015 ± 0.093) x 108318.90 (1.969 ± 0.091) x 108103Ru 39.2 46.3497.08 (2.330 ± 0.113) x 108(2.295 ± 0.106) x 108610.33 (2.231 ± 0.123) x 10899Mo 2.7 7.3181.07 (5.140 ± 0.283) x 108(5.236 ± 0.244) x 108366.42 (5.101 ± 0.622) x 108739.50 (5.306 ± 0.265) x 10895Zr 64.0 46.3724.19 (1.074 ± 0.054) x 108(1.011 ± 0.046) x 108756.72 (9.783 ± 0.481) x 10795Nb 35.0 46.3 765.80 (1.168 ± 0.057) x 108 (1.168 ± 0.057) x 10888Y 106.6 127.4898.04 (2.950 ± 0.217) x 106(2.963 ± 0.215) x 1061836.06 (4.335 ± 1.030) x 10683Rb 86.2 269.4529.59 (5.463 ± 0.577) x 105(5.624 ± 0.520) x 105146552.55 (4.018 ± 0.994) x 105dSome or all gamma lines used for quantification belong to progeny nuclides in equilibrium.Table 6.2: Results from gamma spectroscopy measurements of the Inconel foil used for beammonitor reaction and the resulting proton current estimates.nuclidet1/2[d]energy[keV]activity [Bq] mean activity [Bq] σ [mb]currentestimate [µA]60Co 1924.01173.2 (5.112 ± 0.134) x 105(5.069 ± 0.114) x 105 37.15 ± 2.51 66.6 ± 5.91332.5 (4.993 ± 0.166) x 10557Co 271.8122.1 (9.829 ± 0.355) x 108(1.012 ± 0.026) x 108 66.70 ± 5.69 72.1 ± 7.5136.5 (1.033 ± 0.034) x 108692.4 (1.044 ± 0.082) x 10856Co 77.2846.8 (1.829 ± 0.046) x 108(1.834 ± 0.032) x 108 1.97 ± 0.30 84.0 ± 13.71037.8 (1.838 ± 0.042) x 1081238.3 (1.835 ± 0.042) x 1081476.2.6 Cross sections calculations and uncertaintiesGiven the measured activities of activation products (Section 6.2.4), crosssections are determined by equating either Equations 6.4 and 6.6 or Equa-tions 6.7 and 6.10. The choice of equations depends on whether or not thenuclide in question can be described as having all its precursors decayed atthe time of measurement.Independent cross sections, σi are determined from Equations 6.4 and6.6 for nuclides that have no precursors. Typically, these are excited statessuch as 121mTe, 120mSb, 114mIn, or 110mAg, but it also applies to 230Pa. Thiscase also applies if νσcp σid such that σid ∼= σcd; an example is 226Ac, whoseparent 230Pa has a 0.003% alpha decay.If the nuclide in question has precursors which have decayed by tm, thenEquations 6.4 and 6.6 combine to determine the cumulative cross section,σc. The majority of cross sections reported herein fall into this category;examples include 228Ra, 141Ce, and 99Mo, among others.If a nuclide’s parent is still present at tm, then the parent nuclide’scontribution to the daughter’s production must either be accounted for orneglected, if justifiable. Examples of the latter are 136Cs and 126Sb, whichhave very long-lived parent nuclei (t1/2 > 105 y) which will not be producedwith enough activity to significantly affect their daughter’s decay curves.While ignoring such parent contributions means the measured cross sectionis not fully cumulative with respect to all parent contributions (as definedin Equation 6.5), it provides the cross section estimate that is most relevantfor practical applications: if one wanted to estimate the amount of 126Sb(t1/2 = 12.35 d) produced during an irradiation, the timescale of interestis unlikely to include the distant future where 126Sn (t1/2 = 198 ky) decaycontributes significantly to 126Sb production11. Additional examples wherecontributions from a parent (satisfying λp λd) are negligible include 225Ra(negligible contributions from 229Th), 227Th, and 227Ac.When a parent exists at tm and can’t be neglected, its cumulative crosssection must be determined from Equations 6.4 and 6.6, or neither σid nor σcdcan be reliably reported. Equations 6.7 and 6.10 are then used to determinethe daughter’s cross section, either independent or cumulative depending onthe existence of other previously-decayed precursors. Examples of nuclideswhere such parent-daughter corrections were applied include 225Ac, 224Ra,223Ra, and 121Te.11Unless the parent’s cross section is so much larger than the daughter’s that it com-pensates for the much larger decay constant of the daughter.148When calculating cross sections, uncertainties in the gamma spec-troscopy measurements – typically between 4 and 10% depending on thenuclide, including 2.4% from the efficiency calibration – were combined us-ing the Gaussian law of error propagation with uncertainties from protonflux (6.2%), thorium foil thickness (4.0%), and nuclide decay constants.6.2.7 Fluka simulationsMonte Carlo simulations were conducted using Fluka (version 2011.2x.7)and the Flair interface (version 2.3-0) [128, 129, 205]. Details and descrip-tion of the physics models used by Fluka can be found in the Fluka Manual[128]. Fluka is also introduced in Section 2.3.All simulations used NEW-DEFaults default settings. PHYSICS set-tings included the new evaporation model with heavy fragment evaporationincluded, coalescence activated, and ion splitting disabled. Gamma ray in-teractions at all energies were included. Transport settings included point-wise low-energy neutron cross sections, a 0.0025 cm step size in thin targetcomponents (Inconel and thorium foils), 30 keV production and transportthresholds for (anti)electrons and photons, 100 keV transport threshold forprotons, and full transport of all light and heavy ions linked to the Dpmjetand Rqmd event generators. The choice in the number of primaries usedwas determined by the maximum permissible run time on available clusters,provided that statistical error estimates were at least <1%.Fluka does not explicitly model isomeric state production, instead split-ting residual nuclei equally between available ground or excited states. Thismust be considered when comparing results for nuclei that are affected bythe modelling of isomeric state production. Activation products affected byisomeric state production include any excited states and ground states of nu-clei with excited state for which the excited state is either long-lived enoughto be present at tm or if the excited state does not always decay directly tothe ground state. For practical purposes, ground states with short-lived ex-cited state precursors are not affected by isomeric state production12, sinceany excited states decay quickly to the ground state.The following subsections describe two Fluka geometries used to model232Th(p,x) reactions.12Provided ν = 11496.2.7.1 Thin foil simulationsTo determine 232Th(p,x) cross sections predicted by Fluka, simulationswere conducted of a proton beam incident on a 0.25 mm thick thorium foilunder vacuum, using 4 billion primaries in an instantaneous irradiation13.With radioactive decay disabled, independent cross sections were de-termined from residual nuclei scoring and Equation 6.3, with F (t) = 1.Independent total mass cross sections were then determined (see Section6.2.1), and cumulative mass cross sections for nuclides of interest were thendetermined using Equation 6.5.6.2.7.2 Full target geometry simulationsSimulations of the entire measured cross section experiment were also con-ducted using 1.2 billion primaries. These simulations includes a more com-plete IPF target station and experimental thorium target geometry, themeasured beam profile at the time of measurement, and the exact irradi-ation profile of the experimental irradiation, as described in Section 6.2.3.With radioactive decay enabled, radioactivation products were also scoredafter decay correction by Fluka to the exact times of measurement (seeTable 6.1). Cross sections were calculated from these activation results us-ing the same methodology described in Section 6.2.6 for the measured crosssections.This more complex simulation enables the comparison of measured andcalculated cross sections under similar conditions. Simulating the measuredcross section experiment in this way enables an estimation of any bias inthe real cross section measurements that may be introduced by secondaryparticle interactions or transport originating from other components of thetarget station, which would not be included in the simplified simulations ofSection 6.2.7.1.As described in Section 6.3, the ratio, r, of the cross section determinedby Section 6.2.7.2 divided by the cross section determined by Section 6.2.7.1,can be used to quantify this bias estimate.15020 40 60 80 100 120 140neutrons20406080protons050100150cross section [mb]Figure 6.2: Independent cross sections for the 438 MeV proton irradiationof thorium determined via Fluka, as described in Section 6.2.7.1.6.3 Results and DiscussionFigure 6.2 shows independent cross sections for all nuclides, as determinedvia Fluka. Visible are two distinct regions: spallation products (proton-heavy, Z>83) and fission products (neutron-heavy, Z approx. 30-60). Asproton energy increases, the gap between these regions narrows.Table 6.3 shows measured and calculated cross sections only for the spe-cific nuclides that could be reliably measured in the gamma spectra andlisted in Table 6.1. Figure 6.3a provides a comparison of the measuredcross sections to the independent total mass yields calculated by Fluka,as described in Section 6.2.7.1. As shown, mass numbers for which all con-tributions to the total mass yield can be measured show good agreementbetween the measured and calculated values.While a direct comparison of measured and calculated nuclear forma-tion cross-sections indicates the accuracy of models used in a simulation,in applications where simulations are used to predict the radioactive inven-13Simulations were conducted at incident proton energies of 30, 40, 50, 60, 70, 80, 90,100, 125, 150, 175, 200, 250, 300, 350, 400, 438, 500, 550, 600, 650, 700 750, 800, 900, and1000 MeV.151tory resulting from a complex irradiation, a comparison of the measuredand predicted radioactivities is of more practical relevance than a compar-ison of measured and predicted cross sections. For a given radionuclide ofinterest, the calculated radioactivity will depend not only on its formationcross section at the incident beam energy, but also on precursor nuclidecross section(s) and contributions from secondary hadrons and lower energyprotons. Figure 6.3b compares the measured radioactivities in the thoriumfoil (Section 6.2.6) to the radioactivities calculated by Fluka at the time ofmeasurement (Section 6.2.7.2). This comparison include nuclides for whichmeasured cross sections could not be determined due to the inability toaccount for parent nuclide contributions to the decay (206Bi, 203Pb, 201Tl,140La, 125Sb, 105Rh, 95Nb, and 88Y) and nuclides formed predominantly byneutron capture (233Pa). For 41 of these 47 nuclides, the calculated andmeasured radioactivities agree within a factor of 2. Excluding nuclides af-fected by metastable state production and neutron capture, 37 of the 38remaining calculated and measured radioactivities agree within a factor of2.For individual nuclides, a comparison of calculated and measured crosssections is shown in Figure 6.3, alongside available values from the litera-ture over the 0 to 1000 MeV range [144]. Again, the measured, calculated,and literature values generally agree within a factor of 2 or less for mostnuclides. Measured and Fluka-simulated cross sections especially agree fornuclides not affected by metastable state production. For nuclides relatedto 225Ac production at 438 MeV, Fluka appears to underestimate 225Raproduction while overestimating 225Ac production, despite showing betteragreement with measured values at lower energies. While no cross sectionsfor proton irradiation of thorium near 438 MeV are reported in the litera-ture, extrapolation from values reported at lower energies suggests that themeasured values reported herein for 438 MeV are in reasonable agreementfor all nuclides for which data is available, with the possible exception of225Ra. This potential discrepancy could possibly be attributed to the chal-lenges of quantifying 225Ra via gamma spectroscopy at 40.0 keV, despite theadditional care taken in these measurements (see Section 6.2.4).Fluka-simulated cross sections alternatively calculated using the samegeometry, irradiation and decay parameters, and methodology as the mea-sured cross sections (Section 6.2.7.2) can be compared to the Fluka crosssections of Table 6.3 and Figure 6.4 that were determined by the simulationof thin foil irradiations described in Section 6.2.7.1. As described in Section6.2.7.2, this more complex simulation enables the comparison of measuredand calculated cross sections under similar conditions and estimates any bias1520 40 80 120 160 200 240mass number10-2100102cross-section [mb]FLUKA - independent total mass cross sectionmeasured - partial independent mass cross sectionmeasured - independent total mass cross section0 40 80 120 160 200 240mass number00.511.522.5ratio (FLUKA/measured)unaffected by metastable state productionaffected by metastable state productionneutron capture only (Pa-233)Figure 6.3: (a) Independent total mass cross sections determined by Fluka(Section 6.2.7.1) are compared to measured mass cross sections. The totalmass cross sections could only be determined for mass numbers 228, 227,and 111 – in other cases, cumulative cross sections for a given mass numbercould only be measured on one side of the line of stability and thereforerepresent only a partial contribution to the total independent mass crosssection. Cumulative cross sections for 207Bi, 206Po, and 205Bi are excludedsince they are cumulative (not independent) with respect to the total mass,due to mass changes by alpha decay. (b) A comparison of measured (Section6.2.6) and calculated (Section 6.2.7.2) radioactivities in the the irradiatedtarget.153Table 6.3: Measured and calculated cross sections from the 438 MeV protonirradiation of thorium.Nuclide t1/2 [d] typea cross section [mb]measured Fluka230Pa 17.4 i 1.86 ± 0.23 3.02 ± 0.01228Th 697.7 c 38.18 ± 3.40 51.28 ± 0.06228Ra 2098.8 c 1.64 ± 0.19 1.05 ± 0.01227Th 18.7 c 15.55 ± 1.65 21.39 ± 0.04227Ac 7946.8 c 17.65 ± 1.68 18.51 ± 0.01226Ac 1.2 c 16.44 ± 1.81 15.01 ± 0.03225Ra 14.9 c 4.20 ± 0.40 2.41 ± 0.01225Ac 9.9 c 13.30 ± 1.21 19.32 ± 0.03224Ra 3.6 c 15.90 ± 1.40 17.98 ± 0.03223Ra 11.4 c 5.31 ± 0.39 5.01 ± 0.02207Bi 11515.8 c 21.59 ± 1.92 25.60 ± 0.03206Po 8.8 c 13.70 ± 1.19 23.10 ± 0.14205Bi 15.3 c 6.17 ± 0.54 17.36 ± 0.12144Ce 284.9 c 4.35 ± 0.40 6.77 ± 0.02141Ce 32.5 c 8.36 ± 0.81 9.92 ± 0.03139Ce 137.6 c 2.74 ± 0.38 1.63 ± 0.01136Cs 13.0 c 3.16 ± 0.28 3.63 ± 0.01134Cs 753.8 c 3.97 ± 0.43 3.21 ± 0.01132Te 3.2 c 3.53 ± 0.30 3.20 ± 0.01131Ba 11.5 c 1.44 ± 0.14 1.03 ± 0.01127Sb 3.9 c 5.59 ± 0.50 7.58 ± 0.02126Sb 12.4 cb 6.20 ± 0.55 2.40 ± 0.01125Sn 9.6 cb 2.95 ± 0.39 2.86 ± 0.01124Sb 60.2 cb 10.72 ± 1.45 6.29 ± 0.01122Sb 2.7 c 8.23 ± 0.73 7.35 ± 0.02121Te 19.2 cb 1.67 ± 0.24 1.52 ± 0.01121mTe 164.2 ib 2.42 ± 0.21 1.08 ± 0.01120mSb 5.8 ib 6.87 ± 0.82 2.40 ± 0.01115Cd 2.2 cb 23.86 ± 2.11 36.63 ± 0.05114mIn 49.5 ib 4.92 ± 0.76 1.65 ± 0.01111In 2.8 c 0.71 ± 0.07 0.84 ± 0.01111Ag 7.5 c 62.20 ± 7.92 57.03 ± 0.06110mAg 249.8 ib 7.06 ± 0.63 4.64 ± 0.01106Ru 371.8 c 36.34 ± 3.35 45.00 ± 0.05103Ru 39.2 c 54.10 ± 4.72 53.87 ± 0.0615499Mo 2.7 c 36.55 ± 3.19 37.78 ± 0.0595Zr 64.0 c 27.97 ± 2.43 28.29 ± 0.0483Rb 86.2 c 1.10 ± 0.13 1.05 ± 0.01aDenotes cross section type: i = independent, c = cumulative. Nosupracumulative cross-sections are reported.bCalculated cross sections for these nuclides will be affected by theincomplete modelling of isomeric state production in Fluka.in the measured cross sections introduced by secondary particle interactions.To compare these two methods, we define the ratio, r, of the cross sectiondetermined from the full geometry method (Section 6.2.7.2) divided by thecross section determined from the thin foil simulations (Section 6.2.7.1).For 27 of the 38 nuclides with cross sections reported in Table 6.3 andFigure 6.4, the two different Fluka estimates of the cross section are ingood agreement (r = 1.00 ± 0.06). Most (9 out of 11) of the remainingnuclides have r > 1.06 due to secondary proton or neutron interactions, thesimualted energy spectra for which are shown in Figure 6.5. For spallationproducts 230Pa, 228Th, and 227Th (r = 1.27, 1.09, and 1.11, respectively),the increased nuclide production when simulating the full target station ge-ometry is due to lower energy (<438 MeV) secondary protons; neutron-onlyscoring of activation products in Fluka indicate no neutron contributionsto the production of these nuclei. Note that while the flux of secondaryprotons is only 3.7% of the total proton flux, Figure 6.4 illustrates that thecross sections for these nuclei are higher at energies below 438 MeV, andthese protons thus contribute more than 3.7% to production of these nuclei;this is especially true for 230Pa, the nuclide with greatest r. For fission prod-ucts 144Ce, 141Ce, 136Cs, 132Te, 127Sb, and 125Sn (r =1.12, 1.12, 1.07, 1.15,1.10, and 1.07, respectively) the increased production when simulating thefull target station geometry is due production of the nuclide or its precur-sors via secondary neutron interactions. This is confirmed by neutron-onlyscoring of the activation products in Fluka.15511/25/2019 untitled.svgfile:///Users/andrewrobertson/Desktop/untitled.svg 1/1101 102 103101102Pa-230101 102 103020406080100120Th-228101 102 10300.511.5Ra-228101 102 1030102030405060Th-227101 102 10305101520Ac-227101 102 103051015Ac-226101 102 10301234Ra-225101 102 103051015Ac-225101 102 103051015Ra-224101 102 103012345Ra-223101 102 103051015202530Bi-207101 102 103051015202530Po-206101 102 1030510152025Bi-205101 102 1030102030405060Ce-141101 102 10300.511.522.53Ce-139101 102 10302468101214Cs-136101 102 10301234Cs-134101 102 10305101520253035Te-132101 102 10300.511.522.5Ba-131101 102 1030510152025Sb-127101 102 1030123456Sb-126101 102 1030246810Sn-125101 102 103024681012Sb-124101 102 10302468Sb-122101 102 10300.511.522.533.5Te-121101 102 10300.511.522.5Te-121m101 102 10301234567Sb-120m101 102 1030102030405060Cd-115101 102 103012345In-114m101 102 103051015202530Ce-144101 102 10300.511.522.53In-111101 102 103010203040506070Ag-111101 102 10301234567Ag-110m101 102 1030102030405060Ru-106101 102 1030102030405060Ru-103101 102 103010203040Mo-99101 102 10301020304050Zr-95101 102 103012345Rb-83101102103energy [MeV]cross section [mb]axes and legend for all plotsEXFOR dataFLUKAthis work (438 MeV)Figure 6.4: A comparison of cross sections determined in this work at 438 MeV, to literature (fromthe EXFOR database) and calculated values over the 0 to 1000 MeV range. The type of cross section(independent or cumulative) is indicated in Table 6.3. The axes label and legend for all plots is shownin the lower right.156With the exception of 230Pa, these r values overall suggest that the sec-ondary particle contributions to the production of nuclides in Table 6.3 andFigure 6.4 can be estimated to have a <15% effect on all the measured crosssections reported in this work; in most cases the effect is <6%. However, itshould be acknowledged that no measured data regarding the energy spec-tra of secondary particles during the experiment is available, and in fact,measured 233Pa production values – the only measured nuclide producedsolely through neutron capture – suggest that the neutron flux may be un-derestimated by a factor of 3, as shown in Figure 6.3b. Only two nuclideshave r < 0.94, 205Bi (r = 0.60) and 121Te (r = 0.89), the reasons for whichis unknown.The contribution of secondary protons and neutrons to nuclide produc-tion is further illustrated in Figure 6.6, with nuclides produced via neutroncapture and neutron-induced fission the most prominent. Compared to Fig-ure 6.2, the less symmetric fission yield from lower energy secondary particlescontributes most to fission product production beyond the tails of the fis-sion curve from the primary 438 MeV protons. While some of these nuclidesare shown in Figure 6.6 to be almost entirely produced by secondary par-ticles, they are also almost entirely short-lived precursors that have minorcontributions to the reported cumulative cross sections.6.4 SummaryCross sections for the proton irradiation of thorium by 438 MeV protons havebeen reported for 38 spallation and high-energy fission product nuclei, alongwith comparisons to the Fluka code. In general these cross sections agreewithin a factor of 2 with each other and with literature values extrapolatedfrom 438 MeV to lower proton energies.157100 200 300 400 500energy [MeV]10-410-310-210-1100particles/primary crossing thorium foilprimariesprotonsneutronsFigure 6.5: Energy spectra of primary protons, secondary protons, andsecondary neutrons crossing the thorium foil in the Fluka simulations ofthe IPF target during irradiation, as described in Section 6.2.7.2.15820 40 60 80 100 120 140neutrons20406080protons00.10.20.30.40.50.60.70.80.91fraction of activation from secondary particlesFigure 6.6: Relative contribution of secondary protons and neutrons tonuclide production during the thorium target irradiation, as estimated byFluka simulations described in Section 6.2.7.2.1597 225Ac Purification from Tho-rium Targets7.1 BackgroundThe high-energy (>70 MeV) proton irradiation of naturally enriched tho-rium (232Th) is currently the most widely explored alternative 225Ac produc-tion method [1, 33, 101, 104, 135–141, 143, 160]. While this approach may becapable of producing sufficient quantities of 225Ac, the process co-produceshundreds of other radionuclides through spallation and high-energy fissionreactions. Ac must therefore be separated from most other elements on theperiodic table in order to obtain a radiochemically pure product, in addi-tion to having to separate nanograms of Ac from tens of grams of Th targetmaterial. Multiple methods for extraction of Ac from proton irradiated tho-rium have been developed [104, 136, 143, 160, 206], though none have yetincluded an initial thorium de-bulking method that will reduce column sizes,processing times, and the large volumes of liquid radioactive waste that re-sult. These advantages of thorium de-bulking are especially advantageousif a process is to be used with increasingly larger quantities of thorium insupport of 225Ac production scale-up.Chemical purification methods are also not capable of separating 225Acfrom other Ac isotopes. 227Ac (t1/2 = 21.8 y) is one such isotope thatis co-produced during thorium irradiations (at approximately 0.1-0.3% ra-dioactivity relative to 225Ac) whose presence may prevent the widespread useof thorium-spallation-derived 225Ac. While recent research has shown that227Ac is likely not a concern from a patient dosimetry perspective [207, 208],the long half-life and multiple alpha-emissions of the 227Ac decay chain re-sult in restrictive regulatory limits for disposal of waste containing 227Ac,which creates a significant economic burden on the manufacturers and usersof 225Ac-radiopharmaceuticals that contain 227Ac. Low radiation protec-tion limits for accidental internalization of 227Ac within the body may also160require additional precautions for handling of 225Ac-radiopharmaceuticalscontaining 227Ac.However, production of 227Ac-free 225Ac from the proton irradiation ofthorium is possible, in principle [2], via the co-production of the 225Ac par-ent nuclides, 225Ra (t1/2 = 14.9 d). The initial separation of Ac isotopesfrom the thorium and other spallation and fission products results in anAc product that contains 225Ac, 227Ac, and shorter-lived isotopes such as228Ac (t1/2 = 6.15 h),226Ac (t1/2 = 29.37 h), and224Ac (t1/2 = 2.78 h).This product is sometimes referred to as “first-pass 225Ac” or “directly-produced 225Ac”, and is herein denoted as 227,225Ac†. After the separationof 227,225Ac†, Ra isotopes remain, including 225Ra, 228Ra (t1/2 = 5.8 y),226Ra (t1/2 = 1600 y), and224Ra (t1/2 = 3.6 d). Of these, only225Ra and228Ra decay to Ac isotopes. After then waiting for 225Ra decay to produceadditional 225Ac, repeating the Ra/Ac separation results in a second Acproduct that could theoretically be 227Ac-free. This product is sometimesreferred to as “second-pass 225Ac” or “generator-produced 225Ac”, and isherein denoted 225Ac*.Chapter 7 presents a chemical separation process for the productionof both 227,225Ac† and 225Ac* products, using a novel precipitation-basedthorium de-bulking method. The data presented will demonstrate howAc is separated from most other elements and will compare the quality ofTRIUMF’s first two 227,225Ac† and 225Ac* production runs, demonstrating225Ac* production using an accelerator facility and chemical process thatcould be scaled to useful clinical or commercial quantities and with 227Accontent low enough to be potentially considered 227Ac-free from practicaland regulatory perspectives.7.2 Methods7.2.1 Materials and reagentsAll solvents and reagents were purchased from commercial suppliers andused as received. Trace metal grade HNO3 (>99.999% basis) and Dowex50WX8 resin (200-400 mesh, hydrogen form) was purchased from SigmaAldrich. Anhydrous citric acid (ACS) was purchased from Anachemia(VWR Canada). DGA-normal resin (50-100 µm) was purchased fromEichrom. Deionized water (>18 MΩcm) was produced using a MilliporeDirect-Q R© 3UV water purifier.1617.2.2 Fluka simulationsFluka is a high-energy particle transport code that uses Monte Carlo meth-ods and various physics models to simulate the interactions of particles witha user-defined environment. An introduction to Fluka is provided in Sec-tion 2.3. In this Chapter, Fluka was used to estimate the radioactiveinventory of the thorium foil after proton irradiation. Validation studiesdemonstrating the accuracy of these simulations are described in Chapter 6.All simulations were conducted using Fluka (version 2011.2x.7) and theFlair interface (version 2.3-0) using the NEW-DEFaults default settings[128, 129, 205]. PHYSICS settings included the new evaporation modelwith heavy fragment evaporation included, coalescence activated, and ionsplitting disabled. Gamma ray interactions at all energies were included.Transport settings included pointwise low-energy neutron cross sections, a0.0025 cm step size in thin target components (Inconel and thorium foils),30 keV production and transport thresholds for (anti)electrons and photons,100 keV transport threshold for protons, and full transport of all light andheavy ions linked to the Dpmjet and Rqmd event generators. The choice inthe number of primaries used was determined by the maximum permissiblerun time on available clusters, provided that statistical error estimates wereat least <1%.7.2.3 Gamma spectroscopyThe detector used was a N-type co-axial HPGe gamma spectrometer fromCanberra fitted with a 0.5 mm beryllium window. The detector’s energy,width, and efficiency calibrations were performed using a 152Eu and 133Basource. The geometry of the calibration source and all samples consisted of a20.0 mL dilute HNO3 solution in a scintillation vial positioned at a distancefrom the detector beyond which cascade-summing effects were shown to benegligible. Dead time was kept below 1.5%. Further details regarding thegamma spectrometer and how it was setup and used are provided in Section2.1.Spectra were analyzed using the Genie 2000 software package (version3.4, Canberra Industries) [145, 147]. Gaussian curves were manually fittedto all peaks and compared against gamma ray libraries built using datafrom the National Nuclear Data Center database [83]. Only fitted peakswith >95% significance and a full width at half maximum (FWHM) within20% of the calibrated peak width were accepted. Decay correction beforeand during data acquisition was applied within Genie 2000.162Since thorium irradiated with 438 MeV protons contains on the orderof 102 radionuclides, the resulting gamma spectra can be extremely com-plex. To prevent erroneous nuclide identification or quantification, multiplegamma lines for an individual nuclide each providing consistent individualmeasurements of the total radioactivity were required for positive identi-fication of a nuclide14. The interference-corrected weighted mean of theseresults, as determined by Genie 2000, is then used to quantify the total ra-dioactivity at the time of measurement. Additional care was taken to ensurethat gamma lines used for different nuclides in the library were sufficientlyseparated (>0.5 FWHM) to avoid false identification of a nuclide.Special attention was given to the quantification of 225Ra due to the highslope of the efficiency curve in the low energy region (<100 keV) where 225Raemits its single 40.0 keV gamma ray. Comparison of 225Ra measurements at40.0 keV (using a pure 225Ra sample produced at TRIUMF’s ISOL facility[3, 164]) to the measured grow-in of 221Fr (218 keV) and 213Bi (440 keV) wasused to validate the efficiency calibration at 40.0 keV. Still, in the presence ofmany other thorium target activation production, 225Ra detection becomeschallenging due to the amount of low energy emissions (<100 keV) andscatter produced by other nuclides. Due to its greater detectability, 223Raisotope were used to account for Ra losses during target processing.Quantitative gamma spectroscopy measurements of 225Ac were con-ducted after waiting at least 25 minutes for 221Fr to reach equilibrium with225Ac, so that the 221Fr nuclide’s 218 keV gamma line could be used for225Ac quantification (see Section 1.2.4). In spectra containing many otherpotentially interfering nuclides, a waiting time of at least 6 hours was used sothat 213Bi equilibrium could also be reached; matching 221Fr (218 keV) and213Bi (440 keV) activity values were then used as an indication of positiveand accurate 225Ac quantification.Gamma spectroscopy detection limits for radionuclides of interest weredetermined using the ISO11929 algorithm available in Genie 2000 [147]. Thisalgorithm is a Bayesian adaptation of the Currie method for determiningdetection limits [209, 210].14Exception are made for nuclides – such as 225Ra or 85Sr – that only emit a singleusable gamma ray signal. In such situations, the peak centroid must be within 0.2 keVof the expected peak energy, and have a FWHM that matches the calibrated peak width.Additional scrutiny is fairly placed on such results.1637.2.4 Process development using non-irradiated materialsInitial development tests focused on developing and optimizing the condi-tions for the precipitation, cation exchange, and extraction chromatographyportions of the separation scheme shown in Figure 7.4, taking into consid-eration only the separation of Ac and Ra from bulk quantities of Th sincetracers for the other spallation and fission products were not yet readilyavailable. These tests can be done without additional Ac or Ra tracers byusing the 228Ac (t1/2 = 6.15 h) and224Ra (t1/2 = 3.66 d) radiotracers natu-rally present in the 232Th decay chain15. While HPGe gamma spectroscopy(Section 7.2.3) is able to easily detect these radionuclides, 232Th does notemit sufficient gamma rays to serve as a radiotracer that can measure thehigh degree of Th decontamination required by 225Ac purification schemes.Therefore, a colorimetric assay for Th (Section 7.2.4.1) was initially em-ployed, before 227Th tracers became available from the first irradiated tho-rium target(Section 7.2.4.2). The final development tests done to generatethe elution profiles shown in Figure 7.5 also included 225Ra and 225Ac tracers(Section 7.2.4.3).An important distinction between these tests and the processing of irra-diated thorium targets is that tests with non-irradiated material used tho-rium nitrate material as opposed to thorium metal. This was done due to themuch higher cost of thorium metal. Since the thorium metal is evaporatedto a nitrate salt after the dissolution anyway, the only expected differencesbetween the processes of thorium nitrate material and thorium metal ma-terial are: 1) differences in impurities from two sources of stock materials;and 2) the absence of small quantities of HF that would otherwise be usedin the dissolution of the metal.The elution profiles of Figure 7.5 were obtained using n = 3 replicates ofthe following procedure. 20.0 g of thorium nitrate tetrahydrate (equivalentto 8.0 g of thorium metal) was dissolved in 80 mL of 1 M HNO3 containingapproximately 350 kBq of 225Ra and 225Ac tracers; a 0.5 mL colorimetrysample was removed, and a gamma spectroscopy measurement of the initialsolution was performed.The precipitation and filtration was performed as described in Section7.3.2. Gamma spectroscopy measurements of 228,225Ac and 225,224Ra wereperformed on the diluted filtrate in order to quantify the Ac and Ra recoveryfrom the precipitation; a 1 mL sample was removed to quantify the amount ofthorium remaining in the filtrate via photometric determination (see Section15Prompt counting of all samples is required due to the grow-in of 228Ac from 228Ra.1647.2.4.1). 227Th and 223Ra tracers (see Section 7.2.4.2) were then added.The cation exchange column was then performed as described in Section7.3.2. The load was collected in a single fraction; the citric and nitric acidwashes were collected in 50 mL fractions; the Ra and Ac elution was collectedin 10 mL fractions. All fraction were counted by gamma spectroscopy. Aftercounting by gamma spectroscopy, the elution fractions were combined, a 0.5mL colorimetry sample was removed, and the solution was diluted to 4M HNO3 for loading through the DGA column. 1 mL samples were alsoremoved from all wash fractions for Th colorimetric assay.The DGA column was then performed as described in Section 7.3.2. TheDGA load was collected in 20 mL fractions, the wash in a single fraction,and the Ac elution in 1 mL fractions. All fraction were counted by gammaspectroscopy.The timing of all gamma spectroscopy measurements was as promptas possible (within minutes), such that parent-daughter decay correctionsdid not need to be applied for 228Ra\228Ac, 228Th\224Ra, 227Th\223Ra, or225Ra\225Ac.The average ± standard deviation for Th, Ra, and Ac content in eachfraction (averaged over the multiple tracers and multiple replicates) is thenplotted in Figure 7.5.Figure 7.1: Calibration curves and UV-absorption spectra for thorium-arsenazo complexes in 1 M HNO3 (top) and 1 M citric acid (bottom).1657.2.4.1 Thorium colorimetry measurementsPhotometric determination of Th using the thorium-arsenazo complex hasbeen previously reported [211]. Samples for Th assay were either nitric ofcitric acid from either the dissolution, precipitation, or cation exchange por-tions of the thorium target purification process (Figure 7.4). Aliquots ofsamples were diluted to 960 µL of either 1 M HNO3 or 1 M citric acid; di-lution factors varied between 100-103. The color reagent (Arsenazo-III, 2,7-Bis(2-arsonophenylazo)-1,8-dihydroxynaphthaline-3,6-disulfonic acid, pur-chased from Sigma Aldrich) was then added (40 µL, 25 mg/L), and theabsorbance at 670 nm was then measured using a Cary 100 UV-Vis Spec-trophotometer (Agilent Technologies).Absorption spectra and calibration curves for both nitric and citric acidmatrices are shown in Figure 7.1.7.2.4.2 227Th and 223Ra tracer productionThe first thorium target irradiated and processed at TRIUMF was irradiatedas described in Section 7.3.1, but allowed to decay for 5 months beforebeing processed as described in Section 7.3.2. Detailed results from thisinitial target are excluded from this publication, however, (0.22 ± 0.04)MBq of 225Ra and (0.23± 0.1) MBq of radiochemically pure16 227,225Ac†wereisolated from this irradiated target.The 227,225Ac† product from this initial target was kept for use as a227Ac/227Th generator, with a total 227Ac quantity of (382 ± 20) kBq, asmeasured by gamma spectroscopy of the 227Th grow-in (t1/2 = 18.68 d). The227Ac in 13 mL of 12 M HNO3 was evaporated to dryness and redissolvedin 5 mL of 8 M HNO3. This solution was then passed through an anionexchange column containing 0.5 mL of DOWEX 1X8 resin (200-400) meshconditioned with 4 mL of H2O and 4 mL of 8 M HNO3. The column wasthen washed with 2.5 mL of 8 M HNO3 before the227Th was removed using3.5 mL of 0.05 M HNO3. The total amount of227Th obtained was (332 ±12) kBq, at (99.1 ± 3.1)% chemical yield.The 227Th obtained was left to decay for at least 5 days, allowing for thegrow-in of the additional 223Ra tracer (t1/2 = 11.4 d).7.2.4.3 225Ra and 225Ac tracer production225Ra and 225Ac tracers were produced at TRIUMF’s Isotope Separation16All gamma spectrum peaks were identified as 228Ac and 225Ac peaks.166On-Line (ISOL) facility, as described in Chapter 3 and by Ramogida et aland Kunz et al [3, 164].7.2.5 Process characterization using multi-element ICP-MSstandards and radiotracersTo demonstrate the separation of Ac from the spallation and fission productspresent in the irradiated thorium targets, the fate of these other elements inthe target purification process must be measured. To do this, multi-elementICP-MS standards were used as tracers. The target purification process(described in Section 7.3.2 and shown in Figure 7.4) was performed threeseparate times using three separate multi-elemental tracers:a) 1.1 mL of 71A standard (10 ppm multi-element standard17, 2% HNO3,purchased from Inorganic Ventures) and 1.1 mL of a Y standard (10ppm, 2% HNO3)b) 1.1 mL of a CMS-3 standard (10 ppm multi-element standard18, 2%HNO3 + trace HF, purchased from Inorganic Ventures)c) A blank tracer, containing only 1.1 mL of 2% HNO3Each tracer was diluted to 260 mL of 0.5 M HNO3, and 20 mL of thissolution was then removed so that the initial amount of each tracer could bemeasured by ICP-MS. The remaining solution was then processed throughthe cation and extraction chromatography parts of the target purificationprocess. Samples (≤20 mL) were removed from the cation column load,citric wash, nitric wash, cation column elution, DGA column load, DGAcolumn wash, Ac elution, and Ln elution. All nitric acid samples were thenslowly evaporated in an acid-washed Teflon beaker and then redissolved in2% HNO3 containing 10 ppb In as an internal standard for analysis by ICP-MS.Prior to analysis, the total dissolved solids in the citric wash and nitricwash were reduced. To do this, the pH of the citric wash sample was adjustedto pH 1.00 ± 0.05 using concentrated HNO3; the pH of the nitric wash wasnot adjusted. The samples were then passed at 1 mL/min through a cationexchange column containing 2 mL of Dowex 50X8 (200-400 mesh) resin17Contains 10 ppm for each of: Al, As, Ba, Be, Cd, Ca, Ce, Cr, Co, Cu, Dy, Er, Eu,Gd, Ga, Ho, Fe, La, Pb, Lu, Mg, Mn, Nd, Ni, P, K, Pr, Rb, Sm, Se, Ag, Na, Sr, S, Tl,Th, Tm, U, V, Yb, Zn, Cs, B18Contains 10 ppm for each of: Ge, Hf, Mo, Nb, Ta, Sn, Ti, W, Zr167preconditioned with 20 mL of H2O followed by 20 mL of 8 M HNO3, then 20mL of 1 M citric acid (pH 1.00) for the citric wash sample or 20 mL of 0.5 MHNO3 for the nitric wash sample. The column was then washed (2 mL/min)with 120 mL of 0.1 M HNO3 to remove residual citric acid before elutingthe metals at 1 mL/min with 80 mL of 8 M HNO3. The fractions were freeof detectable citric acid and were evaporated and redissolved in 2% HNO3+ 10 ppb In as previously described. This citric acid removal procedure wasalso performed using known quantities of the ICP-MS tracers listed above,so that recovery factors for individual elements could be determined.Thorium dissolution and precipitation stages of the 227,225Ac† purifica-tion process were omitted from this experiment, to avoid loss or contamina-tion of the tracers during the dissolution or precipitation. All disposables,vials, pipette tips, columns, graduated cylinders, etc., used that came intocontact with these samples were acid washed to remove trace metal con-taminants prior to use. All nitric acids were prepared using EnvironmentalGrade HNO3 obtained from VWR. Trace metals were removed from the cit-ric acid solution using 10 g of Chelex-100 (Bio-Rad) per 100 mL and stirredfor 1 h prior to filtration.ICP-MS analysis of these samples was provided by the University ofBritish Columbia’s Pacific Centre for Isotopic and Geochemical Research.The background amount of each element analyzed (averaged over 2 blankruns) was subtracted from the total amount measured in each fraction. Mea-sured recovery factors for the citric acid removal process (above) were takeninto account.7.2.6 ICP-MS measurements of 227,225Ac† and 225Ac*Aliquots (0.1-0.5 mL) of 227,225Ac† and 225Ac* products were diluted to 10mL using trace metal grade 1 M HNO3. ICP-MS measurements of theseradioactive samples were provided by the Analytical Chemistry Branch atCanadian Nuclear Laboratories (Chalk River, ON). The analysis providedincluded measurement of common stable impurities19 as well as mass num-bers A=120 through A=244, which provides a sensitive measurement (<1pg/mL) of 227Ac content.Blank samples containing 10 mL of trace metal grade 1 M HNO3 werealso prepared, and the amount of stable impurities in these samples wassubtracted from the amount seen in the 225Ac samples, to provide the net19Be, Ca, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Sr, Y, Zr, Nb, Mo, Sn, Ba, W, Pb,Th, and U168quantity of impurities in the 227,225Ac† and 225Ac* product.7.2.7 Radiolabelling tests with 227,225Ac† and 225Ac*distance [mm]distance [mm] distance [mm]countsFigure 7.2: Example TLC trace data including a negative control (left)showing no 225Ac labelling, a positive control (centre) showing complete225Ac labelling, and an example of a TLC indicating partial labelling (right),including the regions used for peak areas and background subtraction.The ability to label disease-targeting biomolecules is an essential require-ment of a quality radionuclide product. Two macrocyclic ligands were cho-sen to demonstrate the radiolabelling abilities of the 227,225Ac† and 225Ac*products: DOTA, the most widely used 225Ac ligand, and macropa, whichis capable of labelling 225Ac at low concentrations [3, 162, 212, 213].227,225Ac† and 225Ac* products (13 mL 12 M HNO3) were evaporated todryness and redissolved in 0.05 M HNO3. 3 µL aliquots of these225Ac solu-tions – each containing 40-45 kBq of 225Ac – were added to 100 µL solutionsof 1 M NH4OAc (pH 7) containing DOTA or macropa at concentrationsbetween 10-4 and 10-8 M. Macropa labelling was conducted at ambient tem-perature; DOTA labelling was conducted at 85 ◦C. All reactions were left for30 minutes before a 5 µL aliquot was removed and spotted onto aluminum-backed ultrapure silica gel 60 with 250 µm thickness TLC plates (Fisher, 1cm x 10 cm, with baseline at 15 mm). After drying, the plates were devel-oped using a 0.4 M sodium citrate (pH 4) solution. 225Ac-ligand complexesremain at the baseline under these conditions, while free 225Ac moves withthe solvent front. Plates were then counted on a BioScan 200 plate imagingscanner equipped with an Autochanger 1000 and analyzed using Win-Scan(version 2.2(11)).Negative controls were performed alongside all labelling tests by adding16911/23/2019 untitled.svgfile:///Users/andrewrobertson/Desktop/untitled.svg 1/1HBeNa Mg P S ArK Ca Sc V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br KrRb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I XeCs Ba Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At RnRaLa Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb LuAc Th Pa UFigure 7.3: Elements with radioisotopes present inside the irradiated tho-rium at 1 week after the end of irradiation, and from which Ac must beseparated in order produce a radiochemically pure product. Elements ingray have isotopes with activities <0.1% of the 225Ac radioactivity, as es-timated by Fluka simulations (see Section 7.2.2). Elements in black haveestimated activities >0.1% of the estimated 225Ac radioactivity.225Ac to a ligand-free but otherwise identical solution of 1 M NH4OAc (pH7). Positive controls were performed using a radiolabelling solution contain-ing 10-3 M of DOTA, heated to 85 ◦C for 60 min. Examples of TLC tracesare shown in Figure 7.2.7.3 Experimental7.3.1 225Ra and 225Ac production by thorium irradiationThorium foils (>99.95% purity, as determined by ICP-MS) of (0.25 ± 0.01)mm thickness and (60.0 ± 0.1) mm diameter were irradiated with (438 ±2) MeV protons at TRIUMF’s 500 MeV Isotope Production Facility (IPF),located immediately in front of the TRIUMF cyclotron’s main beam dump[191]. Further details of the thorium target design have been reported else-where [5]. Targets were irradiated to a total integrated current of 2640 µA*hfor a duration of 36-41 hours (total duration depended on the beam current),producing (521 ± 18) MBq of 225Ac and (91 ± 14) MBq of 225Ra at the end170of irradiation20. Targets were allowed to decay for at least 7 days beforethey were removed from the IPF and transferred to the radiochemistry lab.While sufficient 225Ra and 225Ac quantities are produced in these irradi-ations, a plethora of many other radionuclides – including isotopes of mostelements lighter than uranium – are also co-produced through nuclear spal-lation and fission reactions. Figure 7.3 provides a graphical representation ofthese elements, based on Fluka simulations of the irradiations (see Section7.2.2).The consequence of this is that chemical processes used to extract 225Acfrom these targets must be capable of separating Ac from most other ele-ments on the periodic table.7.3.2 227,225Ac† and 225Ac* purificationThe chemical process used to purify 227,225Ac† and 225Ac* products fromthe irradiated thorium is shown in Figure 7.4. The irradiated thorium metalfoils (mass ranging between 7.8 and 8.0 g) were placed in a borosilicate glassbeaker and dissolved using up to 60 mL of 10 M HNO3 + 12.5 mM HF whileheating directly on a hot plate set to approximately 200 ◦C. The dissolutionsbegan vigorously then settled once the bulk of the foil was dissolved, leavingbehind a black powdery residue which dissolved more slowly; additional heat(hot plate set up to 300 ◦C), HF (up to 60 mL of 12.5 mM), or time (up to4 h) was sometimes required to completely dissolve this residue. Within 2-4hours, the thorium was fully dissolved, yielding a clear and colorless solu-tion. Small (∼mg) amounts of a fine white solid often remained undissolved,hypothesized to be ThO2 or ThF4 [194]. Thorium can also be dissolved inhydrochloric or trichloroacetic acids [194].The solution was then evaporated to a fully dried thorium nitrate salt,with care taken to ensure the salt does not overheat (< 150 ◦C) and oxidizeto ThO2 [214]. The salt was allowed to cool to ambient temperature thenredissolved in 80.0 mL of 1 M HNO3 (final volume (86 ± 2) mL).The thorium was then selectively removed from the solution by precip-itation as thorium peroxide [215–219]. Note that other precipitates [194],including thorium oxalate or thorium iodate, were also explored but werefound to either be too difficult to filter or to result in greater co-precipitationof Ra or Ac than the thorium peroxide approach [219]. Another advantageof the thorium peroxide precipitation is that the precipitate can be easily20(As measured by gamma spectroscopy; average ± standard deviation), n = 3. Notethat results from processing of only 2 targets are included later in the publication.171redissolved by a strong HNO3 acid, allowing for easy clean up of this wasteafter process completion.The thorium peroxide precipitation began by adding 56.0 mL of 30%H2O2 to the thorium nitrate solution. It is important that the H2O2 isadded slowly (<10 mL/min) while rapidly stirring to ensure the formationof fine particulates that are easy to filter; rapid H2O2 addition results ina gelatinous precipitate. The precipitation was allowed to proceed for 2hours at ambient temperature while stirring. Note that it is important toavoid heating during the precipitation as this was found to decrease theamount of Th removed from the solution. As previously reported [216, 220],increasing the H+ concentration during the precipitation was also foundto reduce the amount of thorium removed from the solution, while lowerHNO3 concentrations during the precipitation resulted in a more gelatinousprecipitate that was harder to filter [194, 218], resulting in greater Ac andRa losses. The precipitate was removed from the solution by slowly passingthe white thorium peroxide slurry through a 10-15 µm glass filter. Theprecipitate was then washed with 140 mL of H2O, which increases Ac andRa recovery and simultaneously dilutes the filtrate to 0.25-0.5 M HNO3 forloading onto the following cation exchange column.When the filtering and washing of the precipitate is done well, this pro-cedure was found (by n = 3 tests using non-irradiated materials; see Section7.2.4) to remove >99.95% of the thorium from the solution, with (3.4 ± 0.4)mg of thorium remaining in the filtrate as determined by photometric mea-surements of the thorium-arsenazo complex (see Section 7.2.4.1). Thoughthe procedure remained effective after transitioning to irradiated materials,it is not known if thorium decontamination still remained at >99.95% whenirradiated materials were used. However, the Ra and Ac recoveries in thefiltrate of (96.7 ± 7.9)% and (98.0 ± 2.7)%21, respectively, did not differmeasurably when irradiated materials were used.The selectivity of this thorium peroxide precipitation was determinedby gamma spectroscopy measurements of the filtrate and precipitate fromtests with irradiated thorium, which suggested that only Zr, Nb, and Paco-precipitated enough to remain predominantly in the precipitate: (120.1± 8.9)%22, (112.5 ± 34.7)%, and (91.2 ± 6.1)% of initial 95Zr, 95mNb, and223Pa quantities, respectively, were found in the precipitate; no detectableamounts were found in the filtrate. Uranium (233U) is also expected to21As measured using 225,224Ra and 228,225Ac radiotracers (Section 7.2.4).22The >100% observation is possibly due to interference from other peaks that arepresent in the dissolved target solution, which were not present in the spectrum of theprecipitate.172have been co-precipitated, but was not detectable in the gamma spectra atthe time of measurement [221]. Co-precipitation of (10.1 ± 1.1)% of 103Ruwas also observed. Thorium peroxide precipitates are known to incorporateanions from the solution into their structure [216–218], which was also ob-served for radioactive halogen and semimetal species when the precipitationwas conducted using irradiated materials: (74.2 ± 2.3)%, (55.6 ± 2.9)%,(93.5 ± 7.8)%, (76.9 ± 5.2)%, and (111.2 ± 7.2)% of 127,126,124,122,120mSb,121m,121Te, 131I, 206Bi, and 206Po, respectively, was also observed to remainin the precipitate.After the separation of Ra and Ac from the bulk thorium mass, ionexchange and extraction chromatography was used to separate Ra and Acfrom the remaining trace Th and the many spallation and fission productsshown in Figure 7.3. The chromatography scheme employed was similarto methods developed by others [104, 160, 206], but with minor changesenabled by the pre-removal of the bulk thorium mass by precipitation. Thediluted filtrate (∼275 mL, ∼0.5 M HNO3) was passed at 5 mL/min througha cation exchange column (16 mm diameter) containing 10 mL of Dowex50X8 (200-400 mesh) resin preconditioned with 100 mL of H2O followed by100 mL of 10 M HNO3 then 100 mL of 0.5 M HNO3; under these conditionsmost radiometals present – including Th, Ra, and Ac – remain bound tothe column. The column was then washed (5 mL/min) with 450 mL of 1M citric acid (adjusted to pH 2.0-2.2 with ammonium hydroxide) that leftRa and Ac bound to the column while removing the residual Th (see Figure7.5). The separation of Th from Ra and Ac using cation exchange resin incitric acid depends strongly on the pH [222], and a precise adjustment ofthe citric acid pH is required: higher pH values result in Ac being removedfrom the column while lower pH values result in thorium remaining on thecolumn or requiring a larger wash volume.The column was then washed (5 mL/min) with 50 mL of 0.5 M HNO3to remove residual citric acid before Ra and Ac were eluted at 1.5 mL/minfrom the column in 80 mL of 8 M HNO3. This Ra and Ac fraction wasthen diluted with H2O to 4 M HNO3 and passed at 1 mL/min througha 0.2 mL DGA-normal (TODGA) extraction chromatography column (9mm diameter) conditioned with 10 mL of H2O followed by 10 mL of 4 MHNO3. Under these conditions and in the absence of stable impurities thatmay saturate the DGA column, Ac and lanthanide (Ln) fission products willbind to the resin while Ra remains in the liquid phase. The column was thenwashed with 5 mL of 4 M HNO3 before before Ac is eluted at 1 mL/min in13 mL of 12 M HNO3. Elution of Ac in high molarity HNO3 allows for theseparation from Ln [160], which are then removed from the column in 10173mL of 0.05 M HNO3. At this stage, the process has produced the first-pass227,225Ac† product.Results from radiotracer studies (using non-irradiated materials, as de-scribed in Section 7.2.4) used to characterize the behavior of Th, Ra, and Acduring this chromatography scheme are shown in Figure 7.5. Elution pro-files show that Th, Ra, and Ac were well separated by the process; Ra andAc chemical yields23 were (97.2 ± 2.4)% and (99.7 ± 0.8)%, respectively,with no Th or Ra detectable in the Ac fraction.When processing irradiated targets, similar Ra isolation yields of (98.3± 4.7)% (n = 2) were observed, however, Ac isolation yields were reducedto (44.0 ± 5.3)% (n = 2) due to saturation of the DGA column by stableimpurities; this is elaborated on in Section 7.4. These yields correspondto isolated quantities of (65 ± 10) MBq for 225Ra and (141 ± 9) MBq of227,225Ac†, decay corrected to 7 days after the end of the 2640 µA*h (36-41hour) irradiations.The fate of other elements in the process is illustrated in Figure 7.6 andTable 7.1. This data was collected using stable tracers, supplemented byradiotracer data for Ac, Ra, Bi, Te, Sn, In, Rh, Ru, and Tc (see Section7.2.5). The cation load fraction contained the majority of refractory metalsand semimetals. Other transition metals appeared predominantly eitherin the citric acid wash fraction of the cation column or in the DGA loadfraction after being eluted from the cation column along with Ra and Ac.Other alkaline earth metals appeared mostly with Ra in the DGA loadfraction, but also increasingly appeared in the citric acid wash as their sizedecreases. Lanthanides showed two size dependent trends, with heavierlanthanides increasingly appearing in the citric acid wash fraction and lighterlanthanides appearing in the Ln elution. It is likely that the Ln elutionwas not complete, with most of the lighter La appearing in the Ln elutionbut most of the heavier Nd still remaining on the column. Ru appears tobe the only element that was split more or less evenly between multiplefractions, and as previously mentioned, also appeared in similar quantitiesin the thorium peroxide precipitate.The only element that appeared predominantly in the Ac elution wasAc. However, Table 7.1 shows that small fractions of other elements alsoappeared in this fraction, notably 3% of the initial quantity of La, 2% ofthe initial quantity of Sr, and approximately 0.1-1.0% of refractory metals.These results, including potential future remedies, are further discussed inSections 7.3.3 and 7.4.23average ± standard deviation, n = 3174As shown in Figure 7.4, the production of the second 225Ac* productoccurred by taking the DGA load fraction, containing Ra isotopes, andimmediately passing it through a larger 1.0 mL DGA-normal column inorder to remove any residual 227Ac. After waiting a period of 1-3 weeks24for the grow-in of 225Ac, the DGA column was repeated to again separate Acfrom Ra, providing the second-pass 225Ac* product. When decay correctedfor a 7-day operational cycle of the generator, (21 ± 3) MBq of 225Ac*was isolated from the first 225Ra/225Ac* separation from the generator thatoriginally contained (65 ± 10) MBq of 225Ra at 7 days after the end of the2640 µA*h (36-41 hour) irradiations.Table 7.1: Results (n = 1) for studies using stable multi-element ICP-MS standards as tracers for the column chromatography sections of the227,225Ac† purification process (see Section 7.2.5). Values represent the por-tion of each element found in each fraction of the process, after correcting forbackground quantities measured when no tracers were present. The boldedcolumn represents the final 227,225Ac† product.element portion of initial tracer mass in each fraction [%]loadcitricwashnitricwashDGAloadDGAwashAc elutionLnelutionBe 0.19 55.63 33.36 6.60 0.02 0.000 ± 0.000 0.00Al 10.44 135.82 9.89 0.00 0.00 0.000 ± 0.183 0.00V 15.62 69.92 0.01 0.02 0.00 0.000 ± 0.002 0.00Cr 0.00 5.48 0.00 102.44 2.07 0.000 ± 0.031 0.65Mn 0.00 4.25 2.05 103.53 0.43 0.000 ± 0.008 0.02Co 0.00 0.26 2.06 104.33 0.55 0.000 ± 0.003 0.00Ni 0.10 33.26 41.16 71.75 0.49 0.000 ± 0.036 0.19Cu 0.00 98.33 1.58 0.00 0.00 0.058 ± 0.010 0.12Zn 0.00 0.00 14.52 81.42 1.15 0.000 ± 0.056 0.03Ga 0.01 74.20 0.06 0.04 0.00 0.000 ± 0.001 2.30As 92.79 45.54 2.04 0.08 0.00 0.000 ± 0.001 0.36Se 52.72 80.76 1.85 0.16 0.02 0.040 ± 0.073 0.26Rb 29.36 35.91 0.03 0.00 0.00 0.000 ± 0.000 0.00Sr 0.00 11.62 9.00 95.11 4.83 1.935 ± 0.054 0.00Y 0.29 111.67 12.12 0.00 0.08 0.000 ± 0.003 0.06Ag 10.34 62.11 11.66 3.76 0.01 0.000 ± 0.000 0.00Cd 0.03 0.00 0.37 100.45 0.52 0.028 ± 0.004 0.04Cs 8.30 59.31 0.02 0.00 0.00 0.000 ± 0.000 0.0024Note no consistent operational cycle for the generator has yet been applied.175Ba 0.19 3.97 2.71 102.50 0.00 0.000 ± 0.001 0.00La 0.00 0.00 0.09 3.53 0.34 2.995 ± 0.023 75.24Ce 0.00 0.08 0.08 0.25 0.01 0.038 ± 0.001 53.27Pr 0.00 0.02 0.02 0.09 0.00 0.004 ± 0.000 30.77Nd 0.00 3.19 1.22 0.06 0.00 0.001 ± 0.000 10.45Sm 0.00 76.88 2.01 0.01 0.00 0.000 ± 0.000 0.03Eu 0.00 83.10 0.87 0.02 0.00 0.000 ± 0.000 0.00Gd 0.00 80.84 1.62 0.00 0.00 0.001 ± 0.000 0.14Dy 0.00 85.36 0.53 0.00 0.00 0.000 ± 0.000 0.09Ho 0.00 87.16 0.38 0.00 0.00 0.000 ± 0.000 0.00Er 0.00 88.76 0.12 0.00 0.00 0.000 ± 0.000 0.02Tm 0.00 89.64 0.03 0.00 0.00 0.000 ± 0.000 0.00Yb 0.00 89.79 0.02 0.00 0.00 0.000 ± 0.000 0.00Lu 0.00 90.46 0.01 0.00 0.00 0.000 ± 0.000 0.00Tl 0.07 70.30 20.14 3.59 0.17 0.180 ± 0.003 0.18Pb 2.77 0.00 1.53 127.00 3.17 0.003 ± 0.004 0.06Th 6.69 91.26 0.12 0.79 0.10 0.000 ± 0.000 0.00U 0.05 78.63 0.03 0.14 0.00 0.007 ± 0.001 0.02Ti 19.72 93.21 15.42 0.08 0.00 0.000 ± 0.000 0.00Ge 98.50 0.00 0.00 0.00 0.00 0.000 ± 0.001 0.00Zr 7.73 115.78 8.09 1.83 0.23 0.263 ± 0.020 0.15Nb 41.50 0.00 0.00 4.17 1.23 0.677 ± 0.025 0.63Mo 97.72 0.61 2.12 0.77 0.20 0.183 ± 0.009 0.10Sb 31.70 0.00 0.00 0.03 0.03 0.011 ± 0.001 0.02Hf 5.52 65.92 1.31 1.16 0.19 0.203 ± 0.013 0.12Ta 76.78 0.00 0.08 8.35 2.69 0.257 ± 0.377 1.81W 618.89 0.00 0.05 6.84 2.41 1.126 ± 0.051 1.217.3.3 Comparison of 227,225Ac† and 225Ac* productsThe radionuclidic purity of both 227,225Ac† and 225Ac* products, averagedover two production runs, is shown in Table 7.2. Results for 227,225Ac†, decaycorrected to the end of processing (7 days after end of irradiation), were con-sistent with the results of Table 7.1, with small amounts of La (2.29% 140La)and Sr (0.14% 85Sr) isotopes present in the Ac fraction. While Table 7.1suggest that small amounts of refractory metals (ex. tungsten) may also endup in the Ac fraction, radioisotopes of these elements are not co-producedin large quantities relative to 225Ac or 225Ra during thorium irradiations, asshown in Figure 7.3. The largest 227,225Ac† radionuclide impurity was 226Ac176(t1/2 = 29.37 h), at (5.83 ± 0.82)% of the total radioactivity. 227Ac con-tent in the in the 227,225Ac† product measured (0.15 ± 0.04)% by ICP-MS(Section 7.2.6), which is similar to values reported by other labs producing225Ac from proton-induced spallation of thorium [136, 138–141, 143].In comparison, 227Ac in 225Ac* was reduced to <7.5E-5% in both (n = 2)samples, in one sample measuring below the ICP-MS detection limit (<0.1pg/mL, or <7.1E-5% of the 225Ac activity). This measurement is supportedby gamma spectroscopy measurements which show no detectable 227Th in-growth from 227Ac after a 4 month decay period, supporting 227Ac contentof <5E-4%. 226Ac content is similarly reduced in the 225Ac* product. 228Ac(t1/2 = 6.14 h) impurities are expected to be present in both227,225Ac† and225Ac* products, but likely decayed before gamma spectroscopy measure-ments. While the total amount of 103,106Ru and 85Sr was similar for both227,225Ac† and 225Ac*, the ∼4 times smaller quantity of 225Ac* results inan increase of the percent impurities for these nuclides. The reduced 140La(t1/2 = 1.68 d) impurities present in225Ac* originated from the decay of140Ba (t1/2 = 12.75 d) that follows Ra isotopes through the process andends up in the 225Ra/225Ac generator (see Figure 7.6).The chemical purity of the 227,225Ac† and 225Ac* products determinedby ICP-MS measurements (Section 7.2.6) is shown in Figure 7.7. Most el-ements measure below 0.1 µg per MBq of 225Ac, with Ca the only elementthat was consistently above 0.1 µg/MBq25. As previously mentioned, theseelevated Ca levels were observed only when processing irradiated materi-als, and is discussed further in Section 7.4. While the calcium impuritiesare problematic due to their saturation of the DGA column, reducing the227,225Ac† chemical yields from the process, the amount of calcium and otherstable impurities measured in the product did not appear to negatively affectradiolabelling capabilities of either the 227,225Ac† or 225Ac* products, withthe exception of the one 227,225Ac† product that contained >10 µg/MBq ofstable calcium impurities.Radiolabelling results for both 227,225Ac† and 225Ac* products withDOTA and macropa are shown in Figure 7.8. Radiolabelling yields for bothDOTA and macropa using both radionuclide products was comparable tovalues reported in the literature for other sources of 225Ac [3]. Macropa la-belling yields26 with both radionuclide products was >95% down to chelateconcentrations of 10-6 M; DOTA labelling yields27 with both products was25Ba was above this threshold in 1 or 2 samples.26At ambient temperature, 30 minute reaction time, pH 727At 85◦C, 30 minute reaction time, pH 7177Table 7.2: Average (n = 2) radionuclidic purity of 227,225Ac† and 225Ac*products, decay corrected to the times of final product purification. 227Acvalues were determined by ICP-MS (Section 7.2.6) while all other valueswere determined by gamma spectroscopy (Section 7.2.3).percent radioactivity [%]227,225Ac† 225Ac*Ac-225 93.04 98.82Ac-227 0.15 <7.2E-5Ac-226 5.83 <0.01La-140 2.29 0.01Ru-106 <0.04 0.13Ru-103 0.25 0.72Sr-85 0.14 0.33Th-227 <0.04 <0.17Ra-226 <0.01 <0.06Ra-225 <0.01 <0.05Ra-224 <0.07 <0.02Ra-223 <0.04 <0.14Ce-141 <0.01 <0.03Ba-140 <0.01 <0.04178>95% down to chelate concentrations of 10-4 M, with the exception of theone 227,225Ac† product that contained >10 µg/MBq of stable calcium impu-rities (Figure 7.7).7.4 DiscussionThe chemical process presented in Section 7.3.2 produced two 225Ac productsthat adequately labelled DOTA and macropa, however, no attempts have yetbeen made to optimize the process to improve the radionuclidic and chemicalpurity. Initial conditions for use of the cation and DGA columns were chosenbased off of data from experiments with Th, Ra, and Ac alone (Figure 7.5)and did not yet consider other elements. Given that, the radiochemicalpurity observed for the first two production runs (Table 7.2) is encouraging,though improvements may need to be made to reduce the Sr, Ru, and Laradioimpurities.Given that Sr and Ru have distribution coefficients (Kd) with log(Kd)<1on DGA-normal resin in 4 M HNO3 [169, 223], it is likely that simply in-creasing the volume of the DGA column wash may reduce the amount ofthese impurities in the 225Ac products. If not, Sr-selective extraction resins[224], or anion exchanges resins for Ru removal [225] could be incorporatedinto the process as in-line filters for removal of these radioimpurities with-out expecting considerable Ac losses. Increasing the wash volume may alsoreduce stable impurities such as Pb, Ba, Zn, and Fe [223]. Optimizing thevolume of the Ac elution (currently 13 mL of 12 M HNO3) may also reducethe La impurities: as shown in Figure 7.5, this volume is larger than neededto elute >95% of Ac, and the La Kd under these conditions is known to bemuch larger than that for Ac [160, 169]. Changing the wash and Ac elutionmay also help reduce the Ca impurities, as Ac and Ca separation on DGA-normal resin in high molarity HNO3 has also been previously demonstrated[226].However, removing the source of Ca impurities is likely the best wayto improve chemical purity. Since observing the saturation of the DGA-column by Ca during processing of irradiated thorium, a higher purity cit-ric acid (Honeywell FlukaTM Citric Acid monohydrate, TraceSELECTTM≥99.9998% metals basis) has been found to address this issue. Still, othersources of calcium are expected, due to the differences observed between theprocessing of irradiated and non-irradiated materials: these may include Caimpurities in the thorium metal or Ca leached from the processing equip-ment components (ex. glassware) due to the presence of HF during the179dissolution (see Section 7.2.4).If these initial challenges to the chemical and radionuclidic purity can beresolved without reducing the 225Ra or 225Ac* radiochemical yields, then themethods presented herein may provide a new source of accelerator-produced225Ac with significantly reduced 227Ac content compared to other 227,225Ac†sources produced by irradiation of 232Th. Irradiation of the existing tar-get design (Section 7.3.1) for a full two weeks is expected to produce 566MBq (15.3 mCi) of 225Ra per target, once process losses (5%) and decaylosses28 (10%) are considered. Since each MBq of 225Ra could produce ap-proximately 0.9 MBq of 225Ac*, assuming a 1 week operational cycle of thegenerator, the irradiation and processing of 1 target per week for 35 weeksper year29 could produce approximately 17.8 GBq (0.5 Ci) per year of 225Acwith reduced 227Ac content. Since TRIUMF’s IPF is capable of irradiating12 targets simultaneously [5, 191], an additional 6-fold increase to the po-tential production quantities is also readily available. Additional increasescould be achieved by increasing the thorium target thickness, though thiswould require a re-evaluation of the target’s safety envelope [5].While the 225Ac* product may have reduced 227Ac content, one cleardisadvantage is the lower quantity produced: approximately 5-6 timesmore 225Ac than 225Ra was produced at the end of previous irradia-tions. Still, the 227,225Ac† product may be useful as a parent nuclide in225Ac/213Bi generators if the presence of 227Ac prevents its direct use in225Ac-radiopharmaceuticals.The targeted alpha therapy field has yet to establish an acceptable limitfor 227Ac, though this is crucial to any future production, quality control,and use of both 227,225Ac† and 225Ac*. If the source of 227Ac concerns iswaste disposal and the resulting costs, then an 227Ac limit per patient dose(approximately 10 MBq of 225Ac) equal to the exemption level for for 227Acdisposal provides one potential limit to consider30. In Canada and underguideline exemption quantities recommended by the International AtomicEnergy Agency (IAEA) [227–229], the 227Ac exemption level is 1 kBq. Thiscorresponds to a 227Ac limit on the order of 0.01%, which is not met by227,225Ac† but is easily met by 225Ac* (Table 7.2). In fact even our firstattempts at 225Ac* production demonstrate that at <7.5E-5% 227Ac con-28Assuming 2 days between the end of irradiation and the end of target processing29TRIUMF’s 500 MeV cyclotron typically operates only 8 months per year.30The IAEA defines an exemption level as “A value, established by a regulatory body andexpressed in terms of activity concentration, total activity, dose rate or radiation energy, ator below which a source of radiation need not be subject to some or all aspects of regulatorycontrol” [227].180tent, a batch of 102 patient doses could contain 227Ac below the exemptionlevel and could be considered 227Ac-free from regulatory and practical per-spectives. While other jurisdictions may have more restrictive exemptionlevels that would necessitate additional improvements in the current 227Acimpurities reported in Table 7.2, this work demonstrates that 225Ac prod-ucts with reduced 227Ac content can be derived from the proton spallationof thorium. With an 227Ac decontamination factor of >2000 from just thefirst two attempts at 225Ac* production, it is conceivable that 225Ac* prod-ucts could meet 227Ac limits that are ultimately accepted by the targetedalpha therapy field in the event that 227Ac content in 227,225Ac† products isdetermined to be too high.7.5 SummaryA precipitation- and chromatography-based process for the separation of Acfrom gram quantities of Th and trace quantities of most other elements wasdeveloped and demonstrated. This process has application in the productionof 225Ac from proton irradiated thorium.When sufficient quantities of 225Ra are also co-produced during thoriumirradiation, this process is capable of producing an 225Ac product (225Ac*)with 227Ac quantities >2000 times lower than other thorium-spallation-derived 225Ac products (227,225Ac†). The 227,225Ac† product demonstratedsimilar or better quality when compared to the 225Ac* product in terms ofradiolabelling and chemical purity, and contained 227Ac content low enoughsuch that multiple patient doses of 225Ac contained less than the IAEArecommended exemption level for 227Ac, and could therefore be considered227Ac-free from a regulatory perspective.181dissolve 8 g Th in 60 mL 10 M HNO3 + 12.5 mM HFevaporate to dryness, redissolve in 80 mL 1 M HNO3add 56 mL 30% H2O2, stir for 2 hfilter and wash precipitate with 140 mL H2ODOWEX 50X8 (200-400 mesh, 10 mL)bulk ThRa, Ac, trace Th(diluted filtrate, 0.5 M HNO3)load citric washnitric wash 50 mL 0.5 M HNO3450 mL 1 M citric acid, pH 2.0-2.280 mL 8 M HNO380 mL H2O precipitatetrace ThDGA-normal (0.2 mL)DGA load DGA wash13 mL 12 M HNO35 mL 4 M HNO310 mL 0.05 M HNO3Ra, trace AcRa, Ac227,225Ac†Ln elutionDGA-normal (0.2 mL)13 mL 12 M HNO35 mL 4 M HNO3225Ac*DGA-normal (1.0 mL)Ra225Ra/225Ac generatorFigure 7.4: Flowchart describing the process used to produce 227,225Ac†and 225Ac* products from thorium metal irradiated with high energy (>100MeV) protons. Coloured squares correspond to the fractions shown in theFigure 7.6 legend.182 XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ    YROXPH>P/@ IUDFWLRQRILQLWLDODFWLYLW\>@7K ,9 $UVHQD]R7K5D5D5D$F$F XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ            YROXPH>P/@ IUDFWLRQRILQLWLDODFWLYLW\>@ XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ         YROXPH>P/@ IUDFWLRQRILQLWLDODFWLYLW\>@ XQWLWOHGVYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSXQWLWOHGVYJ    YROXPH>P/@ IUDFWLRQRILQLWLDODFWLYLW\>@7K ,9 $UVHQD]R7K5D5D5D$F$F~250 mL filtrate (0.5 M HNO3)450 mL 1 M citric acid pH 2.0-2.2 50 mL 0.5 M HNO380 mL 8 M HNO3 VYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSVYJ           YROXPH>P/@IUDFWLRQRILQLWLDODFWLYLW\>@ VYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSVYJ        YROXPH>P/@IUDFWLRQRILQLWLDODFWLYLW\>@~260 mL diluted cation eluate (4 M HNO3) 5 mL 4 M HNO3 13 mL 12 M HNO3cation columnDGA column VYJÀOH 8VHUVDQGUHZUREHUWVRQ'HVNWRSVYJ         YROXPH>P/@IUDFWLRQRILQLWLDODFWLYLW\>@Figure 7.5: Elution profiles for Th, Ra, and Ac on the cation exchangecolumn (top) and DGA-normal column (bottom) using thorium colorimetry,227Th, 225,224,223Ra, and 228,225Ac as tracers (see Section 7.2.4). Each datapoint represents the average ± standard deviation (n = 3) of independentelution profile measurements with the 7 individual tracers.183loadcitric washnitric washDGA load (225Ra/225Ac gen.)DGA washAc elution (227,225Ac† product)Ln elutionnot recovered11/18/2019 untitled.svgfile:///Users/andrewrobertson/Desktop/untitled.svg 1/1H HeLi Be B C N O F NeNa Mg Al Si P S Cl ArK Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br KrRb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I XeCs Ba Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At RnFr RaLa Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb LuAc Th Pa UResults from tracer studies of the TRIUMF thorium target processFigure 1. Results after passing multi-element ICP-MS standards through Th-target purification process (precipitation step excluded). Elements with bolded borders were evaluated using radiotracers (96Tc, 103Ru, 101mRh, 114mIn, 117mSn, 121m,121Te, 205,206Bi, 225,224,223Ra, 228,225Ac). The area of each colour is proportional to the amount of the elemental tracer found in the fraction.Figure 7.6: Results from tracer studies of the thorium processing schemechromatography column steps. Elements with bold borders were evalu-ated using radiotracers (96Tc, 103Ru, 101mRh, 114mIn, 117mSn, 121m,121Te,205,206Bi, 225,224,223Ra, 228,225Ac). All other elements were evaluated usingmulti-element ICP-MS standards as tracers. The area of each colour is pro-portional to the amount of the elemental tracer found in the fraction.11/27/2019 untitled.svgfile:///Users/andrewrobertson/Desktop/untitled.svg 1/1Figure 7.7: Average ± standard deviation (n = 2) stable elemental impuri-ties in the 227,225Ac† and 225Ac* products, measured as described in Section7.2.6.18411/21/2019 XQWiWOed.VYgÀOe:///UVeUV/aQdUeZURbeUWVRQ/DeVkWRS/XQWiWOed.VYg 1/14 5 6 7 8-log([chelaWe]) (M)020406080100RCY (%) DOTA, 227,225AcmacUoSa, 227,225AcDOTA, 225AcmacUoSa, 225Ac † †* *Figure 7.8: Concentration dependent radiolabelling studies with 227,225Ac†and 225Ac* products for both DOTA (85◦C, 30 min, pH 7) and macropa(ambient temperature, 30 min, pH 7), as described in Section 7.2.7. Eachdata point represents the average ± standard deviation of n = 6 replicates(n = 3 replicates for each of the two 227,225Ac† and 225Ac* production runs).1858 ConclusionChapter 3 demonstrates how 225Ac can be produced at TRIUMF’s ISOLfacility. Mass A = 225 ion beams containing up to 1.6×108 ions/s and up to1.3×108 ions/s of 225Ra and 225Ac, respectively, were implanted into an alu-minum target. Implantations produced up to 8.6 MBq of 225Ra and up to 18MBq of 225Ac, which were separated using solid phase extraction DGA resin,resulting in a radiochemically pure 225Ac product in >98% yield. Calcium,iron, copper, nickel and zinc were found in the 225Ac product with amountsof (1392 ± 208), (203 ± 20), (47 ± 12), (19 ± 6), and (137 ± 21) ppb,respectively. This 225Ac product was of suitable quantity and quality foruse in preclinical 225Ac-radiopharmaceutical development, as demonstratedby the number of publications that resulted from the 225Ac production runsdescribed in Table 3.1 [3, 4, 162, 163], including Chapter 4 of this thesis.However, due to demands for beam from other experiments, uranium car-bide target reliability, and variations in the 225Ac ion beam yield (between106 and 108 ions/s), the 225Ac available from ISAC is realistically limited toa few tens of MBq per year.The significance of the work presented in Chapter 3 is therefore notin the amount of 225Ac that can be produced, but in the ability to pro-vide relatively small quantities of radioactivity with a limited amount ofinitial work. In contrast to conventional radionuclide production methods,no proton target (as in Chapter 5) or radiochemical separation strategy (asin Chapter 7) development is required for production of a new nuclide atISAC. Instead one selects and tunes the beam to obtain a new mass fromthe mass separator. This versatility is a key strength of this nuclide pro-duction and isolation method. The experience with 225Ac gained from usingthis initial ISOL-based production method motivated and made easier theproduction and handling of 225Ac via the methods that were later developedusing TRIUMF’s IPF facility (see Chapters 5 to 7).With larger-scale 225Ac production from TRIUMF’s IPF, future oppor-tunities to produce novel medical radionuclides using ISAC-ISOL should186take advantage of this facility’s versatility by studying other nuclides besides225Ac. This could include 226Ac, which is an Ac isotope that, as describedbelow, could potentially be directly imaged using its 230 keV gamma line.Other future research efforts regarding ISAC implantations should con-sider the use of different implantation target materials for collection of theion beam. While the aluminum targets used in this work have the advan-tage of being easy to manufacture and handle, the etching of the implantedradioactivity from the material adds large amounts of metal impurities tothe 225Ac radionuclide product, including Al and other trace metals foundin aluminum materials, such as Ca, Fe, Ti, Zn, Zr, and Pb (see Table 3.2).While measurements of the resulting 225Ac product radiolabeling capabilitysuggest this did not negatively impact the usability of the 225Ac producedfrom ISAC, this may not be the case for the collection of other radionuclides.Radiolabeling using nuclides with different chemical properties from Ac maybe more adversely affected by the presence of these stable metal impuri-ties, which can compete with the radiometal during radiolabeling reactions.In addition, the impurity profile of the radionuclide product will changewhen using different post-implantation radiochemical separation strategiesrequired to purify radiometals other than Ac from Ra (a single DGA resinwas used in Chapter 3 to separate 225Ra and 225Ac that were co-implanted).Removing the source of these metal impurities by using a non-metallic im-plantation target could improve the chemical purity of the radionuclidesproduced at ISAC. Potential alternative target materials could include thinhigh-purity salts used in radiolabeling buffers (ex. ammonium acetate) orice, though the latter would likely require development of a cryogenicallycooled implantation chamber.Applications of the ISAC-produced 225Ac include the 225Ac decay chainimaging presented in Chapter 4 [4]. With respect to research questions out-lined in Section 1.4, this work successfully demonstrated that VECTor canindividually quantify distributions of 225Ac progeny nuclides via simulta-neous 221Fr and 213Bi SPECT and also characterized the performance ofthe instrumentation for creating such images, including assessment of imageresolution, contrast recovery, and noise. A hotrod resolution phantom con-taining clusters of thin rods with diameters ranging between 0.85 and 1.70mm was used to assess resolution. To demonstrate ability to simultaneouslyimage dynamic 221Fr and 213Bi activity distributions, a phantom contain-ing a 213Bi generator from 225Ac was imaged. These tests were performedwith two collimators, a high-energy ultra-high resolution (HEUHR) collima-tor and an ultra-high sensitivity (UHS) collimator. Values consistent withactivity concentrations determined independently via gamma spectroscopy187were observed in high activity regions of the images. In hotrod phantomimages, the HEUHR collimator resolved all rods for both 221Fr and 213Biimages. With the UHS collimator, no rods were resolvable in 213Bi imagesand only rods ≥1.3 mm were resolved in 221Fr images. After eluting the213Bi generator, images accurately visualized the reestablishment of tran-sient equilibrium of the 225Ac decay chain. This work demonstrates the po-tential ability of evaluating the pharmacokinetics of the 225Ac decay chainin vivo, but requires the use of a high-performance, high-energy collimator.The ability to separately assess the biodistributions of each alpha emis-sion in the 225Ac decay chain and the resulting integrated dose to var-ious tissues could significantly impact the in vivo assessment of 225Ac-radiopharmaceuticals by enabling more detailed dosimetry. Determining thecomplete 221Fr and 213Bi biodistributions is challenging by ex vivo methodsdue to the short half-lives of 221Fr (t1/2 = 4.8 min) and213Bi (t1/2 = 45.6min). As discussed in Section 4.1, other imaging techniques are not able toprovide such information. While other imaging modalities such as alpha-cameras [180] or Cherenkov imaging [181] have also been used to image thebiodistributions of the 225Ac decay chain or other alpha-emitting medicalisotopes, quantitative SPECT has a distinct advantage over these methodsin that photon energy discrimination can be used to distinguish betweendifferent components of the 225Ac decay chain. The information made avail-able through this technique could be of significant importance to 225Ac ra-diopharmaceutical development. Providing a complete picture of the 225Acdecay chain’s pharmacokinetics over time would measure the fraction of225Ac progeny isotopes maintained at the target site and could resolve per-sisting concerns within the field regarding the safety of serial alpha emittingradionuclides such as 225Ac [100].However, until the use of this imaging technique can be demonstratedin a preclinical model, any suggested benefits to 225Ac-radiopharmaceuticaldevelopment remain hypothetical. As mentioned in Section 1.4, this waspreviously not pursued because of an inability to produce sufficient quan-tities of 225Ac. New 225Ac production methods at TRIUMF described inChapters 5-7 now make such experiments possible.However, even with access to greater quantities of 225Ac this imagingtechnique may be limited by the fact that capturing 221Fr and 213Bi im-ages requires the administration of 225Ac quantities that are 2-3 orders ofmagnitude greater than the amount that would be used therapeutically. Infact, the amount of 225Ac required with VECTor to image the 225Ac decaychain’s biodistribution in a mouse model (approximately 10 MBq or more) iscomparable to a therapeutic 225Ac dose in a human patient [25, 31, 32]. The188consequences of this are that not only may the biodistribution of imageable225Ac quantities differ from the biodistribution of therapeutic quantities –thereby reducing the image’s utility for predicting biological outcomes – butalso that an imageable 225Ac quantity may be too toxic for an animal modelto survive long enough to complete a SPECT scan. Nevertheless future re-search efforts should explore the ability of the VECTor system to image the225Ac decay chain in vivo and explore this unanswered question.It should also be noted that, even if such preclinical imaging is ableto provide more detailed dosimetry of 225Ac-radiopharmaceuticals in pre-clinical models, the technique is unlikely to be applicable to dosimetry inhuman patients. Again, this is because capturing 221Fr and 213Bi imagesrequires the administration of 225Ac quantities that are 2-3 orders of mag-nitude greater than the amount that would be used therapeutically, makingsuch a diagnostic image potentially harmful. Imaging to assess the 225Acdecay chain’s biodistribution and resulting dosimetry in patients prior tothe administration of an 225Ac-radiopharmaceutical may not be possible.Instead, such images must likely use other diagnostic radionuclides; this hasbeen done already, for example, with 68Ga and 111In [25, 230]. This is incontrast to direct imaging with 213Bi-radiopharmaceuticals, which generallyhave a ∼102 times higher maximum tolerable dose [231] and are imageablein therapeutic quantities [179].While diagnostic radionuclides such as 68Ga and 111In may provide aquantitative biodistribution that may be analogous to a subsequent 225Ac-biodistribution, they would not be able to measure the fraction of 225Acprogeny nuclides maintained at the target site or the fraction that providesdose to organs at risk. Additionally, the use of a non-Ac imaging isotopewould create lingering questions about whether the biodistribution of theimaging radiopharmaceutical is still representative of the biodistributionof a chemically different 225Ac-version of the radiopharmaceutical. 226Acis perhaps the only directly imageable SPECT nuclide (using its 230 keVgamma line), however, it similarly comes with technical challenges relatedto radionuclide production.Despite these potential limitations of 225Ac decay chain imaging, thedesire to produce larger 225Ac quantities to enable in vivo imaging experi-ments motivated a change in focus for this thesis away from ISOL-produced225Ac and towards the development of an alternative, larger-scale produc-tion methodology that is described by Chapters 5-7. While this does notdiminish the successes of Chapters 3 and 4 – which achieved TRIUMF’s first225Ac production and demonstrated the ability to simultaneously image mul-tiple components of the 225Ac decay chain – the 225Ac production methods189described in Chapters 5-7 have greater potential to produce GBq quantitiesof 225Ac, enabling studies not reasonable achievable using ISOL-produced225Ac.Regarding research questions proposed in Section 1.4, Chapter 5 specif-ically demonstrates how a thorium target can be designed for irradiation atTRIUMF’s IPF, which proton beam parameters can result in a safe irradi-ation, and how much 225Ac and 225Ra can be produced during irradiations.A new 225Ac-production target system capable of withstanding the powerdeposited by the proton beam was designed and its performance simulatedover a range of potential operating parameters (proton beam widths and in-tensities). Special attention was given to heat transfer and stress simulationswithin the target components during irradiation. Even with the applicationof conservative assumptions to the simulation inputs and with conservativethresholds for target safety, results show that all beams of width >20 mmand current <100 µA result in safety factors on the target windows >1.The target was successfully tested in two irradiations with a 72–73 µA pro-ton beam for a duration of 36.5 h, demonstrating saturation yields of 72.5MBq/µA and 17.6 MBq/µA for 225Ac and 225Ra, respectively.The quantities that can be produced using these IPF targets are signif-icant, both with respect to the amount available at TRIUMF and, poten-tially, the amount produced globally per year (approximately 63 GBq, seeSection 1.3). It is estimated that the simultaneous irradiation of 12 targetsover a 240 hour period could produce 42 GBq of 225Ac and 7 GBq of 225Rawithout requiring any changes to the target or beam parameters. Furtherincreases are possible if the proton current and target thickness are increased(as discussed below). Chapter 5 therefore provides the first demonstrationof TRIUMF’s capability as a potentially significant large-scale producer of225Ac. The methods and results of Chapter 5 may also be useful for targetdevelopment projects at similar institutions or at other TRIUMF irradiationfacilities.While a strength of the work in Chapter 5 is that the modelling shows– even with very conservative assumptions – that these thorium targetscan be safely irradiated, there are significant limitations to the methodolo-gies that were applied. Due to the potential for production of hazardousalpha-emitting, volatile and gaseous radionuclides during the irradiation ofthorium with high-energy protons, the work in Chapter 5 was motivated bythe need to demonstrate confidence that these targets could be irradiatedsafely (see also Appendices C and D). While such work was required beforethe 225Ac production research described in Chapters 6 and 7 could continue,these safety motivations meant that assumptions were made regarding the190input parameters of the models in Chapter 5, especially regarding unknownthermal properties of relevant materials (see Section 5.3).These assumptions in the models’ input parameters are a key limitationof the scientific work of Chapter 5, as is the absence of a comparison ofthe models to empirical data. These assumptions and their implications arediscussed thoroughly in Section 5.3. Assumptions regarding the materialproperties of thorium can be credited in part to the radioactive nature ofthorium and its designation as special nuclear material. Such factors makethorium a more logistically challenging material to study or use and there-fore limit the amount of available data in the literature, relative to othernon-radioactive or non-nuclear materials. For similar reasons, when con-ducting the work described in Chapter 5, it was not realistically possible tomeasure relevant thorium material properties because available equipmentwas located in facilities that lacked regulatory permission to possess or han-dle thorium. Procurement of devices – inside a sufficiently licensed facility– to measure the thermal conductivity of thorium and the thermal contactresistance of the thorium-Inconel interface of the IPF targets will improvethe accuracy of the models presented in Chapter 5 and enable these modelsto be validated against quantitative data.Such improvements to the thermomechanical models of the thorium tar-gets during irradiation will be increasingly important if future efforts areundertaken to increase the thickness of the thorium irradiated in each tar-get in support of increasing 225Ac production. While the IPF target stationhas space for a 32-fold increase in thorium thickness, more thorium meansmore heat deposition within the target by the proton beam, meaning moreheat that must be conducted through the thorium and across the thorium-Inconel interface. The assumptions used in Chapter 5 will therefore becomeincreasingly prohibitive as the amount of thorium within the targets is in-creased.Despite these limitations, the work of Chapter 5 resulted in the de-sign and irradiation of a thorium target at TRIUMF’s IPF, demonstratingthe facility’s 225Ac production capability and enabling subsequent researchregarding the separation of Ac from irradiated thorium targets that is pre-sented in Chapter 7. Despite the limitations of the models that have beendiscussed, the work of Chapter 5 provides a strong foundation for any futurethorium target design efforts, including the use of thermomechanical modelsbased on empirical input data, provided such data becomes available in thefuture.The thin nature of the thorium target design also enabled the crosssection measurements described in Chapter 6. Thorium spallation cross191sections at proton energies of 438 MeV were determined to be (13.30 ±1.21) mb and (4.2 ± 0.40) mb for 225Ac and 225Ra, respectively. A total of36 other independent or cumulative cross sections for 232Th(p,x) reactions at438 MeV were also determined, including those relevant to 225Ac production,such as 227Ac and 226Ac. These measurements contribute not only to thefield of TAT but also to the body of known nuclear data by reporting nuclideformation cross sections that have not previously been measured (see Figure6.4).These 38 cross section measurements were also used to validate Flukasimulations that enable the estimation of the production of the many othernuclides produced during the proton irradiation of thorium. While not thefirst study to do this, other reported Fluka validation studies used differenttarget materials or different proton energy ranges [150–159]. Determiningthat Fluka is able to estimate the radioactive inventory of the irradiatedthorium targets to within a factor of 2 is a valuable conclusion that permitsFluka to be used in practical situations where knowledge of the radioactiveinventory is required but is too onerous or is impossible to measure; examplesinclude radiation safety analyses (see Appendices C and D) or radioactiveshipping inventories. Since Fluka is not the only Monte Carlo based high-energy particle transport code, future work could include a comparison withother codes (for example, Geant4 [232, 233]) or with future versions ofFluka itself. Future efforts could also consider repeating the cross sectionsreported in Chapter 6, as data from only a single irradiation was reported onin Chapter 6 due to the significant amount of effort required to analyze thegamma spectra (see Figure 6.1) and the long decay periods since EOB forthese gamma spectroscopy samples shown in Table 6.1. However, any futurerepetitions of the work would be much easier now that gamma spectroscopyanalysis methods for thorium spallation spectra are established.Nevertheless, Fluka is evidently a valuable tool for estimating the ra-dionuclide inventory that results from the high-energy proton irradiation ofthorium and, consequently, for estimating the requirements of radiochemicalseparation processes used to purify Ac from any irradiated thorium targets(see Figure 7.3). The radiochemical separation developed and characterizedin Chapter 7 is one such process. The work of Chapter 7 accomplishes thegoals set out in Section 1.4 by: demonstrating how existing radiochemi-cal separation methods for isolation of Ac from proton irradiated IPF tar-gets could be modified for use in TRIUMF’s radiochemistry facilities; using225Ra produced during thorium irradiation to chemically isolate a generator-produced Ac product (225Ac*) with fewer long-lived impurities (specifically,227Ac) than the directly-produced Ac product (227,225Ac†); and by charac-192terizing and comparing the quality of these two Ac products.Ac was separated from irradiated thorium and coproduced radioac-tive spallation and fission products using a thorium peroxide precipitationmethod followed by cation exchange and extraction chromatography. Stableand radioactive tracer studies demonstrated the ability of this method to sep-arate Ac from most other elements, providing a directly produced Ac prod-uct (227,225Ac†) with measured 227Ac content of (0.15 ± 0.04)%. The second,indirectly produced Ac product (225Ac*) with 227Ac content of <7.5×10-5%is obtained by repeating the final extraction chromatography step with the225Ra-containing fraction. The 225Ra-derived 225Ac* showed similar or im-proved quality compared to the initial, directly-produced 227,225Ac† productin terms of chemical purity and radiolabeling capability, the latter of whichwas comparable with other 225Ac sources reported in the literature.While the radiochemical process applied (see Figure 7.4) in Chapter 7includes some process steps that are similar to other methods described inthe literature [104], modifications and additional process steps were intro-duced that provide substantial benefit. The most considerable addition isthe initial thorium peroxide precipitation, which has shown to be an effectiveand reliable method for thorium de-bulking without resulting in significantAc or Ra losses (see Section 7.3.2). The removal of >95% of the thoriummass from the solution early in the process enables the use of smaller chro-matography column(s) and fraction volumes in subsequent process steps,reducing the time needed for these steps and the quantity of radioactivewaste that results. Additionally, the initial thorium de-bulking provides fora process that can be more easily applied to any future irradiations of tar-gets containing larger quantities of thorium, as part of efforts to increase225Ac production. While various methods for Ac extraction from irradiatedthorium exist in the literature [104, 136, 143, 160, 206], this is the first toinclude such an initial de-bulking method. The development of this thoriumprecipitation was additionally important when conducting thorium targetprocessing at radiochemistry facilities at TRIUMF, since the reduction inchromatography column volumes and reagent volumes resulted in a reducedequipment footprint that was necessary in order to fit the process insideavailable hot cells.While this thorium peroxide precipitation has shown to be a reliableand effective thorium de-bulking method, future research efforts should fo-cus on exploring alternative precipitation methods and on deepening ourunderstanding of the thorium peroxide precipitation chemistry. While otherprecipitates, including thorium oxalate and thorium iodate were briefly ex-plored [219], they were found to either be too difficult to filter or to result193in greater co-precipitation of Ra or Ac than the thorium peroxide approachunder the conditions tested. These other precipitates may be more effec-tive under alternative conditions, and precipitations using other insolublethorium compounds are yet to be studied [194]. Known advantages of thethorium peroxide approach are its compatibility with previous and subse-quent process steps, the small (<5%) losses of Ac and Ra, and the easeof filtration. Additionally, the ability to easily redissolve the precipitatein a concentrated nitric acid substantially reduces the amount of handlingrequired to dispose of any waste, an important consideration for chemicalprocesses that must be conducted remotely inside a hot cell. However, thesefeatures of the thorium peroxide precipitation have been observed withouta complete understanding of the chemistry involved in thorium peroxideformation or the structure of the thorium peroxide that results [215, 216].Additionally, while actinides are generally known to form insoluble perox-ides (the co-precipitation of uranium with thorium peroxide is previouslyreported [221], and the co-precipitation of protactinium with thorium per-oxide was observed described in Section 7.3.2), the reasons why Ac was notobserved to similarly co-precipitate with thorium peroxide remain unclearand could also be a focus of future research.The subsequent process steps used to purify Ac from irradiated thoriumtargets include ion exchange and extraction chromatography. Chemically,these steps are similar to previously reported methods [104], though thethorium de-bulking enabled practical changes to the cation exchange processstep that make it more reproducible and easier to carry out inside a hot cell.Specifically, by removing the bulk mass of thorium, the separation of Thfrom Ac and Ra on the cation exchange resin in a citric acid liquid phasecan be done as a column wash, as opposed to a column loading step appliedby other methods [104]. In practical terms, this means that pH adjustmentof the citric acid (to within the narrow 2.0-2.2 range required for successfulseparation of Th from Ac and Ra) can be performed outside of the hot cell aspreparation of an input reagent to the process, as opposed to within the hotcell as part of an additional process step. While the process overall resultedin 227,225Ac† and 225Ac* products that demonstrated adequate radiolabellingcapabilities (see Section 7.3.3), future research or development efforts mayneed to address the presence of other stable (ex. Ca2+) or radioactive (ex.140La, 106,103Ru, and 85Sr) impurities, as discussed in detail in Section 7.4.Together, Chapters 5, 6, and 7 demonstrate the production of 225Acfrom a new source (TRIUMF’s IPF). These production methods not onlyaddress the initial motivations for transitioning the work of this thesis awayfrom ISAC-based production (see Section 1.4), but they also have a theo-194retical potential to provide 225Ac in quantities that could markedly increaseglobal 225Ac supply. While 225Ac can also be produced through long-lived229Th generators, increasing 229Th availability is challenging since the grow-in of 229Th (t1/2 = 7340 y) from233U takes decades due to the long 229Thhalf-life (see Section 1.3). Accelerator-based 225Ac production is thereforeadvantageous for its scaleability. Accelerator-based methods involving 226Rairradiation are technically viable but, for reasons detailed in Section 1.3.4.4,have not been pursued to the same extent as 232Th irradiation methods.While the proton spallation of thorium for 225Ac production typically in-cludes the co-production of 227Ac, data reported in Chapter 6 demonstratesthat at proton energies above approximately 100 MeV, 225Ra production issufficient to produce 225Ac via 225Ra/225Ac generators. This reduces 227Acimpurities, as shown in Chapter 7.Together, Chapters 5, 6, and 7 are the first demonstration of 225Ac* pro-duction technology using a thorium irradiation facility and chemical processthat could be scaled to useful clinical or commercial quantities, while main-taining 227Ac content low enough to be potentially considered 227Ac-freefrom practical and regulatory perspectives. Irradiation of the existing tar-get design (Chapter 5) for a full two weeks is expected to produce 566 MBq(15.3 mCi) of 225Ra per target, once process losses (5%) and decay losses(10%) are considered (assuming 2 days between the end of irradiation andthe end of target processing). Since each MBq of 225Ra could produce ap-proximately 0.9 MBq of 225Ac*, assuming a 1 week operational cycle of thegenerator, the irradiation and processing of 1 target per week for 35 weeksper year (TRIUMF’s 500 MeV cyclotron typically operates only 8 monthsper year) could produce approximately 17.8 GBq (0.5 Ci) per year of 225Ac*.Since TRIUMF’s IPF is capable of irradiating 12 targets simultaneously, anadditional 6-fold increase to the potential production quantities is also read-ily available. This potential annual production of 53.4 GBq/y (3 Ci/y) of225Ac* would represent a 1.75-fold increase in the global availability of 225Ac(see Section 1.3) and is readily available from the methods demonstrated inChapters 5 through 7. Such a scale up of 225Ac production beyond therelatively limited number of irradiations and processed targets described inthis thesis has yet to be demonstrated and would likely require the estab-lishment of engineered radiochemistry equipment, a robust quality controlprogram, and (due to the number of long-lived radionuclides co-producedduring thorium irradiation) a sustainable plan for radioactive waste man-agement. Still, the work presented in this thesis provides the foundation forsuch an 225Ac production paradigm should it be pursued in the future.195Bibliography[1] A. K. H. Robertson, C. F. Ramogida, P. Schaffer, and V. 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Arce, M. Asai, T. Aso,E. Bagli, A. Bagulya, S. Banerjee, G. Barrand, B. R. Beck, A. G.Bogdanov, D. Brandt, J. M. Brown, H. Burkhardt, P. Canal, D. Cano-Ott, S. Chauvie, K. Cho, G. A. Cirrone, G. Cooperman, M. A. Corte´s-Giraldo, G. Cosmo, G. Cuttone, G. Depaola, L. Desorgher, X. Dong,A. Dotti, V. D. Elvira, G. Folger, Z. Francis, A. Galoyan, L. Gar-nier, M. Gayer, K. L. Genser, V. M. Grichine, S. Guatelli, P. Gue`ye,P. Gumplinger, A. S. Howard, I. Hrˇivna´cˇova´, S. Hwang, S. Incerti,A. Ivanchenko, V. N. Ivanchenko, F. W. Jones, S. Y. Jun, P. Kai-taniemi, N. Karakatsanis, M. Karamitrosi, M. Kelsey, A. Kimura,T. Koi, H. Kurashige, A. Lechner, S. B. Lee, F. Longo, M. Maire,D. Mancusi, A. Mantero, E. Mendoza, B. Morgan, K. Murakami,T. Nikitina, L. Pandola, P. Paprocki, J. Perl, I. Petrovic´, M. G.Pia, W. Pokorski, J. M. Quesada, M. Raine, M. A. Reis, A. Ri-bon, A. Ristic´ Fira, F. Romano, G. Russo, G. Santin, T. Sasaki,D. Sawkey, J. I. Shin, I. I. Strakovsky, A. Taborda, S. Tanaka, B. Tome´,T. Toshito, H. N. Tran, P. R. Truscott, L. Urban, V. Uzhinsky, J. M.Verbeke, M. Verderi, B. L. Wendt, H. Wenzel, D. H. Wright, D. M.Wright, T. Yamashita, J. Yarba, and H. Yoshida, “Recent develop-223ments in GEANT4,” Nuclear Instruments and Methods in PhysicsResearch, Section A: Accelerators, Spectrometers, Detectors and As-sociated Equipment, vol. 835, pp. 186–225, 2016.224A Additional Details on GammaSpectroscopy Calibrations225 1 us pulse shape2 us pulse shapeA.1 Pulse Shape Timing Effects on Energy Reso-lution226 8 us pulse shape4 us pulse shape227Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 9Chi-square : 4.08Region Start : 51.881 keVRegion End : 54.323 keVNbr Energy Centroid Area %Error FWHM Ratio 1 53.112 217.04 158817.45 0.97 0.794 1.07 10000 20000 30000 40000 50000 60000 7000049 50 51 52 53 54 55 56 57Counts -4.0 -2.0 0.0 2.0 4.049 50 51 52 53 54 55 56 57ResidA.2 Fits to Peaks used in Energy and Shape Cal-ibrations228Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 11Chi-square : 12.30Region Start : 78.504 keVRegion End : 82.412 keVNbr Energy Centroid Area %Error FWHM Ratio 1 79.577 325.40 227298.39 0.52 0.836 1.05 2 80.993 331.19 2849221.75 0.19 0.839 1.05 0 100000 200000 300000 400000 500000 600000 700000 80000076 77 78 79 80 81 82 83 84 85Counts -5.0 0.0 5.0 10.076 77 78 79 80 81 82 83 84 85Resid229Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 25Chi-square : 1.55Region Start : 120.516 keVRegion End : 124.180 keVNbr Energy Centroid Area %Error FWHM Ratio 1 121.809 498.29 2194664.25 0.14 0.881 1.01 2 123.077 503.48 23429.91 1.77 0.883 1.01 0 100000 200000 300000 400000 500000 600000118 119 120 121 122 123 124 125 126 127Counts -2.0 -1.0 0.0 1.0 2.0 3.0118 119 120 121 122 123 124 125 126 127Resid230Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 10Chi-square : 1.23Region Start : 274.913 keVRegion End : 278.089 keVNbr Energy Centroid Area %Error FWHM Ratio 1 276.420 1131.17 248665.17 0.52 1.049 0.98 0 10000 20000 30000 40000 50000 60000272 273 274 275 276 277 278 279 280 281Counts -2.0 -1.0 0.0 1.0 2.0 3.0272 273 274 275 276 277 278 279 280 281Resid231Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 12Chi-square : 2.21Region Start : 301.300 keVRegion End : 304.477 keVNbr Energy Centroid Area %Error FWHM Ratio 1 302.876 1239.45 602191.25 0.25 1.069 0.97 0 20000 40000 60000 80000 100000 120000 140000298 299 300 301 302 303 304 305 306 307Counts -4.0 -2.0 0.0 2.0 4.0298 299 300 301 302 303 304 305 306 307Resid232Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 13Chi-square : 7.35Region Start : 354.322 keVRegion End : 357.499 keVNbr Energy Centroid Area %Error FWHM Ratio 1 356.035 1457.01 1797139.38 0.11 1.127 0.98 0 50000 100000 150000 200000 250000 300000 350000 400000352 353 354 355 356 357 358 359 360Counts -4.0 -2.0 0.0 2.0 4.0 6.0 8.0352 353 354 355 356 357 358 359 360Resid233Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 11Chi-square : 3.83Region Start : 776.854 keVRegion End : 781.253 keVNbr Energy Centroid Area %Error FWHM Ratio 1 779.010 3187.82 182302.28 0.49 1.535 1.04 0 5000 10000 15000 20000 25000 30000774 776 778 780 782 784Counts -4.0 -2.0 0.0 2.0 4.0774 776 778 780 782 784Resid234Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 11Chi-square : 1.22Region Start : 1083.297 keVRegion End : 1091.848 keVNbr Energy Centroid Area %Error FWHM Ratio 1 1085.84 4443.43 109234.41 0.66 1.814 1.09 2 1089.76 4459.48 18329.62 1.01 1.816 1.09 0 2000 4000 6000 8000 10000 12000 14000 160001080 1082 1084 1086 1088 1090 1092 1094 1096Counts -3.0 -2.0 -1.0 0.0 1.0 2.0 3.01080 1082 1084 1086 1088 1090 1092 1094 1096Resid235Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107b_P0-02.CNFSample ID : cal_P0_20160925Sample Date : 2016-09-25 6:54:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 11Chi-square : 3.25Region Start : 1405.022 keVRegion End : 1411.128 keVNbr Energy Centroid Area %Error FWHM Ratio 1 1408.06 5762.45 151396.52 0.42 2.101 1.15 0 2000 4000 6000 8000 10000 12000 14000 16000 180001402 1404 1406 1408 1410 1412 1414 1416Counts -4.0 -2.0 0.0 2.0 4.01402 1404 1406 1408 1410 1412 1414 1416Resid236A.3 Peak Width Values Based on Linear Calibra-tion Curve237Library Listing Report 2016-12-20 10:42:24 PM Page 1 ************************************************************************* ***** L I B R A R Y L I S T I N G R E P O R T ***** ************************************************************************* Filename: C:\GENIE2K\LIBRARIES\BACKGROUND.NLB Nuclide Library Description: Nuclide Half-Life Energy Energy Yield Yield Name (Seconds) (keV ) Uncert. (keV ) (%) Uncert.(Abs.+-) K-40 3.938E+016 1460.822 0.006 10.6600 0.1800 Tl-208 1.832E+002 10.600 0.050 2.7500 0.1200 72.805 0.001 2.0100 0.0600 74.969 3.350 0.0900 0.0600 84.450 0.005 0.4040 0.0110 84.938 0.001 0.7760 0.0120 87.300 0.050 0.2830 0.0080 510.770 0.100 22.6000 0.2000 583.187 0.002 85.0000 0.3000 763.130 0.080 1.7900 0.3000 860.557 0.004 12.5000 0.1000 927.600 0.200 0.1250 0.0110 Pb-210 7.006E+008 10.800 0.050 22.7000 0.1000 46.539 0.001 4.2500 0.0400 Tl-210 7.800E+001 296.000 3.000 79.0000 10.0000 799.600 0.300 98.9600 0.0050 Bi-212 1.500E+003 727.330 0.009 6.6700 0.0900 785.370 0.080 1.1020 0.0130 893.408 0.005 0.3780 0.0190 952.120 0.011 0.1700 0.0300 1078.620 0.100 0.5640 0.0190 1620.500 0.100 1.4700 0.0300 Pb-212 3.830E+004 10.800 0.050 14.3000 0.6000 74.815 0.001 10.2800 0.2500 77.107 0.001 17.1000 0.4000 86.830 0.005 2.0700 0.0500 87.349 0.001 3.9700 0.0900 89.784 0.001 1.4600 0.0300 115.183 0.005 0.5960 0.0090 238.632 0.002 43.6000 0.5000 300.087 0.001 3.3000 0.0400 Bi-214 1.194E+003 11.100 0.050 0.7700 0.0300 76.863 0.001 0.5450 0.0150 79.290 0.005 0.9070 0.0230 89.256 0.001 0.1100 0.0030 92.317 0.001 0.0777 0.0020 273.800 0.050 0.1280 0.0070 280.970 0.040 0.0670 0.0070 333.370 0.050 0.0650 0.0040 348.920 0.060 0.1040 0.0120 351.900 0.500 0.0700 0.0100 386.780 0.050 0.2950 0.0050 388.890 0.050 0.4020 0.0100A.4 Library Used for Background Analysis238Library Listing Report 2016-12-20 10:42:24 PM Page 2 Nuclide Library Description: Nuclide Half-Life Energy Energy Yield Yield Name (Seconds) (keV ) Uncert. (keV ) (%) Uncert.(Abs.+-) Bi-214 1.194E+003 394.050 0.080 0.0126 0.0009 396.020 0.060 0.0260 0.0040 405.720 0.020 0.1690 0.0060 454.790 0.020 0.2920 0.0040 469.770 0.040 0.1320 0.0050 609.320 0.005 45.4900 0.1600 665.447 0.009 1.5310 0.0060 703.110 0.040 0.4720 0.0090 719.870 0.030 0.3920 0.0080 752.850 0.030 0.1280 0.0070 768.360 0.005 4.8940 0.0110 786.350 0.140 0.3200 0.0400 806.180 0.009 1.2640 0.0050 821.180 0.030 0.1610 0.0080 826.450 0.100 0.1170 0.0130 934.056 0.006 3.1070 0.0100 964.080 0.030 0.3650 0.0100 1051.960 0.030 0.3130 0.0070 1069.960 0.070 0.2720 0.0090 1120.292 0.006 14.9200 0.0300 1133.660 0.030 0.2512 0.0010 1155.210 0.008 1.6330 0.0060 1207.680 0.030 0.4510 0.0100 1238.122 0.007 5.8340 0.0150 1280.976 0.010 1.4340 0.0060 1303.750 0.070 0.1070 0.0050 1377.669 0.008 3.9880 0.0110 1385.310 0.013 0.7930 0.0050 1401.515 0.012 1.3300 0.0050 1407.988 0.011 2.3940 0.0070 1509.210 0.010 2.1300 0.0100 1661.274 0.016 1.0470 0.0060 1729.595 0.011 2.8780 0.0080 1764.491 0.010 15.3000 0.0300 1847.429 0.013 2.0250 0.0090 Pb-214 1.608E+003 10.800 0.050 12.0000 0.6000 53.228 0.002 1.0750 0.0070 74.815 0.001 5.8000 0.3000 77.107 0.001 9.7000 0.5000 86.830 0.005 1.1700 0.0600 87.349 0.001 2.2400 0.1100 89.784 0.001 0.8200 0.0400 118.170 0.005 0.0940 0.0005 196.190 0.050 0.0670 0.0080 205.680 0.090 0.0114 0.0013 241.995 0.002 7.2510 0.0160 258.860 0.030 0.5310 0.0040 274.800 0.040 0.3550 0.0100 295.223 0.002 18.4200 0.0400 298.760 0.005 0.0260 0.0050 305.260 0.030 0.0312 0.0021 314.330 0.070 0.0780 0.0060239Library Listing Report 2016-12-20 10:42:24 PM Page 3 Nuclide Library Description: Nuclide Half-Life Energy Energy Yield Yield Name (Seconds) (keV ) Uncert. (keV ) (%) Uncert.(Abs.+-) Pb-214 1.608E+003 323.840 0.040 0.0290 0.0030 351.932 0.002 35.6000 0.0700 462.020 0.060 0.2120 0.0050 480.432 0.020 0.3370 0.0040 487.140 0.060 0.4320 0.0050 511.000 0.009 0.0330 0.0090 533.660 0.020 0.1810 0.0060 538.420 0.080 0.0200 0.0030 543.830 0.070 0.0440 0.0040 580.140 0.030 0.3700 0.0040 785.960 0.080 1.0600 0.0300 839.070 0.080 0.5830 0.0080 Rn-218 3.500E-002 609.310 0.060 0.1240 0.0070 Th-231 9.187E+004 13.300 0.050 59.0000 15.0000 25.640 0.020 14.1000 0.9000 84.214 0.001 6.6000 0.4000 Th-234 2.082E+006 13.300 0.050 7.1000 0.5000 63.290 0.020 3.7000 4.0000 92.380 0.010 2.1300 0.2000 92.800 0.020 2.1000 0.2000 112.810 0.050 0.2100 0.0230 U-234 7.747E+012 120.900 0.020 0.0350 0.0050 U-235 2.221E+016 13.000 0.050 27.0000 4.0000 19.550 0.050 63.0000 0.0500 89.957 0.001 3.4300 0.0900 93.350 0.005 5.5400 0.1400 105.604 0.001 1.3100 0.0030 143.760 0.020 0.2000 0.0020 185.715 0.005 57.0000 0.6000 202.120 0.010 1.0800 0.0230 205.316 0.010 5.0200 0.0600 * = key lineTOTALS: 13 Nuclides 126 Energy Lines240 2 Table 1. List of nuclides in Genie 2000 V3.2 TCS library. AC-228 CD-109† EU-156 IN-114M2† ND-149 RA-224* SC-47* TL-200 AG-108 CD-109M* F-20* IN-115M* NI-65 RA-226* SE-75 TL-200M AG-108M CD-109M2 FE-52* IN-115M2* NP-237 RA-228 SE-77M* TL-201 AG-109M* CD-111M FE-52M IN-116 NP-239 RB-83 SM-153 TL-201M AG-110 CD-115 FE-59 IN-116M OS-185 RB-86* SM-153M TL-202 AG-110M CD-115M GA-67 IN-116M2* OS-191* RB-86M* SN-113† TL-208 AG-111* CE-137 GA-72 IN-117 OS-191M* RB-88 SN-113M* TL-210 AG-111M CE-137M GD-151 IN-117M* OS-193 RE-186 SN-117M TM-168 AL-26 CE-139 GD-153 IR-192 PA-231 RE-186M SN-123* TM-170 AL-28* CE-139M* GD-153M IR-194 PA-233 RE-188 SN-123M* U-0 AM-241* CE-141* GD-153M2 IR-194M PA-234 RE-188M SN-125 U-235* AM-243* CE-143 GD-159* IR-194M2 PA-234M RH-101 SN-125M U-237 AS-74 CE-144* GD-159M K-42 PB-203 RH-101M SR-85 U-238 AS-76 CF-249* GE-75* KR-87 PB-203M* RH-102 SR-85M U-238M* AU-195 CF-251† GE-75M KR-88 PB-203M2 RH-102M SR-87M* U-239* AU-195M* CL-38 GE-77 LA-140 PB-210* RH-102M2* TA-182 V-48 AU-196 CL-38M* GE-77M* LU-172 PB-212* RH-105* TA-182M2 W-187 AU-196M* CM-243 HF-175 LU-172M* PB-214 RH-106 TB-158 XE-127 AU-196M2 CM-245 HF-180M* LU-172M2* PD-109* RH-106M TB-158M* XE-127M AU-198* CO-56 HF-180M2 LU-173 PD-109M* RH-99 TB-158M2 Y-88 AU-198M CO-57 HF-181 LU-174 PD-111 RH-99M TB-160 Y-88M AU-199* CO-58 HG-197 LU-174M PD-111M RU-103* TC-95 Y-90* AU-199M* CO-58M* HG-197M LU-176 PM-143 RU-103M* TC-95M Y-90M BA-131 CO-60 HG-203* LU-176M PM-144 RU-105 TC-98 YB-169 BA-131M CO-60M I-123 MN-52 PM-145 RU-97 TC-99* YB-169M*BA-133 CR-51* I-125 MN-52M* PM-146 S-37* TC-99M* YB-175 BA-133M CS-134 I-126 MN-56 PM-148 SB-122 TE-127 YB-177 BA-135M* CS-134M I-131 MO-99 PM-148M SB-122M TE-127M YB-177M BA-137M* CS-136 I-132 NA-22 PM-149* SB-122M2* TE-129 ZN-65* BA-139* CU-64* I-132M NA-24 PM-151 SB-124 TE-129M ZN-69* BA-140 DY-165 I-133 NB-92 PR-142 SB-124M* TE-131 ZN-69M* BI-207 DY-165M I-133M NB-92M PR-144 SB-124M2 TE-131M ZR-95* BI-207M ER-167M* I-134 NB-94 PR-144M SB-125 TE-132 ZR-97 BI-212 ER-171 I-134M NB-94M* PT-188 SB-126 TE-132M BI-214 EU-152 I-135 NB-95* PT-191 SB-126M TH-0 BR-77 EU-152M IN-111 NB-95M PT-191M* SB-127 TH-228 BR-77M* EU-152M2* IN-111M* NB-95M2* PT-197 SC-44 TH-231 BR-82 EU-154 IN-113M* NB-97* PT-197M SC-44M TH-232 BR-82M EU-154M IN-114 NB-97M* PU-239 SC-46 TH-234* CA-47 EU-155 IN-114M ND-147 RA-0 SC-46M* TI-44 A.5 Isotopes in the Genie 2000 v3.2 Cascade Sum-ming Library241Library Listing Report 2017-01-09 5:38:44 PM Page 1 ************************************************************************* ***** L I B R A R Y L I S T I N G R E P O R T ***** ************************************************************************* Filename: C:\GENIE2K\CAMFILES\PTCAL.NLB Nuclide Library Description: Nuclide Half-Life Energy Energy Yield Yield Name (Seconds) (keV ) Uncert. (keV ) (%) Uncert.(Abs.+-) MN-54 2.702E+007 834.827* 0.000 99.9750 0.0050 CO-57 2.341E+007 122.063* 0.000 85.5100 0.1800 136.476 0.000 10.6000 0.1800 CU-64 4.572E+004 511.000* 0.000 35.2000 0.4000 1345.770 0.060 0.4750 0.0110 ZN-65 2.112E+007 511.000 0.000 200.0000 0.0000 1115.520* 0.000 50.7500 0.1000 ZR-89 2.823E+005 511.000 0.000 45.5000 0.5000 909.150* 0.150 99.0400 0.0050 CD-109 4.009E+007 88.032* 0.000 3.7200 0.1100 SN-113 9.945E+006 255.120 0.000 1.9300 0.1000 391.688* 0.000 64.9000 0.7000 TE-123m 1.364E+010 159.000* 0.000 0.0000 0.0000 CS-137 9.521E+008 661.650* 0.000 85.1200 0.2300 HG-203 4.026E+006 279.190* 0.000 77.3000 0.8000 RA-225 1.287E+006 40.000* 1.000 30.0000 0.0500 AM-241 1.364E+010 59.537* 0.001 35.9000 0.4000 * = key lineTOTALS: 12 Nuclides 17 Energy LinesA.6 Library Used for Peak-to-Total Calibration242Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 14Chi-square : 2.19Region Start : 29.675 keVRegion End : 32.117 keVNbr Energy Centroid Area %Error FWHM Ratio 1 30.424 124.07 604438.13 2.06 0.796 1.19 2 30.810 125.65 1275426.75 1.34 0.797 1.19 0 100000 200000 300000 400000 500000 60000027 28 2 30 31 32 33 34Counts -5.0 0.0 5.0 10.0 15.027 28 2 30 31 32 33 34ResidA.7 Fits to Peaks used in the Efficiency Calibra-tionThe data presented in this section was acquired as described in Section 2.1.5.243Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 10Chi-square : 12.64Region Start : 38.222 keVRegion End : 41.397 keVNbr Energy Centroid Area %Error FWHM Ratio 1 39.426 160.93 507707.16 0.63 0.816 1.17 2 40.011 163.32 963352.38 0.51 0.818 1.17 0 50000 100000 150000 200000 250000 300000 35000036 37 38 3 40 41 42 43 44Counts -5.0 0.0 5.0 10.036 37 38 3 40 41 42 43 44Resid244Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 9Chi-square : 2.56Region Start : 51.654 keVRegion End : 54.584 keVNbr Energy Centroid Area %Error FWHM Ratio 1 53.100 216.92 59922.52 1.69 0.810 1.11 6000 10000 14000 18000 22000 260004 50 51 52 53 54 55 56 57Counts -2.0 0.0 2.0 4.04 50 51 52 53 54 55 56 57Resid245Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : VMS Standard Peak Search FitBkgnd Type : StepIterations : 2Chi-square : 4.47Region Start : 78.518 keVRegion End : 82.670 keVNbr Energy Centroid Area %Error FWHM Ratio 1 79.609 325.47 77969.36 1.44 0.857 1.09 2 80.988 331.11 947035.56 0.13 0.830 1.05 0 50000 100000 150000 200000 250000 30000076 77 78 7 80 81 82 83 84 85Counts -6.0 -4.0 -2.0 0.0 2.0 4.076 77 78 7 80 81 82 83 84 85Resid246Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 20Chi-square : 16.17Region Start : 120.528 keVRegion End : 123.703 keVNbr Energy Centroid Area %Error FWHM Ratio 1 121.797 498.20 786961.00 0.30 0.865 1.00 2 122.928 502.83 9598.58 3.67 0.867 1.00 0 50000 100000 150000 200000 25000011 120 121 122 123 124 125 126Counts -10.0 -5.0 0.0 5.0 10.011 120 121 122 123 124 125 126Resid247Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : VMS Standard Peak Search FitBkgnd Type : StepIterations : 1Chi-square : 5.60Region Start : 243.154 keVRegion End : 246.330 keVNbr Energy Centroid Area %Error FWHM Ratio 1 244.716 1001.37 127079.59 0.54 1.029 1.00 0 5000 10000 15000 20000 25000 30000 35000241 242 243 244 245 246 247 248Counts -4.0 -2.0 0.0 2.0 4.0241 242 243 244 245 246 247 248Resid248Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 12Chi-square : 1.30Region Start : 300.811 keVRegion End : 304.475 keVNbr Energy Centroid Area %Error FWHM Ratio 1 302.850 1239.35 246015.23 0.42 1.068 0.98 0 10000 20000 30000 40000 50000 600002 8 2 300 301 302 303 304 305 306 307Counts -2.0 -1.0 0.0 1.0 2.0 3.02 8 2 300 301 302 303 304 305 306 307Resid249Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 12Chi-square : 2.95Region Start : 342.590 keVRegion End : 346.011 keVNbr Energy Centroid Area %Error FWHM Ratio 1 344.276 1408.90 311955.56 0.34 1.108 0.98 0 10000 20000 30000 40000 50000 60000 70000340 341 342 343 344 345 346 347 348Counts -4.0 -2.0 0.0 2.0 4.0340 341 342 343 344 345 346 347 348Resid250Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 13Chi-square : 1.72Region Start : 354.074 keVRegion End : 357.983 keVNbr Energy Centroid Area %Error FWHM Ratio 1 356.010 1456.92 699148.38 0.17 1.120 0.98 0 20000 40000 60000 80000 100000 120000 140000 160000351 353 355 357 35 361Counts -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0351 353 355 357 35 361Resid251Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 10Chi-square : 1.84Region Start : 381.928 keVRegion End : 385.349 keVNbr Energy Centroid Area %Error FWHM Ratio 1 383.835 1570.80 92059.26 0.64 1.134 0.97 0 4000 8000 12000 16000 2000037 380 381 382 383 384 385 386 387 388Counts -3.0 -2.0 -1.0 0.0 1.0 2.0 3.037 380 381 382 383 384 385 386 387 388Resid252Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : VMS Standard Peak Search FitBkgnd Type : StepIterations : 1Chi-square : 2.60Region Start : 409.051 keVRegion End : 412.960 keVNbr Energy Centroid Area %Error FWHM Ratio 1 411.147 1682.44 21809.62 1.00 1.194 1.00 500 1000 1500 2000 2500 3000 3500 4000 4500 5000406 408 410 412 414 416Counts -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0406 408 410 412 414 416Resid253Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 10Chi-square : 2.16Region Start : 776.350 keVRegion End : 781.238 keVNbr Energy Centroid Area %Error FWHM Ratio 1 778.959 3187.68 66625.45 0.80 1.528 1.04 0 2000 4000 6000 8000 10000 12000772 774 776 778 780 782 784Counts -3.0 -2.0 -1.0 0.0 1.0 2.0 3.0772 774 776 778 780 782 784Resid254Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 12Chi-square : 1.25Region Start : 864.818 keVRegion End : 869.951 keVNbr Energy Centroid Area %Error FWHM Ratio 1 867.456 3549.79 19807.60 2.17 1.619 1.06 0 500 1000 1500 2000 2500 3000 3500862 864 866 868 870 872 874Counts -2.0 -1.0 0.0 1.0 2.0 3.0862 864 866 868 870 872 874Resid255Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 11Chi-square : 1.23Region Start : 1082.064 keVRegion End : 1092.572 keVNbr Energy Centroid Area %Error FWHM Ratio 1 1085.80 4443.30 38682.43 0.92 1.802 1.09 2 1089.71 4459.32 6634.42 1.59 1.804 1.09 0 1000 2000 3000 4000 5000 60001078 1080 1082 1084 1086 1088 10 0 10 2 10 4 10 6Counts -2.0 -1.0 0.0 1.0 2.0 3.01078 1080 1082 1084 1086 1088 10 0 10 2 10 4 10 6Resid256Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 10Chi-square : 1.47Region Start : 1108.943 keVRegion End : 1115.051 keVNbr Energy Centroid Area %Error FWHM Ratio 1 1112.05 4550.75 50832.14 0.92 1.806 1.09 0 1000 2000 3000 4000 5000 6000 70001106 1108 1110 1112 1114 1116 1118Counts -4.0 -2.0 0.0 2.0 4.01106 1108 1110 1112 1114 1116 1118Resid257Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 12Chi-square : 0.77Region Start : 1296.334 keVRegion End : 1302.441 keVNbr Energy Centroid Area %Error FWHM Ratio 1 1299.15 5316.55 5420.52 3.10 1.990 1.13 0 100 200 300 400 500 600 70012 4 12 6 12 8 1300 1302 1304 1306Counts -2.0 -1.0 0.0 1.0 2.0 3.012 4 12 6 12 8 1300 1302 1304 1306Resid258Datasource : C:\GENIE2K\CAMFILES\Detector Maintenance\cal_R01107a_P5-01.CNFSample ID : cal_20mL_farSample Date : 2016-09-22 8:15:00 PMFit Engine : Sum / Non-Linear LSQ FitBkgnd Type : StepIterations : 10Chi-square : 2.78Region Start : 1404.786 keVRegion End : 1411.625 keVNbr Energy Centroid Area %Error FWHM Ratio 1 1408.02 5762.28 62844.36 0.59 2.083 1.15 0 1000 2000 3000 4000 5000 6000 70001400 1402 1404 1406 1408 1410 1412 1414 1416Counts -4.0 -2.0 0.0 2.0 4.01400 1402 1404 1406 1408 1410 1412 1414 1416Resid259A.8 List of 133Ba and 152Eu Calibration SourcesR-# Description ActivityR-01106Stock 133Ba solution, (5.108± 3%) kBq/mL on2016-06-01(102.3 ± 3.1) kBq attime of purchaseR-01107Stock 152Eu solution, (5.157± 3%) kBq/mL on2016-06-01(103.4 ± 3.1) kBq attime of purchaseR-01107a20 mL vial containing 20 mLvolume(30.05 ± 0.90) kBqof 133Ba(30.23 ± 0.91) kBqof 152EuR-01107b20 mL vial containing 20 mLvolume(1.505 ± 0.045) kBqof 133Ba(1.515 ± 0.045) kBqof 152EuR-01107cHPLC vial containing 1.5 mLvolume(1.507 ± 0.045) kBqof 133Ba(1.520 ± 0.046) kBqof 152EuTable A.1: List of calibration sources belonging to TRIUMF Life Sciencesgroup used for the calibration of the detector. All activity values refer tothe activity on 2016-06-01.260B Alpha Spectroscopy Procedures26120191008 114800 Template: Document-18187 Rel.7 Page 1 of 15 Document-174953 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document Type: Operating Procedures Release: 1 Release Date: 2019-10-07 Author(s): Brooke McNeil, Andrew Robertson Name: Approval Record Author: Brooke McNeil Approved By: Andrew Robertson Note: Before using a copy (electronic or printed) of this document you must ensure that your copy is identical to the released document, which is stored on TRIUMF’s document server. 262 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 2 of 15 History of Changes Release Number Date Description of Changes Author(s) 1 2019-10-07 Initial Release Brooke McNeil, Andrew Robertson Keywords: Alpha spectrometer, microprecipitation, cerium fluoride, 225Ac, HF Distribution List: Brooke McNeil, Andrew Robertson, Paul Schaffer, Valery Radchenko, Caterina Ramogida, Vicky Hannemaayer, Hua Yang 263 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 3 of 15 1 Scope The following document describes how to perform microprecipitation to determine 225Ac activity on the ORTEC alpha spectrometer. Microprecipitation is a common method used to allow for the measurement of actinides by alpha spectrometry. In the microprecipitation method, a stable carrier, with a mass of tens to hundreds of micrograms, is added so that the insoluble carrier precipitate, which is cerium fluoride in the following described method, aids the precipitated analyte, present in much smaller quantities (mBq to Bq), to be captured by the filter rather than be lost in vacuum filtration. Microprecipitation is useful for alpha spectroscopy as the sample layer formed is thin, which prevents self-absorption of alpha particles in the sample material. 2 Safety 2.1 PPE requirements Personal protective equipment necessary for the purification procedure includes: • Lab coat • Safety glasses • Gloves (Double, thick nitrile) and sleeve protectors • Fume hood 2.2 Training requirements Required training: • Chemical Safety • Lab Safety • WHMIS • Advanced Radiation Protection • HF Handling • Alpha Radiation Workers must be designated as a Nuclear Energy Worker and must have completed forty hours of supervised training prior to handling 225Ac. 2.3 Safety Requirements This procedure involves the use of concentrated hydrofluoric acid. Consults SDS and HF handling SOP prior to performing this procedure. 264 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 4 of 15 3 Materials 3.1 Apparatus • Falcon tubes (15 mL) • Tweezers • Transfer pipets • Heat lamp • Funnel apparatus • Clamp • Vacuum flask • Vacuum • Double sided tape • Resolve filter – 0.1 μm 25 mm polypropylene (Eichrom part: RF-100-25PP01) 3.2 Reagents and Solutions All reagents should be made using MilliQ water. • 500 μg/mL Ce carrier (3.570 mM cerium nitrate hexahydrate) • 80% ethanol • 100% ethanol • Hydrofluoric acid (49%) • 0.05 M HNO3 265 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 5 of 15 4 Microprecipitation Procedure1 1. To a solution of 225Ac, using 0.05 M HNO3, dilute such that the concentration is 1-10 Bq/μL. 2. To a 15 mL Falcon tube, add 100 μL of the 225Ac solution and then make the volume up to 10 mL with 0.05 M HNO3. 3. Add 200 μL of the cerium carrier solution (100 μg Ce) and 1 mL of concentrated (49%) hydrofluoric acid to the tube. 4. Vortex and allow the solution to mix for at least 30 minutes before filtering. 5. Set up the vacuum apparatus as shown below in Figure 1. Fig. 1. Vacuum apparatus set up for microprecipitation _____________________________________________________________________________ 1For information on assaying other elements, refer to the Eichrom procedure, “Rare Earth Fluoride Microprecipitation”, Method No. SPA01. 266 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 6 of 15 6. Place a Resolve filter (White filter located between two blue protective sheets) onto the filter apparatus and lower the funnel apparatus and use a clamp to secure the two apparatuses. 7. Apply vacuum (10 in. Hg) and use a transfer pipet to add 5 mL of 80% ethanol to condition the filter and allow all of the solution to pass through the filter. 8. Use a transfer pipet to add 3 mL of MilliQ water to the filter and allow all of the solution to pass through. 9. While continuously mixing the sample solution with the transfer pipet, add the sample to the filter. Once all of the sample has passed through, add 5 mL of MilliQ water to the used Falcon tube and then add to the filter. Allow the entire solution to pass through the filter. 10. Wash the sides of the funnel apparatus with 5 mL of MilliQ water followed by 3 mL of anhydrous ethanol once the solution has completely passed through. Run the vacuum for an additional 2 minutes to allow the filter to further try. 11. Turn off the vacuum and use tweezers to remove the filter from the filter apparatus. Place the filter in a dish and put under the heat lamp for approximately 3 minutes or until it is dry which can be observed by it turning from a dull grey to bright white in colour. Once dry, remove from heat to prevent overheating and wrinkling of the filter. 12. Allow the sample to reach transient equilibrium (At least overnight) before measuring on the alpha spectrometer. 267 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 7 of 15 5 Measurement on the Alpha Spectrometer The following instructions are based on the ORTEC Soloist Alpha Spectrometer and for use with the Alpha Acquisition and Analysis Software. Figure 2 shows the set-up of the alpha spectrometer. Fig. 2. ORTEC Soloist Alpha Spectrometer The main components of the alpha spectrometer include the detector, vacuum chamber (Figure 3), pulser control, and vacuum control. 1. Plug in the vacuum and turn the vacuum control dial to vent (Setting shown in Figure 2). 2. Open the vacuum chamber door, which is shown below in Figure 3. 268 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 8 of 15 Fig. 3. Vacuum Chamber 3. Attach the filter, using double sided tape, to the sample holder, shown in Figure 4, and insert the sample holder into the second last slot from the detector, which is the gold cylinder shown at the top of the chamber in Figure 3. Fig. 4. Sample Holder 5. Close the vacuum chamber door and ensure it is sealed. If it is not sealing, apply vacuum grease around the O ring using a KimWipe and wipe away any excess. Turn the vacuum control dial to pump. 6. Allow the sample to be pumped down for at least one minute. 269 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 9 of 15 7. In the alpha spectrometer software (Alpha Analysis and Acquisition), enter in the sample details by clicking the icon, as shown in Figure 5 below. Fig. 5. Example Sample Information for a Microprecipitation Sample 8. To load the correct calibration files in the sample info, click “Load Cal”, found in the right bottom corner in Figure 5, and select “alpha_P09.CAL” and the efficiency calibration box to select this file for the efficiency calibration, as shown below in Figure 6, and then click load. To load the energy calibration, select “alpha_enerCal_temp.CAL” and the energy calibration box and then click load. 270 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 10 of 15 Fig. 6. Alpha spectrometer calibration files 9. To edit the counting time, click on the icon and enter the desired counting time. 10. Under acquire, click start to begin counting the sample and allow to count for the desired amount of time. An alpha spectrum for the Ac-225 decay chain should appear as shown below in Figure 7. 271 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 11 of 15 Fig. 7. Alpha Spectrum of 225Ac Decay Chain 11. Once the sample has finished counting, click “Analyze” and then select “Execute Sequence” and then select “Ac-225 ALPHA”, as shown below in Figure 8. 272 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 12 of 15 Fig. 8. Analysis of Alpha Spectrometer Data 12. The analysis sequence will generator a report that identifies the radionuclides and their activity in the sample. 13. The final amount of 225Ac in the sample, assuming transient equilibrium of the decay chain during the measurement, is calculated by taking the output value for the 217At peak and multiplying by the filtration efficiency of (53.0 + 3.8)%. See Section 6 for more details on how this efficiency was determined. 6 Analysis sequence The Ac-225 ALPHA analysis sequence settings are shown in Figures 9 to 14. Fig. 9. Analysis sequence steps 273 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 13 of 15 Fig. 10. Peak Locate Unidentified Second Difference settings Fig. 11. Sum/Non-Linear LSQ Fit Settings Fig. 12. Efficiency Correction Alpha Settings 274 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 14 of 15 Fig. 13. Nuclide Identification – NID with Interference Correction Settings Fig. 14. Standard Report Settings 7 Analysis and Microprecipitation Efficiency To determine the efficiency of the microprecipitation method, the gamma spectrometer was used to determine the activity present initially in the sample solution and the activity found in the wash. The analysis sequence used was “Ac-225 and Ra-225.” It was determined that the initial activity in the sample solution was (146.5 + 5.5) Bq (via 221Fr) and thus if the microprecipitation method was 100% efficient, approximately (146.5 + 5.5) Bq would be expected to be found in the alpha sample. When the filters were counted in the alpha spectrometer until the activity uncertainty reached below 5% and the “Ac-225 ALPHA” analysis sequence with 275 Quantitative Alpha Spectroscopy of 225Ac: Standard Operating Procedure Document-174953 Release No. 1 Release Date.: 2019-10-07 20191008 114800 Template: Document-18187 Rel.7 Page 15 of 15 the previously mentioned calibration settings were used, it was determined that the average (n =10) measured activity in the microprecipitation sample was (80.9 + 3.2) Bq of 217At and (85.2 + 4.0) Bq of 213Po. To determine if it was an issue of microprecipitation efficiency or alpha spectrometer calibration settings, the wash fractions of the microprecipitation procedure were collected and counted on the gamma spectrometer. It was determined that the activity in the wash was (68.9 + 0.3) Bq, which corresponds to (47.0 + 3.8)% of the initial activity and thus the microprecipitation efficiency was (53.0 + 3.8)%. 276C Safety Analysis Report for Irra-diation of Thorium Targets277S RL124: Irradiation of Thorium Targets at the TRIUMF 500 MeV Isotope ProductionFacilityauthored by Andrew K. H. RobertsonAugust 27, 20181 Identification 22 Introduction 22.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.2 Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.3 Experimental Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.4 Impact Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.5 Previous L124 Irradiations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Description 33.1 Location of Experiment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.2 The 500 MeV Isotope Production Facility . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.3 Target Design and Manufacture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.4 Target Irradiation Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.5 Target Failure Modes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Definition of Hazards 74.1 Methods Used for Estimation of Radiation Hazards . . . . . . . . . . . . . . . . . . . . . . 74.2 Radiation Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Safety Measures 115.1 Preparation of Thorium Foils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115.2 Target Manufacture and Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125.3 Target Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135.4 Target Removal from Beam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166 Definition of Responsibilities 176.1 Thorium Inventory Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Decommissioning and Disposal 17References 17Appendices 19a Single-event Derived Release Limits Used for Off-Site Dose Estimates 20b Radioactive Inventory of Thorium Foil at EOB 22c Airborne Dose Calculations 411278 2 Experiment L124: Irradiation of Thorium Targets at the TRIUMF 500 MeV Isotope Production FacilityThe experiment spokespersons Andrew Robertson, Keith Ladouceur, Cornelia Hoehr, and Paul Schaf-fer. The experiment safety coordinator is Andrew Robertson. The experimental users are AndrewRobertson and Louis Moskven.Andrew Robertson TRIUMF Life Sciences4004 Wesbrook Mall, Vancouver BCarobertson@triumf.ca604 222 1047 ext. 6733 (office)778 228 7471 (cell) . BackgroundTargeted alpha therapy (TAT) shows high potential as an effective treatment option for small tumoursand metastases [1]. Actinium-225 (t1/2 = 9.92 d) is a promising TAT radionuclide, which can be useddirectly in combination with biomolecules or as a generator source of the shorter TAT radionuclide,bismuth-213 (t1/2 = 45.6 min). Development of 225Ac and 213Bi radiopharmaceuticals has progressedslowly due to the limited availability and the resulting high cost of these isotopes. Global annual 225Acproduction is approximately 63 GBq (1.7 Ci) [2–6].. ScopeIn coordination with L125 [7], experiment L124 aims to develop regular production and processing ofclinically relevant quantities of 225Ac (100 mCi, or 3.7 GBq) and 213Bi and potentially other valuablemedical radionuclides at TRIUMF using irradiation facilities at the 500MeV Isotope Production Facility(IPF) on beamline 1A (BL1A) and processing facilities in the MHESA RCR1 lab. While the scopeof L125, Isolation of Medical Isotopes from Irradiated Thorium Metal Targets, concerns the processing ofmedical isotopes from irradiated thorium targets, this experiment covers the target fabrication andirradiation at IPF. In other terms, L124 begins when the radioactive thorium metal is added to thetarget during its manufacture and ends when the irradiated target leaves the IPF hotcell.These experiments are distinct so as to separate the safety review process for each stage of the project.In this manner, safety approval for irradiating thorium targets for possible shipment and processingoff-site will be independent of safety approval for processing the targets on site.. Experimental Objectives1. Produce clinically relevant quantities of actinium-225 (100 mCi, or 3.7 GBq)1from thorium metalirradiated with high energy (>450 MeV) protons. Impact StatementThis project leverages unique TRIUMF infrastructure to produce understudied and sought-after iso-topes with potential to significantly aid the treatment of aggressive cancers. However, much remainsto be understood about the chemistry and biology needed to attach 225Ac or 213Bi to biomolecules thatspecifically target and treat cancer. As a result, the use of 225Ac and 213Bi in TAT is an area of researchthat has great interest.1 While the long-term experimental objective is to produce 100 mC (3.7 GBq) i of 225Ac per irradiation, the first irradiationdescribed in this review is for the production of ⇠12 mCi (440 MBq) of 225Ac.279 3This work therefore has high translational potential, with the ability to enable other experimentsat TRIUMF and other institutions that are otherwise be impractical due to the high cost and limitedavailability of 225Ac and 213Bi (current cost is a minimum purchase of 20 mCi (740 MBq) of 225Ac for$35000). As such, this effort is expected to enable new collaborations between TRIUMF and other TATresearch centres. A recent survey of experimenters in the TAT field suggests that demand for 225Acfrom researchers within Canada is at minimum 5.6 GBq (150 mCi) per month and growing.The knowledge and experience with thorium target irradiation, target processing, and waste man-agement that will be developed through L124 and L125 will directly support any future efforts atTRIUMF to scale up production to commercial quantities, as well as the future larger-scale 225Acproduction at ARIEL.. Previous L124 IrradiationsThe first irradiation under the purview of L124 occurred in December 2016, and involved the irradia-tion of a thorium oxide test target receiving 2.5 µAh of beam. This irradiation was done in single-usermode and with T1 and T2 removed from BL1A. While not ideal for post-irradiation processing of thetarget, thorium oxide foils from the ISAC Target Group were incorporated into an IPF target. Sinceno other thorium sources were readily available at the time, the irradiation of this target was the mostexpedient way to demonstrate IPF’s ability to produce 225Ac from spallation of thorium. As such,the thorium oxide target was also sealed in a way that prevented the removal of the thorium post-irradiation. However, crude gamma spectroscopy measurements of the irradiated target indicated thatthe December 2016 irradiation met its objective of demonstrating the feasibility of 225Ac productionvia proton spallation of thorium at IPF.The next two L124 irradiations used a thorium metal design (see Document-148097L124 ThoriumMetal Target for IPF, Release 3. Both targets were successfully irradiated (one in December 2017 andanother in May 2018) with 2640 µAh of beam at typical BL1A high-current operating conditions (⇠100µA). No damage to the target capsule or the thorium target material was observed after these irradia-tions. . Location of ExperimentManufacturing of the non-thorium components of the target capsule will take place in the TRIUMFMachine Shop, without any thorium present. Since this portion of the manufacturing is standardwork for the Machine Shop, it is covered by their internal safety standards and practices and not bythis safety review.Preparation of the thorium foils will occur inside a glovebox in the RCR1 (MHESA B1 level).Sealing of the thorium foils within the target capsule will be conducted in the TRIUMF MachineShop. Post-manufacturing tests of the target will also be conducted in ATG workspaces.Irradiation of the targets will then take place at the 500MeV Isotope Production Facility (IPF) locatednear the end of BL1A, as shown in Fig. 1. After irradiation, the targets will remain in the IPF hotcellfor one week to permit the decay of short-lived radioisotopes.. The 500 MeV Isotope Production FacilityIrradiation of the targets will occur at IPF, located near the end of BL1A (Fig. 1). Immediately up-stream from the Thermal Neutron Facility (TNF), IPF is the second-last facility before the BL1A beamdump. The description and safety report of this facility is primarily contained in the Document-563,TRIUMF Safety Report v.3 (2011) [8], with further descriptions in earlier reports [9, 10]. The IPF wasfirst conceptualized in 1978 (Fig. 2) [9].Targets are inserted into the IPF hotcell by way of a shielded flask [11]. Within the target irradiationstation there is space for six target cassettes; each cassette can hold a pair of targets. Independent chain280 4Figure 1: Beamline 1A layout with key beam diagnostic and target locations noted.drives are used to insert and remove individual cassettes from the beam line. This can be performedwhether the beam is on or off. The cassettes can be placed in three positions: in the proton beam,a “parked” position just above the beam, or in the IPF hotcell. The operators of the facility haveconsiderable experience inserting and removing targets, including molybdenum targets, the morerecent KCl targets [12], and the December 2016 L124 test thorium oxide target (see Section 2.5). As thetarget capsules for the thorium targets are nearly identical, there will be no difference in the handlingprocedures.When cassettes are lowered into the proton beam, they are submerged in a volume of water andre-circulated water is injected into each cassette to cool the outer surface of the targets directly (seeFig. 3). The water also flows through an ion exchange resin to remove metal ions from the water. Aminimum of four targets must be located in the beamline for the safety interlock conditions to be met.In the case where fewer than four targets are scheduled for irradiation, the remaining cassette spacesare filled with helium targets. As a single thorium target will be run during this irradiation, threehelium targets will be inserted to meet the interlock requirements (helium targets are used to reducethe energy deposited into the cooling water, as each helium target in the beam occupies a volume thatwould otherwise be occupied by cooling water).Thermocouples are used to measure the outer temperature of the target capsule and the temperatureof the cooling water; the resistivity of the cooling water is also monitored. Protect monitors are usedto monitor beam position, however, information on the beam profile at full current is not availablesince the nearest profile monitor, 1AM11 (Fig. 1), can only take <10 µA. Similarly, accurate currentmeasurements at IPF cannot be obtained as the nearest current monitor, 1AM10 (Fig. 1), is located justafter T2, roughly 15 m from IPF. Therefore, beam losses between T2 and IPF are not accounted for by1AM10 readings.. Target Design and ManufactureThe target material consists of a thorium metal foil (60 mm diameter, 0.25 mm thickness, or 0.293g/cm2) supplied by IBI Labs (Boca Raton, Florida). The supplied foils currently have a significantoxide layer that will be removed before the targets are fabricated. The thoriummetal foil is hermeticallysealed within a target capsule consisting of a steel, ring-shaped body and 0.13 mm thick Inconel R-718entrance and exit windows2. The outer dimensions of the target are approximately 10 cm diameterand 1 cm thickness. A schematic of the target is shown in Fig. 4. The target body is shaped to centrethe thorium foil radially within the target and to also press it against the entrance window, facilitatingimproved cooling of the thorium foil via conduction through the window. Windows are attached to281 5Figure 2: Diagrams of the 500 MeV Isotope Production Facility (IPF) [9].Figure 3: Diagrams of the IPF target station, with 6 cassettes at beam level. Inset image shows two targets percassette. Blue arrows indicate cooling water flow; red arrows indicate proton beam direction [13].282 6Figure 4: L124 target design.the target body by electron-beam welding, the process of which also seals the thorium within thetarget capsule.Sealing of the target with an electron-beam weld – which is conducted under vacuum – will ensurethat the interior volume of the fabricated target is under vacuum.After manufacturing, leak tests of the target will be conducted following standard ATG proceduresfor leak testing IPF targets.Detailed description and analysis of the target design, manufacturing, and post-manufacture testingcan be found in the design note, L124 Thorium Metal Target for IPF (Document-148097) [13].. Target Irradiation ParametersThe target will be irradiated at IPF under typical high-current BL1A beam parameters (480 MeV, ⇠100µA at extraction or ⇠450 MeV, ⇠85 µA at IPF3) so that use of IPF can occur independent of the needsof other BL1A users. While the experiment ultimately aims to produce 3.7 GBq (100 mCi) quantitiesof 225Ac, for this first initial production run the duration of the irradiation will be chosen such thatapproximately 440MBq (12mCi) of 225Ac will remain in the target at 1week after end of bombardment(EOB); this duration will be 2640 µA*h of beam on target. After the irradiation, the target will beremoved from the beam and left inside the parked position within the IPF water column until theyreach thermal equilibrium with the cooling water. After checking for signs of target failure (Section3.2) and after taking and analyzing (via gamma spectroscopy) a sample of the IPF cooling water, thetarget will be raised to the IPF hotcell, where it will remain until one week after EOB, permitting thedecay of short-lived radioisotopes before targets are removed from the IPF hotcell.2 The composition of Inconel R-718 is as follows: 50.00-55.00% Ni, 17.00-21.00% Cr, 4.75-5.50% Nb, 2.80-3.30% Mo, 0.65-1.15% Ti,<1.00%Co, 0.20-0.80%Al,<0.35%Mn,<0.35% Si,<0.30%Cu,<0.08%C,<0.015% S,<0.015% P,<0.006% B, Fe remainder [14].3 Beam losses between the cyclotron and IPF are approximately 15% with the short 12 mm T2 target [15]283   7During the initial irradiation of a new target design, commissioning tests on the target will be per-formed as described in Commissioning Plan for Irradiation of L124 ThoriumMetal Targets at IPF (Document-148095) [16].. Target Failure ModesAs defined in L124 Thorium Metal Target for IPF (Document-148097) [13], an IPF target is classified asfailed if the hermetic seal encapsulating the thorium foil is lost, or if the target body, entrance, or exitwindow is compromised before, during, or after irradiation. The thorium foil is not a safety-criticalcomponent from a failure modes perspective, so long as failure of this component does not result infailure of target windows or target body. Melting of the thorium would be considered among the worstfailure paths, as temperatures would be well above safe limits for the Inconel windows of the targetassembly. Excessive deformation, cracking, or pin-hole formation in the thorium foil is of limiteddanger to the target assembly.   The hazards associated with this experiment are radiological hazards.. Methods Used for Estimation of Radiation HazardsEstimates of the radioisotope inventory of the irradiated thorium targets were obtained using FLUKAsimulations [17]. These simulations were performed by Andrew Robertson with guidance from MinaNozar. The simulated radioactive inventory and resulting dose estimates presented in this documentwere based off of a 454 MeV, 55 µA, 48 hour irradiation, which produces 440 MBq (12 mCi) of 225Acone week after EOB. A Gaussian beam profile was used with a FWHM of 3.18 cm and 3.25 cm inthe x and y directions, respectively; beam direction was set along the z-axis. The geometry includedthe target, as described in Section 3.3, as well as the cassettes, cooling water, and entrance windowfor the IPF target station. NEW-DEFAULTS default settings were used. Physics and transport settingswere set to enable nuclear coalescence and evaporation, photonuclear interactions, and low-energyneutron transport and cross-sections. Production and transport thresholds were set to 30 keV forelectrons, positrons, and gammas. A 100 keV proton energy transport threshold was also set. A 0.001cm maximum step size was set for charged particles in the thorium foil; a 0.005 cm maximum was setfor other regions. A total of 800 million primary particles were simulated. Note that the accuracy ofthese FLUKA simulations is limited due to the limited understanding of the beam parameters at theend of BL1A, since the nearest diagnostics are many metres upstream.Given the estimated radioisotope inventory, dose rate estimates of the target were calculated usingan Excel-based calculator developed by the TRIUMF Radiation Protection Group (RPG) that calculatesgamma radiation dose rates – both with or without shielding – from a given isotope assuming a pointsource geometry. Comparison with dose rates determined via FLUKA simulation show these methodsagree within <10% for unshielded dose rates at 1 m from the target.Similar simulations and calculations conducted as part of L124 in 2016 using a thorium oxide testtarget were within 20% of all measurements of 225Ac radioactivity and dose rate at 1m from the target.This supports the reliability of these FLUKA simulations and dose calculations for approximating theradiation hazards associated with this experiment.While some changes to the target design have been made since the FLUKA simulations were run,the changes are expected to negligibly affect the isotope inventory and resulting dose rates since thetotal mass and approximate radial distribution of thorium and steel (the components producing >99%of the dose rate from the target) has changed by <1%.Internal and external dose estimates resulting from the worst-case release of volatile radioisotopeswere calculated as described in TRIUMF Safety Analysis Reports (SARs) for ISAC targets: ActinideTarget Safety Analysis Report (Document-12972) and Actinide Target SAR Addendum for Thorium Oxide(Document-110961) [18,19]. These documents contain dose estimates resulting from a worst-case release284   8of volatile radioisotopes from ISAC actinide targets. These calculations assume all volatile radioactiveisotopes within the target become uniformly distributed within a sphere of 15 m radius and that aworker wearing no respiratory protection is located at the centre of the sphere for a duration of 30minutes. This scenario (“Scenario C” described in Document-110961) assumes that all the radioactiveair released through the ventilation systems is somehow drawn into an office building. Decay ofshort-lived isotopes and the dispersion of these radioactive gasses during the 30 minute exposure isneglected. It should be noted that this is an extremely conservative model.Off-site dose estimates to members of the public resulting from a worst case release of volatileand gaseous radioisotopes were also calculated using the methods described the ISAC actinide targetSARs [18,19].While Actinide Target Safety Analysis Report (Document-12972) and Actinide Target SAR Addendum forThorium Oxide (Document-110961) guide the methodology for on-site and off-site airborne dose esti-mates described in this document, the following modifications were made to these methods to incor-porate additional information gained in the years following their publication:1. The ISAC SARs used a 1minute half-life cut-off of for isotopes used in the calculations. However,220Rn (t1/2 = 55.6 s) has since been shown to be a real potential airborne dose hazard [20]. Dosecalculations herein include 220Rn. This results in a <1% change to the dose estimates.2. TRIUMF is currently in the process of updating its Derived Release Limits (DRLs) – annuallimits for radioactivity released into the environment – and defining Single-event Derived ReleaseLimits (SDRLs) – limits for a single accidental release of radioactivity into the environment. Theold SDRLs used in the ISAC actinide target SARs are considered outdated. SDRLs used in thisdocument to estimate the off-site dose to members of the public resulting from a worst caserelease of radioisotopes were provided by RPG [21]. These SDRLs are listed in Appendix A.3. When considering airborne radiation hazards resulting from an accidental release of radioactivity,one must consider which elements have the potential to become airborne. In the ISAC actinidetarget SARs, the volatile elements with potential to become airborne are: hydrogen, chlorine,argon, selenium, bromine, krypton, iodine, xenon, radon, and polonium [18, 19]. Using a con-servative approach, the ISAC actinide target SARs also assume a 100% release of these isotopes.Dose calculations in this document closely follow this definition of relevant isotopes, but withextra attention paid to the chemical form and potential volatility of polonium isotopes, whichresults in polonium being excluded entirely from airborne dose calculations. Further details areprovided in Section 4.1.1.All values for Annual Limits on Intake (ALI) used in this document were obtained from the ActinideTarget SAR Addendum for Thorium Oxide (Document-110961), unless otherwise specified [19]... Assessment of Potential Release of Polonium IsotopesRelevant LiteraturePolonium is known to be a potentially volatile isotope, however, the potential for polonium to becomeairborne depends greatly on its chemical and physical form. When calculating airborne dose estimates,the ISAC actinide target SARs conservatively assume polonium isotopes to be 100% volatile [18, 19].However, making the same assumptions for this report results in estimated airborne on-site and off-siteworst case doses that are, respectively, 92.7% and 99.8% attributable to polonium isotopes. Therefore,special consideration is made in this document regarding the potential of polonium to be volatile atvarious stages of the experiment so that more realistic dose estimates can be made.As a hazardous radioactive (and most often alpha-emitting) element with no stable isotopes, thechemistry of polonium has not been extensively studied. Polonium is most commonly studied in thecontext of radiation protection and in its use as an environmental tracer, in both cases typically asnaturally occuring 210Po from 238U decay [22]. Human-made polonium is typically only produced inmilligram quantities or less. It’s chemical properties are known to be very similar to tellurium, andtellurium is often used as an analogue for predicting polonium’s chemical behaviour when informationon polonium itself is not directly available [23–25]. It should be noted that tellurium is not treated285   9as volatile in the ISAC actinide target SARs, though polonium’s even lighter homolog, selenium, is[18,19].Polonium is known to easily and spontaneously deposit onto other metal surfaces, and this charac-teristic is routinely exploited to easily prepare 210Po alpha spectroscopy samples [22,23,26,27]. Whenkept below 100 C, the deposited polonium is not volatile and remains on the metal surface [22].Above 100  the volatility increases, with 90% of the polonium being lost at 300 C [22].This non-volatility of trace polonium metal quantities is in contrast to the known volatility of solidpolonium metal samples. This is because samples of purified solid polonium metal of measurablemass (i.e. >trace amounts) are: 1) only ever produced in µg-mg quantities, having a high surfacearea to volume ratio; and 2) such samples are self-heating due to the energy deposited from their ownalpha decay [23]. This self-heating effect is so intense (140W/g) that solid polonium samples preparedin non-trace quantities can easily become much hotter than their surroundings, resulting in a 50% lossof the material over a three day period [28].Inorganic polonium compounds are not volatile in aqueous solutions; the element is soluble in acids,and at near neutral pH forms colloids and permanently sticks to the surfaces of containers [22,23,25,27].In room temperature aqueous solutions, polonium can potentially become volatile via incorporationinto volatile organic compounds (ex. via a bacteria) [22,29,30]. The only volatile inorganic poloniumcompounds are halides (ex. polonium tetrachloride) [22,23,27], though these are soluble in water andare thus only volatile in solid form.Polonium-containing particulates also have the potential to disperse polonium in air. The mostnotable example of this occurred in 1957 at a fire in the Windscale nuclear reactor (Cumbria, UK) –which at the time was producing 210Po via bismuth irradiation – resulting in the release of 8.8 TBq of210Po into the environment [26,31]. The released polonium was found to be contained within bismuthparticles of 1 µm mean diameter [31].To summarize the above information, polonium has the potential to become airborne if in one of thefollowing forms:1. A solid or liquid heated above 100 C2. A purified solid metal of measurable mass (i.e. >trace quantities)3. A solid halide compound4. A volatile organic compound5. A fine particulateAssessment of Polonium Volatility During L124 IrradiationIn the context of L124, Irradiation of Thorium Targets at the TRIUMF 500 MeV Isotope Production Facility,airborne dose estimates concern the release of volatile and gaseous radioisotopes into the air resultingfrom a target failure during irradiation. Both on-site doses (dose to a TRIUMF worker) and off-sitedoses (dose to a member of the public) are estimated. For polonium to become a contributing elementto these doses it would have to go through the following steps:1. Leave the target thorium material, in which the polonium is produced2. Leave the cooling water package in which the targets are submerged at a 10 m depth3. Leave the ventilation systems on the target station, including the ducting and HEPA filtersThe following analyzes polonium’s potential volatility in each of these three steps.Step 1Polonium is likely to be volatile as the thorium is expected to reach temperatures above 500 C ("Form1"). However, note that in the event of a target failure, water will enter the target capsule, lowering thetemperature of the thorium.Step 2Polonium is not volatile in this situation as the cooling water remains below 50 C – any trace quantitiesof polonium that leave the thorium foil after a target failure will remain in the cooling water system.286   10Most likely, this polonium will be trapped by the ion exchange resin on the water package or willdeposit itself on interior surfaces of the water package."Form 1" is discounted because of the temperature of the water. The cooling water temperature ismonitored during irradiation and elevated temperatures result in a beam trip."Form 2" is entirely impossible."Form 3" is discounted. While halogens including fluorine, chlorine, bromine, iodine, and astatineare co-produced in the thorium during the irradiation, these are soluble in the cooling water and arenot expected to be released. This is supported anecdotally by target failures at the BL2C target station:while krypton radioisotopes have been shown to leave both the failed target and the cooling waterpackage, the bromine isotopes that are retained in the water column [32]."Form 4" is discounted because no biological organisms capable of incorporating polonium intovolatile organic compound can be conceived to exist inside the cooling water that is cycled at highvelocity through both the proton beam and the ion exchange resin."Form 5" is discounted because fine particulates will not become airborne when wet. Furthermore,combustion of a target immersed in water is inconceivable.Step 3Polonium that leaves the cooling water system is unlikely to be volatile in significant quantities thissituation. Inorganic polonium that somehow leaves the cooling water would be expected to deposititself on the interior surfaces of the ducting. This is supported by observations at ISAC in whichpolonium – brought into the ventilation system via its parent isotope, radon – sticks to the interiorsurfaces of the ducting [33].However, it is conceivable that water vapour from the cooling water condenses on some surfacesabove the water, and ultimately evaporates to leave behind polonium halide salts. However, consider-ing that polonium concentrations in the cooling water will be below picomolar levels, vaporization ofthe cooling water will occur at a much slower rate than at which polonium will be trapped in the ionexchange resin or irreversibly deposit itself onto the surfaces of the cooling water system."Form 1" is discounted as the temperature of air or vapours inside the ventilation would not beexpected to rise above 100 C (see Step 2)."Form 2" is again considered impossible."Form 3" is considered conceivable but extremely unlikely to occur in significant quantities."Form 4" is discounted, for reasons similar as in Step 2: one would not expect biological organismsinhabiting the ventilation system that could incorporate polonium into organic molecules."Form 5" is discounted as particulates would be expected to be trapped in the HEPA filters.ConclusionFor the above reasons, in the context of L124 polonium is not be considered as volatile and can beexcluded from airborne dose estimates.. Radiation HazardsThe thorium metal used as a target material is naturally radioactive, even before it is irradiated. Whilethe metal itself does not pose a significant contamination hazard, the oxide layer on the metal’s surfacedoes.The irradiation of thorium is expected to produce significant quantities of hazardous radioisotopes.The simulated radioactive inventory present within the thorium foil at EOB is shown in Appendix B.This inventory includes gamma-, beta-, and alpha-emitting isotopes. Some of these isotopes are alsovolatile halogens, noble gases, and elements that are potentially volatile depending on their chemicalform (the definition of the relevant volatile and gaseous isotopes used in this document is providedin Section 4.1). As such, the irradiated thorium presents significant external and internal radiationhazards, including airborne radiation hazards.Table 1 lists the activity at EOB and the ALI of the non-radon alpha-emitting radionuclides withhalf-lives >1 hour produced in the target. The selection of isotopes for this table was copied fromActinide Target SAR Addendum for Thorium Oxide [19].287  11Table 1: Activity and ALI of the non-radon alpha-emitting radionuclides produced within the thorium foil withand present at EOB and with half-lifes >1 hour. These ALI values were obtained from the Actinide TargetSAR Addendum for Thorium Oxide (Document-110961) [19]. Information on quantities of other isotopes,including radons and those with half-lifes <1 hour can be found in Appendices B and C.Nuclide ALI [Bq] Activity [Bq] A/ALIPo-204 7.41E+05 2.47E+09 3.33E+03Po-205 2.25E+08 2.12E+09 9.42E+00Po-206 4.20E+06 7.10E+08 1.69E+02Po-207 1.33E+08 3.51E+09 2.64E+01Po-208 8.33E+03 7.62E+06 9.15E+02Po-209 8.33E+03 2.37E+05 2.85E+01Po-210 9.09E+03 5.31E+07 5.84E+03At-207 1.05E+07 3.12E+09 2.97E+02At-209 1.68E+06 4.90E+09 2.92E+03At-211 1.82E+05 4.70E+09 2.58E+04Ra-223 3.51E+03 1.51E+08 4.30E+04Ra-224 4.17E+03 1.37E+09 3.29E+05Ra-226 9.09E+03 1.99E+03 2.19E-01Ac-224 2.02E+05 4.02E+09 1.99E+04Ac-225 3.08E+03 6.73E+08 2.19E+05Ac-226 2.00E+04 2.70E+09 1.35E+05Ac-227 4.26E+02 8.45E+05 1.98E+03Th-227 2.63E+03 4.41E+08 1.68E+05Th-228 6.25E+02 2.71E+07 4.34E+04Pa-228 3.92E+05 1.77E+08 4.52E+02Pa-229 5.26E+04 1.95E+08 3.71E+03Pa-230 3.51E+04 7.64E+07 2.18E+03U-230 1.67E+03 2.12E+05 1.27E+02U-232 7.69E+02 5.67E+03 7.37E+00Total: 1.01E+06The non-thorium components of the target capsule will also become radioactive. However, theseisotopes are non-volatile and are not alpha-emitters. These components of the target present significantexternal radiation hazards as well as surface contamination hazards.Dose estimates and worst-case release estimates for different stages in the experiment are providedin Section 5.  . Preparation of Thorium Foils.. Procedure and Safety MeasuresThe foils currently contain an oxide layer that is loosely bound to the thoriummetal. Since the presenceof the oxide during the post-irradiation dissolution of the foil is problematic, the oxide layer will beremoved from the foils using an abrasive (ex. steel wool, or similar) before they are placed in thetargets. The steel wool will be kept wet during this process to minimize the dispersion of particulatesthat are removed. This work will be performed inside a glove box in the RCR1 lab, in order to containthe resulting contamination. The interior of the glove box will additionally be covered with plasticto reduce contamination of the glovebox interior. Afterwards, any resulting loose contamination willbe cleaned up. Workers performing this work will wear a respirator and disposable full-body “tank”suit. The prepared foils will be checked for removable contamination; only foils that do not have anyremovable contamination will be brought to the machine shop from RCR1.288  12Figure 5: Image showing the inward deformation of IPF target windows for targets that are sealed under vacuumby an electron-beam weld.Prepared foils may be stored in the ISAC target lab glove box, which provides inert atmosphereenvironment to prevent further oxidization. This lab already regularly handles and stores actinides(thorium and uranium)... Gamma Radiation Exposure During Foil PreparationAs the measured dose rate at 0.5 m from a single thorium foil is <2 µSv/h, the dose accrued whilepreparing the foils is considered negligible... Contamination of Workers During Foil PreparationThe ALI for 232Th is 120 mg for inhalation and 23 g for ingestion [34], while a single foil is <8.5g. Additionally, since the thorium metal is non-dispersible, the airborne contamination is low. Theuse of wet steel wool will minimize dispersion of the thorium oxide that is removed. Given that thework will be conducted in a sealed glove box and that full PPE, including respirators, will be wornwhen decontaminating the glove box, the potential for internalizing harmful quantities of thorium isconsidered low.. Target Manufacture and Testing.. Procedure and Safety MeasuresAfter welding of the exit window to the target body, the thorium foil will be removed from a sealedplastic bag and placed between the target body and the entrance window. The thorium will then besealed within the target by electron-beam welding of the entrance window to the target body.Sealing of the target under vacuum in the electron-beam welder will result in the fabricated targetcapsule’s interior also being under vacuum. This results in the thin entrance and exit windows de-forming inwards, as shown in Fig. 5. Since the windows will not remain deformed if vacuum is lostinside the target, this deformation provides a visual check of the integrity of the target seal. Targetswill also be leaked checked by placing them in a pressure vessel that is filled with helium gas to 30psi for 24 hours. Any leaks in the hermetic seal of the target will result in helium penetration into thetarget capsule, and a loss of the the inward deformation of the windows.Swell testing of the targets will also be performed by heating them to 350 C for 25 minutes. Targetsthat swell by >1.14 mm fail the swell test.Additional details of the target manufacturing and testing process can be found in the EngineeringNote, L124 Thorium Metal Target for IPF (Document-148097) [13].289  13Table 2: Room temperature material properties of thorium and Inconel-718 relevant to results of thermal andstress simulations [36,37].Material Melting Point [K] Yield Stress [MPa] Ultimate Stress [MPa]Inconel 718 1533 460 895Thorium 2028 144 219.. Gamma Radiation Exposure During Target Manufacture and TestingAs the measured dose rate at 0.5 m from a single thorium foil is <2 µSv/h at 1 m, the dose accruedwhile sealing the thorium foil within the target and testing the target is considered negligible... Contamination of Workers During Target Manufacture and TestingThe ALI for 232Th is 120 mg for inhalation and 23 g for ingestion [34], while a single foil is <8.5 g.Additionally, since the thorium metal is a durable and non-volatile metal, the potential for removablecontamination – particularly airborne contamination – is considered extremely low. Given that the foilswill be already checked for removable contamination, the PPE described in Section 5.2.1 is sufficientto prevent workers from being contaminated by 232Th during sealing of the thorium within the targetcapsule.. Target Irradiation.. Summary of Thermal and Stress Analysis of Target During IrradiationFull details of this analysis can be found in the target’s Engineering Note, L124 Thorium Metal Target forIPF (Document-148097), with additional information found in the Design Reviews, L124 Design Review2017-11-09 (Document-148946) [13,35]. A summary of the analysis and conclusions are provided herein.All combinations of the following parameters were studied in multiple thermal and stress simula-tions:• Given that BL1A typically operates at extracted currents of ⇠100-110 µA, with beam losses of15% [15] simulations of on-target beam currents of 60, 80, 100, and 120 µA were studied.• Since beam profile affects the volumetric heat load deposited in the target, Gaussian beam pro-files with 15, 20, 25, 30 35, and 40 mm FWHM were simulated. As the beam is expected to betuned to approximately a 20 mm FWHM at IPF, the 15 mm case is considered extreme.Material properties of thorium and Inconel-718 relevant to the thermal and stress results are shownin Table 2.While comprehensive results of the thermal and stress analysis can be found in L124 Thorium MetalTarget for IPF (Document-148097), Figure 6 provides a summary of the most important results relevantto the potential for target failure: the stress experienced by the target windows during irradiation. Thisanalysis conservatively uses the yield stress (as opposed to the ultimate tensile stress) as a benchmarkfor the safety of the target. Irradiation conditions for which the maximum stress experienced by thewindow are below the yield stress of Inconel 718 are considered highly unlikely to fail.These results suggest irradiation conditions that maintain a minimum width of 20 mm FWHM anda maximum current of 100 µA on target will not result in target failureWhile damage to the thorium foil is possible, it is important to emphasize that none of the simulatedcases – regardless of beam width, current, fractional contact, or thermal resistivity – result in stressesto the windows that could cause a target failure (as defined in Section 3.5)... Procedure and Safety MeasuresThe thorium target will be lowered into the proton beam and irradiated as described in Section 3.4.During the irradiation, monitoring devices described in Section 3.2 will be used to monitor the targetand beam. The controls system implemented at IPF (Fig. 7) will cause the proton beam to trip off if all290  14Figure 6: Maximum simulated stress values experienced by the target window during irradiations by protonbeams of various widths and currents.conditions for an acceptable target irradiation are not met. However, these checks are only applied atthe start of the irradiation (using 1AM11) and are not actively monitored during the irradiation, since1AM11 can handle only up to 10 µA. Correct beam profile (minimum 20 mm FWHM) will be ensuredby the beam tune. Correct beam position will be ensured by beam collimators after T1 and T2 and IPFprotect monitors, and a poor beam position that results in the beam hitting the outer ring of the targetwould result in heating of the target capsule that would be detected by the thermocouple attachedto the target (beam is tripped when this thermocouple reaches 100 C). Acceptable beam current willoccur by ensuring that the current read by 1AM10 does not exceed 100 µA. An 80 µA current limitwill be applied for the initial irradiation of new target designs.Additionally, radiation monitors on the IPF hotcell exhaust stack and cooling water resistivity mon-itors will be used to detect a potential target failure, with a sudden increase in both stack exhaustradioactivity and cooling water resistivity indicating a target failure. However, it should be noted thatthese methods may not reliably detect a non-catastrophic (small) leak... Worst-Case Release Estimates Resulting from Target FailureThe greatest potential hazard associated with this experiment is the release of volatile and gaseousalpha-emitting isotopes from within the target capsule during the irradiation, resulting from a failureof the capsule’s hermetic seal (Section 3.5). While it must be considered, it is unlikely to occur giventhe post-manufacturing tests of the target (Section 5.2.1), the results of the thermal analysis (Section5.3.1), and a long history of safely irradiating similar targets at IPF.Calculations of the the maximum credible on-site dose to a TRIUMF worker and the maximumcredible off-site dose to a member of the public were performed as described in Section 4.1 usingthe simulated radioisotope inventory of the target at EOB (listed in Appendix B). Details of thesecalculations can be found in Appendix C. Due to the state of the nuclear ventilation at IPF, and thelack of charcoal filtration on the exhaust stack, these calculations assume that none of the volatile orgaseous isotopes present within the thorium are filtered before leaving the IPF exhaust stack.291  15Figure 7: IPF Safety Flow Chart overview.292  16Figure 8: Breakdown of maximum credible on-site (left) and off-site (right) doses resulting from an L124 targetfailure.The calculated maximum credible dose to a worker at the TRIUMF site resulting from a target failureis 13.68 mSv (0.04 mSv external dose, 13.64 mSv inhalation dose). Radon isotopes contribute the most(98% of total) to this dose estimate, 62% and 25% of which is attributed to 211Rn and 210Rn, respectively(Fig. 8).Following methods described in Section 4.1, the associated maximum credible off-site dose is 25 µSv,which is dominated (78.2% of total) by iodine isotopes (Fig. 8).Both the on- and off-site doses can be compared to the maximum credible releases determined viasimilar methods for the ISAC thorium target: 15 mSv on-site and 0.84 mSv off-site4.While these values represent the maximum possible dose, realistic doses resulting from an L124target failure are expected to be lower for the following reasons:1. These calculations assume that none of the volatile or gaseous isotopes remain trapped insidethe 0.25 mm thick thorium metal foil in which they are produced.2. A target failure during irradiation would occur at the target station, which sits under 9 m ofcooling water. Experience from target failures at the beamline 2C Solid Target Facility (STF) hasshown that the water column will trap and limit the release of volatile halogen isotopes [32],which in this case contribute 84.5% to the off-site dose.3. Methods for calculating maximum credible on-site doses (Section 4.1) use a very conservativeapproach.. Target Removal from Beam.. Procedure and Safety MeasuresThe IPF chain drive used to insert and remove targets from the beam is operated remotely. At EOB,targets will be raised to the parked position and left there, still within the IPF water column, untilthey reach thermal equilibrium with the cooling water and signs of a target failure have been checked.In addition to signs of a target failure described in Section 3.2, a sample of the IPF cooling waterwill taken and analyzed by RPG (via gamma spectroscopy) before targets are raised from the parkedposition into the IPF hotcell.Once the target is raised to the hotcell level the target will be visually checked for signs of target fail-ure before being placed inside a transfer flask located within the hotcell, which will provide additional4 Charcoal filters on the ISAC exhaust stack are assumed to remove 99.5% of the polonium, iodine, bromine, and seleniumisotopes. This assumption is not made for IPF releases since charcoal filters are not present on that stack.293   17radiation shielding. The target will remain in the flask and inside the IPF hotcell until one week afterEOB, at which point it will be removed from the IPF hotcell and transferred to Experiment L125 [7]... External Radiation Exposure to Workers at IPFDuring manipulation of the targets within the IPF hotcell, the hotcell operator is exposed gammaradiation emitted from the target through the 12” thick hot cell lead glass window. Operators willwear dosimeters during this work (the area in front of the IPF hotcell is a direct-reading-dosimeter-required area).Exposure to these radiation fields occurs for less than 10minutes, at least one hour after end of beam(due to the time taken to analyze the water sample). At EOB, the simulated dose rate at 1 m from thetarget is 128.8 mSv/h without shielding. However, assuming at least 10 cm of lead shielding providedby the IPF hotcell, the expected dose rate will be below 0.53 mSv/h. While the actual dose rate wouldbe expected to be lower due to decay of many short-lived isotopes during the hour the target is inthe parked position5, a maximum 10-minute duration in a maximum 0.53 mSv/h field will result in0.09 mSv of dose to the hotcell operator. As a comparison, the gamma dose to personnel from IPFmolybdenum targets is 1.3 mSv/h while operating the hotcell. The typical dose to an operator duringa molybdenum target transfer is 0.07 mSv (an average of a three minute exposure at 1.3 mSv/h).   Andrew Robertson is the experimental safety coordinator.The Applied Technology Group (ATG) has overall responsibility for operation of the 500 MeV Iso-tope Production Facility. This includes target manufacture, preparation, and quality assurance, as wellas the insertion and removal of targets from the beamline, and sampling of the IPF cooling water.RPG and Operators in the 500 MeV Control Room are responsible for monitoring ventilation stacksfrom the IPF during the experiment and for collecting any required air samples from these stacks.RPG also has responsibility for analyzing the cooling water sample.The TRIUMF Cyclotron Operations group is responsible for delivering the proton beam to the IPFand for monitoring the safe operating conditions of the beam and targets. Specifically, this includesthe responsibility of ensuring that the beam is tuned such that the beam profile is not too narrow(minimum 20 mm FWHM), and ensuring that the current on the nearest upstream monitor from IPF(1AM10) does not exceed 95 µA during the irradiation.. Thorium Inventory ManagementThe 232Th that makes up the target material is a controlled nuclear substance, the inventory of whichTRIUMF reports in detail to the Canadian Nuclear Safety Commission (CNSC). Only thorium that hasbeen exempted from restrictions on its modification will be used in the experiment. The spokespersonsare also responsible for ensuring that items containing thorium are appropriately labelled, that thequantity of thorium therein is recorded, and for reporting on a monthly basis to the RadioactiveMaterials Coordinator any changes to the location, mass, chemical form, or physical form of anythorium materials.   At the end of the post-irradiation cool-down of the target in the IPF hotcell, the targets will be trans-ferred to Experiment L125. Therefore, disposal and decommissioning related to the combined L124and L125 project is covered by the L125 Safety Report and is not included herein [7].5 At 8 hours after EOB, the simulated dose rate at 1 m from the target is 24.5 mSv/h without shielding, and 90 µSv/h with 10cm of lead shielding.294 18[1] Clemens Kratochwil, Frank Bruchertseifer, Frederik L Giesel, Mirjam Weis, Frederik A Ver-burg, Felix Mottaghy, Klaus Kopka, Christos Apostolidis, Uwe Haberkorn, and Alfred Morgen-stern. 225Ac-PSMA-617 for PSMA targeting alpha-radiation therapy of patients with metastaticcastration-resistant prostate cancer. J. Nucl. Med., 57(12):1941–4, jul 2016.[2] B L Zhuikov. Successes and problems in the development of medical radioisotope production inRussia. Physics-Uspekhi, 59(5):481–486, 2016.[3] V Radchenko, J W Engle, J J Wilson, J R Maassen, F M Nortier, W A Taylor, E R Birnbaum, L AHudston, K D John, and M E Fassbender. Application of ion exchange and extraction chromatog-raphy to the separation of actinium from proton-irradiated thorium metal for analytical purposes.J. Chromatogr. A, 1380:55–63, feb 2015.[4] R. A. Aliev, S. V. Ermolaev, A. N. Vasiliev, V. S. Ostapenko, E. V. Lapshina, B. L. Zhuikov, N. V.Zakharov, V. V. Pozdeev, V. M. Kokhanyuk, B. F. Myasoedov, and S. N. Kalmykov. Isolation ofMedicine-Applicable Actinium-225 from Thorium Targets Irradiated by Medium-Energy Protons.Solvent Extr. Ion Exch., 32(5):468–477, 2014.[5] Alfred Morgenstern. Bismuth-213 and actinium-225–generator performance and evolving ther-apeutic applications of two generator-derived alpha-emitting radioisotopes. Curr. Radiopharm.,5(3):221–227, 2012.[6] International Atomic Energy Agency. Technicial Meeting on Alpha emitting radionuclides andradiopharmaceuticals for therapy. Technical report, International Atomic Energy Agency, Vienna,2013.[7] Andrew K. H. Robertson. Safety Report for L125: Isolation of Medical Isotopes from IrradiatedThorium Metal Targets (Document-148963). Technical report, TRIUMF, Vancouver, Canada, 2017.[8] L Moritz. TRIUMF Safety Report (Document-563). Technical report, TRIUMF, Vancouver, 2011.[9] J. J. Burgerjon and R. Thomas. Irradiation Facility for Isotope Production Concept #2 (Document-95666). Technical report, TRIUMF, Vancouver, 1978.[10] J. J. Burgerjon, B. D. Pate, R. E. Blaby, E. G. Page, J. Lenz, and B. T. Trevitt. The TRIUMF 500 MeV,100 uA Isotope Production Facility. In Proc. 27th Conf. Remote Syst. Technol., San Francisco, 1979.[11] Rene van den Elzen. TRIUMF ATG Target Change Procedure for the 500 MeV Irradiation Facility(ATG-PRO-OPR-500-001). Technical report, TRIUMF, Vancouver, 2006.[12] Ewart Blackmore. Safety Report for the Irradiation of Potassium Chloride Targets in the TRIUMF500 MeV Isotope Production Facility (Document-65086). Technical report, TRIUMF, Vancouver,2012.[13] L. Moskven and AKH. Robertson. L124 Thorium Metal Target for IPF (Document-148097). Tech-nical report, TRIUMF, Vancouver, Canada, 2017.[14] Inconel 718, Alloy 718, UNS N07718 - MEGA MEX.[15] Yuri Bylinsky. personal communication.[16] Andrew K H Robertson. Commissioning Plan for Irradiation of L124 Thorium Metal Targets atIPF (Document-148095). Technical report, TRIUMF, Vancouver, Canada, 2017.[17] A. Ferrari, P. R. Sala, A. Fasso, and J. Ranft. FLUKA: a multi-particle transport code. Technicalreport, CERN, Geneva, 2005.[18] A Trudel and J Mildenberger. Actinide Target Safety Analysis Report (Document-12972). Technicalreport, TRIUMF, Vancouver, Canada, 2011.295 19[19] J Mildenberger and A Trudel. Actinide Target SAR Addendum for Thorium Oxide (Document-110961). Technical report, TRIUMF, Vancouver, Canada, 2014.[20] J Mildenberger. Rn-220 from ISAC target pits (Document-130951). Technical report, TRIUMF,Vancouver, Canada, 2016.[21] Joe Mildenberger. personal communication.[22] K. Murray Matthews, Chang Kyu Kim, and Paul Martin. Determination of 210Po in environmen-tal materials: A review of analytical methodology. Appl. Radiat. Isot., 65(3):267–279, 2007.[23] K. W. Bagnall. The Chemistry of Polonium. Adv. Inorg. Chem. Radiochem., 4:197–229, 1962.[24] E. Wiberg and N. Wiberg. Inorganic Chemistry. Academic Press, Berlin, 2001.[25] N. Hussain, T. G. Ferdelman, T. M. Church, and George W. Luther. Bio-volatilization of polonium:Results from laboratory analyses. Aquat. Geochemistry, 1(2):175–188, 1995.[26] R. Wilson, K. Araj, A. O. Allen, P. Auer, D. G. Boulware, F. Finlayson, S. Goren, C. Ice, L. Lidofsky,A. L. Sessoms, M. L. Shoaf, I. Spiewak, and T. Tombrello. Report to the American Physical Societyof the sudy group on radionuclide release from severe accidents at nuclear power plants. Rev.Mod. Phys., 57(3), 1985.[27] P. E. Figgins. The Radiochemistry of Polonium. Technical report, Mound Laboratory, US AtomicEnergy Commission, Miamisburg, OH, 1961.[28] Polonium: Los Alamos National Laboratory.[29] Noriyuki Momoshima, L. I Xiang Song, Susumu Osaki, and Yonezo Maeda. Formation andemission of volatile polonium compound by microbial activity and polonium methylation withmethylcobalamin. Environ. Sci. Technol., 35(14):2956–2960, 2001.[30] H Mabuchi. On the volatility of some polonium compounds. J. Inorg. Nucl. Chem., 25(1955):657–660, 1963.[31] M. J. Crick and G. S. Linsley. An assessment of the radiological impact of the Windscale reactorfire, October 1957. Int. J. Radiat. Biol., 46(5):479–506, 1984.[32] A Trudel. Worst Case Emissions Analysis Report (Document-55017). Technical report, TRIUMF,Vancouver, Canada, 2015.[33] J. Mildenberger and A. Trudel. Actinide Target 2uA Irradiation Report (Document-34296). Tech-nical report, TRIUMF, Vancouver, Canada, 2011.[34] International Commission on Radiological Protection. ICRP Publication 68: Dose Coefficients forIntakes of Radionuclides by Workers. Ann. ICRP, 24(4), 1994.[35] Anders Mjos. L124 Design Review 2017-11-09 (Document-148946). Technical report, TRIUMF,Vancouver, Canada, 2017.[36] Volume 2 ASM International Handbook. Properties and selection: Nonferrous alloys and special-purpose materials. In ASM Met. Handb., volume 2, page 1300. 1990.[37] Special Metals Corporation. Inconel 718 Alloy, 2007.296Nuclide SDRL [TBq] Nuclide SDRL [TBq] Nuclide SDRL [TBq] Nuclide SDRL [TBq]H-3 2.00E+03 FE-55 3.01E-01 KR-75 5.10E+02 SN-113 1.44E-01BE-7 9.23E-01 FE-52 3.42E+00 KR-76 4.67E+02 SB-122 4.37E-01C-11 2.68E+02 FE-59 3.44E-02 KR-77 2.19E+02 SB-124 2.00E-02C-14 1.69E+02 CO-55 1.41E+00 KR-79 7.78E+02 SB-125 7.09E-03N-13 4.02E+02 CO-56 1.01E-02 KR-81 3.51E+04 TE-121 2.29E-01O-14 5.78E+02 CO-57 8.39E-02 KR-83M 6.89E+06 TE-121M 3.93E-02O-15 1.18E+03 CO-58 3.80E-02 KR-85 7.87E+04 TE-123M 6.11E-02F-17 1.73E+03 CO-60 7.16E-04 KR-85M 1.31E+03 TE-132 1.68E-01F-18 3.56E+01 CO-61 2.11E+02 KR-87 2.62E+02 I-120 3.04E+01NE-24 1.42E+03 NI-56 2.21E-01 KR-88 8.17E+01 I-120M 2.45E+01NA-22 1.57E-03 NI-57 7.69E-01 KR-89 4.54E+02 I-121 1.34E+02NA-24 1.22E+00 CU-64 1.63E+01 RB-81 2.35E+01 I-122 6.38E+02MG-28 8.76E-01 CU-67 2.07E-01 RB-82M 4.05E+00 I-123 2.47E+01Al-26 3.47E-05 ZN-65 1.57E-02 RB-83 4.29E-02 I-124 9.14E-02SI-31 1.29E+02 GA-67 2.61E+00 RB-84 4.52E-02 I-125 3.72E-02P-32 8.70E-02 GA-68 5.50E+01 RB-86 6.78E-02 I-126 2.08E-02P-33 6.74E-01 GE-68 9.29E-02 RB-88 2.43E+02 I-128 1.02E+03S-35 9.71E-01 GE-75 4.71E+02 RB-89 1.01E+02 I-129 3.05E-03CL-34M 5.60E+01 AS-71 1.08E+00 SR-82 2.98E-02 I-130 2.51E+00CL-36 7.43E-03 AS-72 6.99E-01 SR-85 7.29E-02 I-131 3.41E-02CL-38 6.48E+01 AS-73 4.22E-01 SR-85M 2.67E+02 I-132 2.43E+01CL-39 4.79E+01 AS-74 1.01E-01 SR-89 5.28E-02 I-132M 1.05E+02AR-37 7.38E+07 AS-76 1.09E+00 Y-88 1.10E-02 I-133 9.31E-01AR-39 1.03E+06 SE-73 7.61E+00 ZR-88 7.88E-02 I-134 4.92E+01AR-41 1.59E+02 SE-73M 3.39E+02 ZR-89 4.93E-01 I-135 7.70E+00AR-42 1.18E+03 SE-75 3.31E-02 ZR-95 4.79E-02 XE-118 1.99E+03AR-43 3.44E+02 SE-79 2.37E-02 ZR-97 1.49E+00 XE-119 4.33E+02AR-44 1.24E+02 SE-81 2.83E+03 NB-95 8.84E-02 XE-120 1.86E+02K-43 2.68E+00 SE-81M 6.79E+02 NB-95M 1.08E+00 XE-121 1.26E+02K-44 6.83E+01 SE-83 6.38E+01 NB-97 7.59E+01 XE-122 1.73E+02CA-45 1.60E-01 SE-84 1.65E+03 MO-99 1.43E+00 XE-123 3.05E+02CA-47 2.63E-01 BR-74 3.19E+01 TC-96 2.20E-01 XE-125 3.29E+02SC-43 1.39E+01 BR-75 3.27E+01 TC-99M 8.19E+01 XE-127 7.50E+02SC-44 7.26E+00 BR-76 1.54E+00 RU-103 9.74E-02 XE-129M 8.85E+03SC-44M 3.90E-01 BR-77 3.37E+00 PD-100 8.87E-01 XE-131M 2.41E+04SC-46 1.65E-02 BR-80 1.50E+03 PD-103 9.94E-01 XE-133 6.01E+03SC-47 1.12E+00 BR-80M 8.85E+01 AG-105 1.10E-01 XE-133M 7.40E+03TI-44 1.76E-03 BR-82 6.97E-01 AG-108M 9.13E-05 XE-135 8.04E+02V-48 4.72E-02 BR-83 3.97E+02 AG-110M 4.40E-03 XE-135M 7.74E+02CR-51 2.14E+00 BR-84 6.41E+01 AG-111 2.77E-01 XE-137 3.82E+03MN-52 1.18E-01 BR-85 9.85E+03 CD-109 6.06E-02 XE-138 1.68E+02MN-54 1.19E-02 BR-87 8.18E+02 IN-111 1.57E+00 CS-127 2.68E+01MN-56 1.43E+01 KR-74 3.25E+02 IN-114M 2.93E-02 CS-129 6.96E+00-      -   20 -      - 297Nuclide SDRL [TBq] Nuclide SDRL [TBq]CS-130 4.28E+00 RN-207 3.25E+02CS-131 4.80E+00 RN-208 3.00E+01CS-132 4.90E-01 RN-209 5.80E+01CS-134 2.30E-03 RN-210 3.01E+02CS-137 1.79E-02 RN-211 1.44E+01CS-138 4.65E+01 RN-212 4.79E+01BA-128 6.44E-01 RN-220 3.06E+02BA-131 3.24E-01 RN-221 1.99E-03BA-137M 6.36E-04 RN-222 3.47E+00Eu-152 6.67E-04 RN-223 4.52E+01TA-182 1.77E-02 RA-223 1.73E-03Re-182 3.99E+00 RA-224 7.06E-03Re-182 3.40E-01 RA-225 1.33E-03Re-184 6.33E-02 RA-226 4.36E-04RE-184M 3.12E-02 RA-228 9.33E-05RE-186 4.15E-01 AC-225 8.85E-03AU-195 1.49E-01 AC-227 6.42E-05AU-198 6.69E-01 AC-228 8.77E-01AU-199 1.53E+00 TH-227 1.45E-02HG-197 3.24E+00 TH-228 8.70E-04HG-199M 6.72E+01 TH-232 3.63E-04HG-203 1.40E-01 U-234 3.82E-03TL-200 2.01E+00 U-235 5.13E-04TL-201 5.46E+00 U-238 4.26E-03TL-202 3.40E-01 NP-237 9.53E-04PB-203 2.65E+00 PU-238 6.63E-04PB-212 4.52E-01 PU-239 6.10E-04BI-203 2.31E+00 PU-240 6.08E-04BI-205 9.53E-02 PU-241 3.27E-02BI-207 2.12E-04 PU-242 6.34E-04BI-210 3.66E-01 AM-241 6.35E-04BI-212 3.69E+00PO-203 5.79E+01PO-204 1.00E+00PO-205 2.46E+01PO-206 3.12E-01PO-207 9.00E+00PO-208 1.18E-04PO-209 1.08E-04PO-210 9.05E-05PO-211 2.05E+05PO-212M 9.41E+10PO-218 1.34E+01RN-206 1.55E+02-      -   21298Nuclide Z A Activity [Bq] +- [%] Nuclide Z A Activity [Bq] +- [%] U-233 92 233 5.34E+00 0.54 Ac-226 89 226 2.70E+09 1 U-232 92 232 5.47E+03 4.01 Ac-225 89 225 6.73E+08 0.87 U-230 92 230 2.12E+05 2.06 Ac-224 89 224 4.02E+09 1.11 Pa-233 91 233 4.48E+08 0.51 Ac-223 89 223 4.51E+09 0.98 Pa-232 91 232 1.68E+08 4.03 Ac-222 89 222 1.98E+09 1.09 Pa-231 91 231 1.14E+03 0.44 Ac-222m 89 222 1.78E+09 1.11 Pa-230 91 230 7.64E+07 2.06 Ac-221 89 221 3.58E+09 1.07 Pa-229 91 229 1.95E+08 3.54 Ac-220 89 220 2.46E+09 1.27 Pa-228 91 228 1.77E+08 4.53 Ac-219 89 219 2.34E+09 1.4 Pa-227 91 227 4.59E+07 9.45 Ac-218 89 218 1.46E+09 1.71 Pa-226 91 226 3.26E+07 12.45 Ac-217 89 217 1.15E+09 1.93 Pa-225 91 225 3.86E+06 32.66 Ac-216 89 216 3.04E+08 2.81 Pa-224 91 224 2.57E+06 40.31 Ac-216m 89 216 3.04E+08 2.81 Pa-223 91 223 1.29E+06 57.44 Ac-215 89 215 7.25E+08 2.4 Th-233 90 233 9.03E+09 0.51 Ac-214 89 214 4.40E+08 2.89 Th-231 90 231 1.51E+10 0.44 Ac-213 89 213 2.22E+08 4.17 Th-230 90 230 1.07E+03 0.46 Ac-212 89 212 5.28E+07 8.83 Th-229 90 229 7.32E+03 0.59 Ac-211 89 211 6.87E+06 24.04 Th-228 90 228 2.71E+07 0.57 Ac-210 89 210 1.72E+06 49.62 Th-227 90 227 4.41E+08 0.79 Ra-230 88 230 6.82E+07 7.74 Th-226 90 226 6.33E+09 0.69 Ra-229 88 229 1.36E+08 5.73 Th-225 90 225 2.93E+09 1.16 Ra-228 88 228 1.73E+05 4.1 Th-224 90 224 1.54E+09 1.77 Ra-227 88 227 3.27E+08 3.08 Th-223 90 223 9.54E+08 2.14 Ra-226 88 226 1.99E+03 2.02 Th-222 90 222 4.14E+08 3.38 Ra-225 88 225 5.49E+07 2.61 Th-221 90 221 2.03E+08 4.66 Ra-224 88 224 1.37E+09 0.93 Th-220 90 220 1.39E+08 6 Ra-223 88 223 1.51E+08 1.67 Th-219 90 219 9.35E+07 6.8 Ra-222 88 222 8.00E+09 0.63 Th-218 90 218 7.38E+07 7.82 Ra-221 88 221 4.06E+09 0.93 Th-217 90 217 4.81E+07 10.02 Ra-220 88 220 3.63E+09 1.18 Th-216 90 216 4.06E+07 10.65 Ra-219 88 219 2.65E+09 1.18 Th-216m 90 216 2.06E+07 10.65 Ra-218 88 218 2.82E+09 1.18 Th-215 90 215 2.53E+07 12.44 Ra-217 88 217 2.16E+09 1.32 Th-214 90 214 6.01E+06 25.84 Ra-216 88 216 2.54E+09 1.31 Ac-232 89 232 2.83E+07 11.79 Ra-215 88 215 1.95E+09 1.65 Ac-231 89 231 4.83E+09 0.91 Ra-214 88 214 2.51E+09 1.38 Ac-230 89 230 2.86E+09 1.24 Ra-213 88 213 2.01E+09 1.51 Ac-229 89 229 4.65E+09 1.05 Ra-213m 88 213 9.85E+08 1.51 Ac-228 89 228 3.36E+09 1.14 Ra-212 88 212 1.82E+09 1.49 Ac-227 89 227 8.45E+05 0.88 Ra-211 88 211 1.07E+09 1.92       22       299 Ra-210 88 210 7.35E+08 2.47 Rn-215 86 215 2.73E+09 1.16 Ra-209 88 209 2.50E+08 4.18 Rn-214 86 214 2.87E+09 1.17 Ra-208 88 208 5.71E+07 8.14 Rn-214m 86 214 5.24E+07 4.73 Ra-207 88 207 3.96E+06 34 Rn-214n 86 214 5.24E+07 4.73 Ra-207m 88 207 2.15E+06 34 Rn-213 86 213 2.43E+09 1.25 Fr-228 87 228 8.58E+05 70.53 Rn-212 86 212 4.09E+09 0.95 Fr-227 87 227 8.15E+06 21.88 Rn-211 86 211 2.54E+09 1.27 Fr-226 87 226 8.58E+06 21.27 Rn-210 86 210 3.64E+09 1.02 Fr-225 87 225 2.23E+07 13.97 Rn-209 86 209 2.35E+09 1.25 Fr-224 87 224 3.95E+07 10.99 Rn-208 86 208 2.36E+09 1.35 Fr-223 87 223 6.31E+07 8.49 Rn-207 86 207 1.66E+09 1.52 Fr-222 87 222 8.77E+07 6.39 Rn-206 86 206 1.38E+09 1.77 Fr-221 87 221 8.22E+08 1.12 Rn-205 86 205 6.43E+08 2.58 Fr-220 87 220 5.22E+08 1.84 Rn-204 86 204 3.63E+08 3.08 Fr-219 87 219 4.75E+09 0.95 Rn-203 86 203 6.45E+07 5.72 Fr-218 87 218 3.64E+09 1.07 Rn-203m 86 203 6.05E+07 5.89 Fr-218m 87 218 1.38E+08 3.64 Rn-202 86 202 4.76E+07 8.63 Fr-217 87 217 4.05E+09 0.93 Rn-201 86 201 1.07E+06 44.27 Fr-216 87 216 2.96E+09 1.22 Rn-201m 86 201 1.07E+06 44.27 Fr-215 87 215 2.96E+09 1.17 Rn-200 86 200 8.58E+05 70.53 Fr-214 87 214 1.85E+09 1.45 At-218 85 218 8.58E+05 70.52 Fr-214m 87 214 3.93E+08 2.1 At-217 85 217 8.22E+08 1.12 Fr-213 87 213 2.85E+09 1.17 At-216 85 216 5.24E+08 1.84 Fr-212 87 212 1.91E+09 1.46 At-215 85 215 4.75E+09 0.95 Fr-211 87 211 1.94E+09 1.49 At-214 85 214 3.78E+09 1.07 Fr-210 87 210 1.31E+09 1.67 At-214m 85 214 2.43E+06 23.26 Fr-209 87 209 1.05E+09 1.88 At-214n 85 214 2.43E+06 23.26 Fr-208 87 208 5.30E+08 2.9 At-213 85 213 4.06E+09 0.93 Fr-207 87 207 3.13E+08 3.51 At-212 85 212 2.97E+09 1.22 Fr-206 87 206 4.63E+07 6.53 At-212m 85 212 1.57E+07 11.68 Fr-206m 87 206 4.46E+07 6.53 At-211 85 211 4.70E+09 0.85 Fr-205 87 205 1.33E+07 17.77 At-210 85 210 2.43E+09 1.26 Fr-204 87 204 8.58E+05 70.53 At-209 85 209 4.90E+09 0.95 Rn-224 86 224 1.72E+06 49.62 At-208 85 208 1.88E+09 1.04 Rn-223 86 223 8.58E+05 70.53 At-207 85 207 3.12E+09 1.08 Rn-222 86 222 9.14E+05 37.21 At-206 85 206 1.59E+09 1.32 Rn-221 86 221 8.15E+06 25.41 At-205 85 205 1.80E+09 1.44 Rn-220 86 220 1.38E+09 0.93 At-204 85 204 8.72E+08 1.89 Rn-219 86 219 1.64E+08 2.19 At-204m 85 204 1.39E+08 3.42 Rn-218 86 218 8.04E+09 0.62 At-203 85 203 6.44E+08 2.47 Rn-217 86 217 4.09E+09 0.93 At-202 85 202 2.77E+08 3.72 Rn-216 86 216 3.69E+09 1.17 At-202m 85 202 9.25E+07 4.64       23300 At-201 85 201 1.31E+08 5.29 Bi-205 83 205 1.88E+08 1.1 At-200 85 200 3.93E+07 10.59 Bi-204 83 204 2.29E+09 1.1 At-200m 85 200 2.15E+07 10.8 Bi-204m 83 204 9.01E+06 16.04 At-199 85 199 9.01E+06 21.77 Bi-203 83 203 1.17E+09 1.24 Po-218 84 218 9.13E+05 37.21 Bi-203m 83 203 1.52E+07 11.8 Po-217 84 217 1.79E+06 25.41 Bi-202 83 202 1.36E+09 1.61 Po-216 84 216 1.38E+09 0.93 Bi-201 83 201 6.03E+08 1.88 Po-215 84 215 1.64E+08 2.2 Bi-201m 83 201 2.98E+07 8.48 Po-214 84 214 8.04E+09 0.62 Bi-200 83 200 5.07E+08 2.23 Po-213 84 213 4.88E+09 0.82 Bi-200m 83 200 2.63E+07 7.68 Po-212 84 212 4.62E+09 0.95 Bi-200n 83 200 2.63E+07 7.68 Po-211 84 211 5.49E+09 0.74 Bi-199 83 199 4.27E+08 2.17 Po-211m 84 211 1.72E+06 34.73 Bi-199m 83 199 5.62E+07 6.16 Po-210 84 210 5.31E+07 0.8 Bi-198 83 198 1.81E+08 3.61 Po-209 84 209 2.37E+05 0.7 Bi-198m 83 198 5.32E+07 5.87 Po-208 84 208 7.62E+06 0.79 Bi-197 83 197 1.51E+08 3.75 Po-207 84 207 3.51E+09 0.93 Bi-197m 83 197 4.72E+07 6.18 Po-207m 84 207 1.61E+07 12.46 Bi-196 83 196 5.08E+07 7.19 Po-206 84 206 7.10E+08 0.87 Bi-196m 83 196 2.77E+07 8.79 Po-205 84 205 2.12E+09 1.18 Bi-195 83 195 2.79E+07 9.1 Po-204 84 204 2.47E+09 1.1 Bi-195m 83 195 1.97E+07 9.6 Po-203 84 203 9.55E+08 1.48 Bi-194 83 194 5.58E+06 16.13 Po-203m 84 203 8.09E+07 4.92 Bi-194m 83 194 5.58E+06 16.13 Po-202 84 202 1.33E+09 1.61 Bi-194n 83 194 5.58E+06 16.13 Po-201 84 201 3.35E+08 2.4 Bi-193 83 193 3.43E+06 24.04 Po-201m 84 201 1.07E+08 4.46 Bi-193m 83 193 3.43E+06 24.04 Po-200 84 200 4.87E+08 2.54 Bi-192 83 192 8.58E+05 49.62 Po-199 84 199 1.53E+08 4.22 Bi-192m 83 192 8.58E+05 49.62 Po-199m 84 199 6.01E+07 6.08 Pb-214 82 214 9.02E+05 37.21 Po-198 84 198 1.37E+08 5.59 Pb-213 82 213 1.70E+06 25.41 Po-197 84 197 1.58E+07 12.68 Pb-212 82 212 9.66E+08 0.94 Po-197m 84 197 1.39E+07 13.61 Pb-211 82 211 1.61E+08 2.22 Po-196 84 196 1.24E+07 19.79 Pb-210 82 210 1.20E+06 0.67 Bi-214 83 214 1.75E+06 39.08 Pb-209 82 209 4.84E+09 0.83 Bi-213 83 213 8.09E+08 1.15 Pb-207m 82 207 4.43E+05 0.76 Bi-212 83 212 1.45E+09 1.08 Pb-204m 82 204 8.58E+05 49.62 Bi-211 83 211 4.91E+09 0.91 Pb-203 82 203 4.09E+08 1.23 Bi-210 83 210 9.14E+08 1.07 Pb-203m 82 203 1.14E+06 34.73 Bi-208 83 208 3.08E+01 1.22 Pb-203n 82 203 1.14E+06 34.73 Bi-208m 83 208 8.58E+05 49.62 Pb-202 82 202 9.27E+01 1.58 Bi-207 83 207 4.76E+05 0.76 Pb-202m 82 202 5.58E+06 19.13 Bi-206 83 206 6.98E+07 1 Pb-201 82 201 6.18E+08 1.93       24301 Pb-201m 82 201 4.93E+06 20.61 Tl-192 81 192 6.63E+07 7.94 Pb-200 82 200 4.46E+08 2.24 Tl-192m 81 192 1.67E+07 10.87 Pb-199 82 199 5.07E+08 2.28 Tl-191 81 191 3.37E+07 7.76 Pb-199m 82 199 1.22E+07 13.93 Tl-191m 81 191 1.82E+07 10.34 Pb-198 82 198 2.57E+08 3.28 Tl-190 81 190 1.61E+07 12.14 Pb-197 82 197 2.09E+08 3.21 Tl-190m 81 190 1.05E+07 13.42 Pb-197m 82 197 2.34E+07 9.72 Tl-189 81 189 1.06E+07 14.92 Pb-196 82 196 2.36E+08 3.44 Tl-189m 81 189 6.65E+06 18.35 Pb-195 82 195 1.20E+08 3.91 Tl-188 81 188 2.16E+06 29.46 Pb-195m 82 195 3.69E+07 7.33 Tl-188m 81 188 1.93E+06 32.66 Pb-194 82 194 2.16E+08 4.29 Tl-187 81 187 1.14E+06 49.62 Pb-193 82 193 3.96E+07 7.88 Tl-187m 81 187 8.58E+05 49.62 Pb-193m 82 193 1.74E+07 11.08 Hg-199m 80 199 6.44E+05 57.44 Pb-192 82 192 4.95E+07 9.98 Hg-197 80 197 9.34E+07 3.36 Pb-191 82 191 4.65E+06 21.91 Hg-197m 80 197 1.13E+06 37.22 Pb-191m 82 191 4.29E+06 22.42 Hg-195 80 195 1.80E+08 4.21 Pb-190 82 190 5.58E+06 26.89 Hg-195m 80 195 3.19E+06 19.42 Tl-210 81 210 3.50E+02 39.09 Hg-194 80 194 1.87E+03 4.01 Tl-209 81 209 1.69E+07 1.15 Hg-193 80 193 1.69E+08 4.27 Tl-208 81 208 5.21E+08 1.08 Hg-193m 80 193 1.33E+07 11.39 Tl-207 81 207 4.90E+09 0.91 Hg-192 80 192 1.10E+08 6.4 Tl-206 81 206 1.19E+03 1.07 Hg-191 80 191 6.65E+07 6.64 Tl-202 81 202 2.81E+05 36.19 Hg-191m 80 191 1.46E+07 11.88 Tl-201 81 201 1.66E+08 1.95 Hg-190 80 190 6.13E+07 7.83 Tl-201m 81 201 8.58E+05 49.62 Hg-189 80 189 2.88E+07 10.72 Tl-200 81 200 2.28E+08 2.23 Hg-189m 80 189 1.18E+07 12.07 Tl-200m 81 200 6.44E+05 57.44 Hg-188 80 188 3.28E+07 11.04 Tl-199 81 199 5.08E+08 2.32 Hg-187 80 187 6.37E+06 20.19 Tl-199m 81 199 3.86E+06 22.54 Hg-187m 80 187 4.93E+06 22.38 Tl-198 81 198 2.60E+08 3.31 Hg-186 80 186 1.21E+07 18.22 Tl-198m 81 198 1.57E+06 29.38 Hg-185 80 185 1.65E+06 44.25 Tl-198n 81 198 1.57E+06 29.38 Hg-185m 80 185 1.07E+06 44.27 Tl-197 81 197 2.47E+08 3.35 Hg-184 80 184 8.58E+05 70.53 Tl-197m 81 197 9.65E+06 14.59 Au-197m 79 197 4.29E+05 70.53 Tl-196 81 196 2.44E+08 3.37 Au-196m 79 196 5.72E+05 49.62 Tl-196m 81 196 8.37E+06 16.93 Au-196n 79 196 5.54E+05 49.62 Tl-195 81 195 1.80E+08 4.26 Au-196 79 196 3.14E+05 49.62 Tl-195m 81 195 1.18E+07 13.87 Au-195 79 195 9.51E+05 4.2 Tl-194 81 194 2.29E+08 4.16 Au-195m 79 195 6.44E+05 57.44 Tl-194m 81 194 1.35E+07 13.04 Au-194 79 194 1.50E+06 40.29 Tl-193 81 193 1.25E+08 5.12 Au-193 79 193 1.30E+08 4.62 Tl-193m 81 193 2.40E+07 9.61 Au-193m 79 193 1.93E+06 32.66       25302 Au-192 79 192 1.15E+08 6.21 Ir-185 77 185 2.83E+07 11.85 Au-191 79 191 9.02E+07 6.1 Ir-184 77 184 2.66E+07 13.41 Au-191m 79 191 4.72E+06 21.17 Ir-183 77 183 1.74E+07 15.56 Au-190 79 190 7.42E+07 7.45 Ir-182 77 182 1.59E+07 16.73 Au-190m 79 190 6.44E+06 17.52 Ir-181 77 181 1.08E+07 19.42 Au-189 79 189 4.83E+07 8.62 Ir-180 77 180 3.43E+06 34.67 Au-189m 79 189 7.72E+06 16.6 Ir-179 77 179 1.30E+06 56.91 Au-188 79 188 4.66E+07 9.02 Ir-178 77 178 3.26E+02 70.53 Au-187 79 187 2.67E+07 12.49 Os-185 76 185 2.79E+05 11.95 Au-187m 79 187 7.72E+06 15.13 Os-183 76 183 1.78E+07 14.53 Au-186 79 186 2.58E+07 13.35 Os-183m 76 183 1.66E+06 34.73 Au-185 79 185 8.27E+06 19.36 Os-182 76 182 1.67E+07 14.1 Au-185m 79 185 6.22E+06 19.8 Os-181 76 181 1.32E+07 16.67 Au-184 79 184 3.42E+06 34.73 Os-181m 76 181 2.36E+06 29.38 Au-183 79 183 3.29E+06 34.14 Os-180 76 180 1.07E+07 20.39 Au-182 79 182 8.58E+05 70.53 Os-179 76 179 4.30E+06 30.81 Pt-193 78 193 4.92E+03 4.61 Os-178 76 178 2.58E+06 40.27 Pt-193m 78 193 1.18E+05 70.53 Os-177 76 177 1.69E+06 49.57 Pt-191 78 191 2.74E+07 6.81 Os-176 76 176 8.68E+05 69.71 Pt-189 78 189 5.80E+07 8.12 Re-183 75 183 2.62E+05 14.17 Pt-188 78 188 7.63E+06 7.93 Re-182 75 182 4.53E+06 13.9 Pt-187 78 187 3.88E+07 10.47 Re-181 75 181 1.45E+07 16.31 Pt-186 78 186 3.82E+07 10.64 Re-180 75 180 1.29E+07 18.75 Pt-185 78 185 2.15E+07 13.68 Re-179 75 179 7.74E+06 22.51 Pt-185m 78 185 6.87E+06 17.96 Re-178 75 178 5.15E+06 28.05 Pt-184 78 184 1.89E+07 14.82 Re-177 75 177 4.70E+06 29.37 Pt-184m 78 184 7.72E+06 16.12 Re-176 75 176 3.01E+06 37.09 Pt-183 78 183 6.50E+06 21.62 Re-174 75 174 1.29E+06 57.44 Pt-183m 78 183 3.22E+06 24.9 Re-173 75 173 8.82E+05 68.63 Pt-182 78 182 9.87E+06 20.6 W-181 74 181 9.96E+04 16.36 Pt-181 78 181 3.53E+06 33.73 W-179 74 179 8.16E+06 21.85 Pt-180 78 180 8.60E+05 69.75 W-178 74 178 4.51E+05 24.71 Ir-190m 77 190 4.29E+05 57.44 W-177 74 177 5.56E+06 26.88 Ir-190n 77 190 4.29E+05 57.44 W-176 74 176 6.02E+06 25.79 Ir-190 77 190 9.62E+04 57.44 W-175 74 175 3.00E+06 37.22 Ir-189 77 189 4.23E+06 8 W-174 74 174 3.43E+06 34.73 Ir-189m 77 189 2.86E+05 70.53 W-173 74 173 2.60E+06 39.93 Ir-189n 77 189 2.86E+05 70.53 W-172 74 172 2.15E+06 52.57 Ir-188 77 188 2.89E+06 13.52 Ta-179 73 179 1.77E+04 21.24 Ir-187 77 187 3.95E+07 10.17 Ta-178 73 178 4.49E+05 24.71 Ir-186 77 186 3.32E+07 10.4 Ta-177 73 177 2.71E+06 24.9 Ir-186m 77 186 1.07E+06 44.27 Ta-176 73 176 7.14E+06 23.22       26303 Ta-175 73 175 5.75E+06 27.75 Tm-164 69 164 5.71E+06 25.88 Ta-174 73 174 5.15E+06 28.06 Tm-164m 69 164 1.50E+06 37.22 Ta-173 73 173 3.46E+06 38.71 Tm-163 69 163 6.87E+06 27.11 Ta-172 73 172 5.15E+06 30.44 Tm-162 69 162 3.12E+06 34.73 Ta-171 73 171 1.29E+06 57.44 Tm-162m 69 162 1.72E+06 34.73 Ta-170 73 170 8.58E+05 70.53 Tm-161 69 161 1.29E+06 57.44 Ta-169 73 169 8.58E+05 70.53 Tm-160 69 160 8.26E+05 70.59 Hf-175 72 175 9.82E+04 25.71 Tm-159 69 159 8.58E+05 70.53 Hf-173 72 173 3.45E+06 31.86 Er-167m 68 167 9.87E+04 70.53 Hf-172 72 172 1.37E+04 25.6 Er-165 68 165 6.61E+06 21.74 Hf-171 72 171 2.81E+06 37.22 Er-163 68 163 9.87E+06 21.51 Hf-170 72 170 1.88E+06 44.27 Er-161 68 161 6.44E+06 26.63 Hf-169 72 169 2.15E+06 44.27 Er-160 68 160 4.13E+06 27.75 Lu-173 71 173 6.61E+03 31.43 Er-159 68 159 3.43E+06 34.73 Lu-172 71 172 4.02E+05 44.12 Er-158 68 158 3.86E+06 32.66 Lu-172m 71 172 1.07E+06 44.27 Er-155 68 155 8.58E+05 70.53 Lu-171 71 171 7.09E+05 27.47 Ho-167 67 167 8.58E+05 70.53 Lu-171m 71 171 1.29E+06 40.31 Ho-166 67 166 3.70E+05 60.64 Lu-170 71 170 2.39E+06 27.54 Ho-166m 67 166 1.36E+00 70.53 Lu-170m 71 170 1.72E+06 34.73 Ho-164 67 164 1.29E+06 57.44 Lu-169 71 169 2.94E+06 29.38 Ho-164m 67 164 6.44E+05 57.44 Lu-169m 71 169 1.29E+06 40.31 Ho-163 67 163 1.11E+01 18.15 Lu-168 71 168 1.33E+06 46.35 Ho-163m 67 163 2.15E+06 34 Lu-168m 71 168 8.58E+05 49.62 Ho-162 67 162 3.48E+06 30.9 Lu-167 71 167 8.58E+05 70.53 Ho-162m 67 162 2.15E+06 30.9 Lu-166 71 166 9.27E+05 49.62 Ho-161 67 161 1.63E+07 15.56 Lu-166m 71 166 5.72E+05 49.62 Ho-161m 67 161 4.93E+06 19.67 Lu-166n 71 166 5.72E+05 49.62 Ho-160 67 160 8.27E+06 19.59 Lu-165 71 165 8.58E+05 49.62 Ho-160n 67 160 1.57E+06 29.38 Lu-165m 71 165 8.58E+05 49.62 Ho-160m 67 160 1.57E+06 29.38 Yb-169 70 169 1.63E+05 31.62 Ho-159 67 159 1.03E+07 20.94 Yb-169m 70 169 1.07E+06 52.57 Ho-159m 67 159 3.43E+06 25.62 Yb-167 70 167 3.86E+06 32.66 Ho-158 67 158 5.16E+06 26.51 Yb-166 70 166 2.48E+06 26.89 Ho-158m 67 158 7.15E+05 44.27 Yb-165 70 165 4.29E+06 30.9 Ho-158n 67 158 7.15E+05 44.27 Yb-164 70 164 3.00E+06 37.22 Ho-157 67 157 4.29E+06 30.9 Yb-163 70 163 2.15E+06 44.27 Ho-156 67 156 2.57E+06 40.31 Tm-170 69 170 1.38E+04 57.44 Ho-155 67 155 3.00E+06 37.22 Tm-168 69 168 3.17E+04 44.27 Ho-154 67 154 4.29E+05 70.53 Tm-167 69 167 1.07E+06 22.54 Ho-154m 67 154 4.29E+05 70.53 Tm-166 69 166 4.96E+06 25.3 Dy-165 66 165 1.69E+06 49.62 Tm-165 69 165 4.30E+06 24.9 Dy-165m 66 165 1.17E+06 51.37       27304 Dy-159 66 159 1.41E+05 17.38 Eu-161 63 161 2.15E+06 44.27 Dy-157 66 157 1.39E+07 17.6 Eu-160 63 160 1.09E+07 19.65 Dy-157m 66 157 4.93E+06 20.61 Eu-159 63 159 2.15E+07 13.82 Dy-155 66 155 8.06E+06 21.73 Eu-158 63 158 4.46E+07 9.54 Dy-153 66 153 3.84E+06 32.66 Eu-157 63 157 6.47E+07 7.53 Dy-152 66 152 3.43E+06 34.73 Eu-156 63 156 8.25E+06 5.36 Tb-165 65 165 8.58E+05 70.53 Eu-155 63 155 1.39E+05 4.77 Tb-164 65 164 8.58E+05 70.53 Eu-154m 63 154 9.01E+06 14.94 Tb-163 65 163 3.43E+06 34.73 Eu-154 63 154 7.87E+03 14.94 Tb-162 65 162 1.03E+07 19.2 Eu-152n 63 152 5.44E+06 16 Tb-161 65 161 2.58E+06 16.52 Eu-152m 63 152 5.28E+06 16 Tb-160 65 160 9.78E+04 28.06 Eu-152 63 152 2.98E+03 16 Tb-158m 65 158 5.15E+06 20.08 Eu-150m 63 150 7.35E+06 15.83 Tb-158 65 158 2.17E+02 20.08 Eu-150 63 150 8.42E+02 15.83 Tb-157 65 157 8.07E+02 13.01 Eu-149 63 149 3.20E+05 14.97 Tb-156n 65 156 4.00E+06 18.97 Eu-148 63 148 3.88E+05 17.06 Tb-156m 65 156 2.98E+06 18.97 Eu-147 63 147 8.17E+05 16.19 Tb-156 65 156 1.73E+06 18.97 Eu-146 63 146 2.58E+06 21.46 Tb-155 65 155 4.64E+06 13.35 Eu-145 63 145 1.35E+06 26.37 Tb-154m 65 154 2.50E+06 26.35 Eu-144 63 144 3.00E+06 37.22 Tb-154 65 154 2.41E+06 26.35 Sm-160 62 160 4.72E+06 32.09 Tb-154n 65 154 1.98E+06 26.35 Sm-159 62 159 1.07E+07 19.59 Tb-153 65 153 7.21E+06 15.85 Sm-158 62 158 2.45E+07 12.77 Tb-152 65 152 7.41E+06 20.18 Sm-157 62 157 5.49E+07 8.5 Tb-152m 65 152 3.00E+06 25.84 Sm-156 62 156 9.81E+07 5.79 Tb-151 65 151 6.90E+06 21.67 Sm-155 62 155 1.46E+08 5.1 Tb-151m 65 151 3.22E+06 26.63 Sm-153 62 153 1.59E+08 3.78 Tb-150 65 150 3.00E+06 25.84 Sm-151 62 151 1.12E+04 2.95 Tb-150m 65 150 2.57E+06 28.06 Sm-145 62 145 8.67E+04 13.87 Tb-149 65 149 4.29E+05 70.45 Sm-143 62 143 1.07E+07 19.59 Tb-149m 65 149 4.29E+05 70.53 Sm-143m 62 143 3.43E+06 20.08 Gd-163 64 163 2.15E+06 44.27 Sm-143n 62 143 3.43E+06 20.08 Gd-162 64 162 7.29E+06 23.26 Sm-142 62 142 4.29E+06 30.9 Gd-161 64 161 9.87E+06 19.67 Sm-141 62 141 1.08E+06 44.27 Gd-159 64 159 2.14E+07 12.28 Sm-141m 62 141 1.07E+06 44.27 Gd-153 64 153 1.08E+05 13.25 Pm-158 61 158 8.58E+06 21.27 Gd-151 64 151 1.66E+05 16.85 Pm-157 61 157 2.19E+07 13.84 Gd-149 64 149 1.28E+06 23.12 Pm-156 61 156 4.57E+07 9.1 Gd-148 64 148 3.50E+02 24.03 Pm-155 61 155 9.93E+07 5.97 Gd-147 64 147 2.26E+06 32.45 Pm-154 61 154 1.22E+08 5.25 Gd-146 64 146 4.86E+04 49.62 Pm-154m 61 154 4.12E+07 6.92 Eu-162 63 162 2.15E+06 44.27 Pm-153 61 153 2.64E+08 4.27       28305 Pm-152 61 152 3.08E+08 3.57 Pr-153 59 153 4.24E+07 9.59 Pm-152m 61 152 3.53E+07 6.23 Pr-152 59 152 9.11E+07 6.96 Pm-152n 61 152 3.53E+07 6.23 Pr-151 59 151 2.32E+08 4.59 Pm-151 61 151 3.81E+08 2.98 Pr-150 59 150 3.50E+08 3.07 Pm-150 61 150 9.23E+07 6.79 Pr-149 59 149 5.85E+08 2.97 Pm-149 61 149 3.93E+08 2.36 Pr-148 59 148 6.51E+08 2.38 Pm-148 61 148 7.48E+06 7.7 Pr-148m 59 148 1.85E+08 3.59 Pm-148m 61 148 1.08E+06 7.7 Pr-147 59 147 1.16E+09 1.9 Pm-147 61 147 2.19E+05 3.83 Pr-146 59 146 1.42E+09 1.62 Pm-146 61 146 4.21E+04 7.83 Pr-145 59 145 1.76E+09 1.45 Pm-145 61 145 1.33E+04 8 Pr-144 59 144 2.55E+08 3.78 Pm-144 61 144 1.85E+05 9.27 Pr-144m 59 144 1.23E+08 3.92 Pm-143 61 143 3.20E+05 8.61 Pr-143 59 143 1.01E+08 1.35 Pm-142 61 142 3.26E+07 10.64 Pr-142 59 142 1.27E+08 5.46 Pm-141 61 141 2.23E+07 14.99 Pr-142m 59 142 7.70E+07 5.46 Pm-140 61 140 4.51E+06 24.71 Pr-140 59 140 1.38E+08 5.17 Pm-140m 61 140 4.08E+06 25.41 Pr-139 59 139 1.36E+08 6.14 Pm-139 61 139 3.00E+06 37.22 Pr-138 59 138 4.93E+07 7.1 Pm-139m 61 139 1.29E+06 40.31 Pr-138m 59 138 2.83E+07 8.28 Pm-138 61 138 8.58E+05 57.44 Pr-137 59 137 4.59E+07 9.99 Pm-138m 61 138 4.29E+05 57.44 Pr-136 59 136 2.66E+07 13.6 Pm-138n 61 138 4.29E+05 57.44 Pr-135 59 135 1.20E+07 18.97 Nd-156 60 156 1.22E+07 18.68 Pr-134 59 134 2.79E+06 29.01 Nd-155 60 155 2.51E+07 12.95 Pr-134m 59 134 2.36E+06 29.38 Nd-154 60 154 8.09E+07 7.46 Pr-133 59 133 1.29E+06 57.44 Nd-153 60 153 1.29E+08 5.91 Ce-152 58 152 1.46E+07 16.99 Nd-152 60 152 2.73E+08 3.93 Ce-151 58 151 3.78E+07 10.76 Nd-151 60 151 4.16E+08 3.36 Ce-150 58 150 1.20E+08 5.75 Nd-149 60 149 7.84E+08 2.5 Ce-149 58 149 2.02E+08 4.46 Nd-147 60 147 1.56E+08 1.69 Ce-148 58 148 4.67E+08 2.77 Nd-141 60 141 7.94E+07 7.39 Ce-147 58 147 6.68E+08 2.38 Nd-141m 60 141 2.85E+07 8.87 Ce-146 58 146 1.08E+09 1.95 Nd-140 60 140 2.21E+07 8.54 Ce-145 58 145 1.37E+09 1.73 Nd-139m 60 139 1.50E+07 12.11 Ce-144 58 144 9.21E+06 1.44 Nd-139 60 139 1.98E+07 12.5 Ce-143 58 143 1.37E+09 1.28 Nd-138 60 138 2.10E+07 13.1 Ce-141 58 141 1.03E+08 1.22 Nd-137 60 137 8.15E+06 21.88 Ce-139 58 139 3.44E+06 3.69 Nd-137m 60 137 3.86E+06 22.54 Ce-139m 58 139 1.14E+08 4.48 Nd-136 60 136 3.43E+06 34.73 Ce-138m 58 138 1.21E+08 4.2 Nd-135 60 135 4.29E+05 70.53 Ce-137 58 137 1.50E+08 4.67 Nd-135m 60 135 4.29E+05 70.53 Ce-137m 58 137 4.47E+07 5.15 Pr-154 59 154 1.39E+07 16.48 Ce-135 58 135 6.98E+07 7.15       29306 Ce-135m 58 135 3.52E+07 7.82 Ba-137m 56 137 4.52E+08 2.24 Ce-134 58 134 2.05E+07 9.03 Ba-136m 56 136 4.24E+08 2.41 Ce-133m 58 133 1.26E+07 12.9 Ba-135m 56 135 1.69E+08 2.75 Ce-133 58 133 1.39E+07 13.26 Ba-133 56 133 1.23E+05 3.26 Ce-132 58 132 1.03E+07 21.75 Ba-133m 56 133 9.13E+07 3.93 Ce-131 58 131 2.79E+06 29.01 Ba-131 56 131 2.54E+07 4.2 Ce-131m 58 131 2.36E+06 29.38 Ba-131m 56 131 9.44E+07 4.72 La-150 57 150 1.13E+07 20.83 Ba-130m 56 130 7.55E+07 5.07 La-149 57 149 5.60E+07 8.31 Ba-129m 56 129 3.43E+07 7.52 La-148 57 148 1.03E+08 5.65 Ba-129 56 129 4.16E+07 7.87 La-147 57 147 2.82E+08 3.73 Ba-128 56 128 1.53E+07 10.82 La-146 57 146 2.46E+08 3.38 Ba-127 56 127 1.37E+07 19.03 La-146m 57 146 1.53E+08 3.7 Ba-126 56 126 4.29E+06 34 La-145 57 145 8.18E+08 2.15 Cs-147 55 147 2.99E+06 35.87 La-144 57 144 1.09E+09 1.89 Cs-146 55 146 7.12E+06 24.58 La-143 57 143 1.62E+09 1.52 Cs-145 55 145 3.40E+07 10.11 La-142 57 142 2.03E+09 1.5 Cs-144 55 144 4.36E+07 6.21 La-141 57 141 2.42E+09 1.25 Cs-144m 55 144 3.90E+07 6.22 La-140 57 140 4.43E+08 2.24 Cs-143 55 143 2.03E+08 3.92 La-137 57 137 3.16E+01 2.63 Cs-142 55 142 3.48E+08 3.08 La-136 57 136 2.78E+08 3.9 Cs-141 55 141 6.39E+08 2.43 La-136m 57 136 1.39E+08 3.9 Cs-140 55 140 8.63E+08 2.12 La-135 57 135 2.54E+08 3.58 Cs-139 55 139 1.32E+09 1.74 La-134 57 134 1.75E+08 5.2 Cs-138 55 138 1.54E+09 1.63 La-133 57 133 1.51E+08 5.06 Cs-138m 55 138 4.80E+08 2.18 La-132 57 132 6.50E+07 8.07 Cs-137 55 137 3.22E+05 1.17 La-132m 57 132 3.11E+07 8.63 Cs-136m 55 136 6.72E+08 1.84 La-131 57 131 4.25E+07 9.71 Cs-136 55 136 1.01E+08 1.84 La-130 57 130 1.85E+07 14.7 Cs-135 55 135 4.50E+00 1.12 La-129 57 129 7.29E+06 26.08 Cs-135m 55 135 6.48E+08 1.91 La-129m 57 129 3.65E+06 26.08 Cs-134m 55 134 4.01E+08 2.23 Ba-149 56 149 3.40E+06 33.73 Cs-134 55 134 1.41E+06 2.23 Ba-148 56 148 1.94E+07 14.6 Cs-132 55 132 1.14E+08 2.84 Ba-147 56 147 4.93E+07 8.62 Cs-131 55 131 7.63E+07 2.76 Ba-146 56 146 1.08E+08 6.18 Cs-130 55 130 3.67E+08 3.48 Ba-145 56 145 2.00E+08 4.19 Cs-130m 55 130 1.83E+08 3.48 Ba-144 56 144 4.68E+08 2.7 Cs-129 55 129 2.75E+08 3.25 Ba-143 56 143 6.24E+08 2.53 Cs-128 55 128 2.02E+08 4.31 Ba-142 56 142 1.17E+09 1.93 Cs-127 55 127 1.49E+08 5.42 Ba-141 56 141 1.45E+09 1.57 Cs-126 55 126 6.05E+07 7.84 Ba-140 56 140 2.21E+08 1.35 Cs-125 55 125 2.70E+07 12.03 Ba-139 56 139 2.28E+09 1.4 Cs-124 55 124 4.72E+06 29.38       30307 Cs-124m 55 124 2.36E+06 29.38 I-131 53 131 3.78E+08 1.18 Cs-123 55 123 2.15E+06 44.27 I-130 53 130 1.02E+09 1.86 Cs-123m 55 123 1.07E+06 44.27 I-130m 53 130 5.94E+08 1.86 Xe-144 54 144 4.61E+06 25.01 I-128 53 128 1.09E+09 1.78 Xe-143 54 143 1.27E+07 15.42 I-126 53 126 8.81E+07 2.05 Xe-142 54 142 6.46E+07 6.62 I-125 53 125 2.19E+07 1.98 Xe-141 54 141 1.14E+08 5.07 I-124 53 124 1.31E+08 3.44 Xe-140 54 140 2.56E+08 3.68 I-123 53 123 3.87E+08 3.31 Xe-139 54 139 3.21E+08 3 I-122 53 122 1.65E+08 5.34 Xe-138 54 138 6.71E+08 2.37 I-121 53 121 9.23E+07 7.6 Xe-137 54 137 7.86E+08 2.24 I-120m 53 120 1.03E+07 14.54 Xe-135 54 135 2.10E+09 1.34 I-120 53 120 1.12E+07 15.24 Xe-135m 54 135 7.94E+08 1.51 I-119 53 119 8.58E+06 23.51 Xe-134m 54 134 8.27E+08 1.48 Te-138 52 138 1.40E+07 13.13 Xe-133 54 133 3.83E+08 1.16 Te-137 52 137 2.19E+07 10.89 Xe-133m 54 133 2.83E+08 1.88 Te-136 52 136 1.04E+08 5.14 Xe-132m 54 132 6.48E+08 1.87 Te-135 52 135 1.28E+08 5.17 Xe-131m 54 131 4.80E+07 2.07 Te-134 52 134 3.32E+08 3.61 Xe-129m 54 129 5.01E+07 2.76 Te-133 52 133 2.89E+08 2.59 Xe-127 54 127 2.11E+07 2.87 Te-133m 52 133 2.25E+08 2.71 Xe-127m 54 127 2.22E+08 3.51 Te-132 52 132 3.25E+08 2.17 Xe-125 54 125 1.80E+08 4.12 Te-131 52 131 7.43E+08 2.02 Xe-125m 54 125 9.14E+07 4.54 Te-131m 52 131 2.76E+08 2.15 Xe-123 54 123 4.81E+07 9.18 Te-129 52 129 1.41E+09 1.53 Xe-122 54 122 1.74E+07 14.39 Te-129m 52 129 2.62E+07 1.77 Xe-121 54 121 6.87E+06 25.62 Te-127 52 127 1.06E+09 1.3 Xe-120 54 120 8.58E+05 70.53 Te-127m 52 127 9.41E+06 1.68 I-142 53 142 8.24E+05 49.68 Te-125m 52 125 1.68E+07 1.73 I-141 53 141 9.22E+06 18.12 Te-123m 52 123 5.79E+06 2.11 I-140 53 140 2.83E+07 10.47 Te-121 52 121 2.52E+07 2.94 I-139 53 139 7.64E+07 5.67 Te-121m 52 121 2.07E+06 3.1 I-138 53 138 1.40E+08 4.9 Te-119 52 119 7.35E+07 5.28 I-137 53 137 2.25E+08 4.54 Te-119m 52 119 1.93E+07 5.54 I-136 53 136 2.36E+08 3.27 Te-118 52 118 1.57E+07 7.48 I-136m 53 136 1.59E+08 3.39 Te-117 52 117 1.72E+07 15.85 I-135 53 135 8.78E+08 2.08 Te-117m 52 117 8.58E+06 15.85 I-134 53 134 1.22E+09 2.02 Te-116 52 116 6.44E+06 24.9 I-134m 53 134 4.88E+08 2.25 Sb-136 51 136 3.92E+06 23.24 I-133 53 133 1.45E+09 1.46 Sb-135 51 135 2.05E+07 12.04 I-133m 53 133 7.00E+08 1.71 Sb-134m 51 134 3.39E+07 7.25 I-132 53 132 1.37E+09 1.67 Sb-134 51 134 1.62E+07 9.28 I-132m 53 132 5.73E+08 2.02 Sb-133 51 133 1.14E+08 5.19       31308 Sb-133m 51 133 6.95E+07 5.52 Sn-127 50 127 2.56E+08 2.71 Sb-133n 51 133 3.47E+07 5.52 Sn-127m 50 127 2.74E+08 2.88 Sb-132m 51 132 1.14E+08 4.29 Sn-126 50 126 4.33E+01 1.97 Sb-132 51 132 6.33E+07 5.44 Sn-125 50 125 1.05E+08 1.59 Sb-131 51 131 3.15E+08 3.37 Sn-125m 50 125 8.16E+08 1.61 Sb-130 51 130 2.30E+08 3.02 Sn-123m 50 123 2.71E+09 1.21 Sb-130m 51 130 2.23E+08 3.07 Sn-123 50 123 1.05E+07 1.48 Sb-129 51 129 5.26E+08 2.25 Sn-121 50 121 3.64E+09 0.83 Sb-129m 51 129 3.95E+08 2.35 Sn-121m 50 121 1.01E+05 1.11 Sb-128m 51 128 7.73E+08 2.03 Sn-119m 50 119 4.94E+06 1.27 Sb-128 51 128 4.56E+08 2.08 Sn-117m 50 117 6.02E+07 1.8 Sb-127 51 127 6.22E+08 1.4 Sn-113 50 113 9.72E+05 7.14 Sb-126m 51 126 1.00E+09 1.68 Sn-113m 50 113 4.25E+07 7.2 Sb-126n 51 126 5.02E+08 1.68 Sn-111 50 111 7.29E+06 23.26 Sb-126 51 126 6.75E+07 1.68 Sn-110 50 110 1.72E+06 49.62 Sb-125 51 125 4.35E+06 1.08 In-132 49 132 1.02E+06 44.31 Sb-124m 51 124 1.26E+09 1.61 In-131m 49 131 2.09E+06 27.81 Sb-124n 51 124 6.28E+08 1.61 In-131 49 131 6.41E+05 36.37 Sb-124 51 124 3.56E+07 1.61 In-131n 49 131 6.35E+05 36.37 Sb-122m 51 122 8.66E+08 1.56 In-130n 49 130 3.72E+06 20.8 Sb-122 51 122 6.95E+08 1.56 In-130m 49 130 3.71E+06 20.8 Sb-120 51 120 5.43E+08 2.21 In-130 49 130 1.84E+06 27.5 Sb-120m 51 120 1.16E+08 2.21 In-129m 49 129 1.00E+07 14.75 Sb-119 51 119 5.91E+08 1.92 In-129 49 129 7.29E+06 16.74 Sb-118 51 118 2.33E+08 2.99 In-128m 49 128 1.95E+07 10.08 Sb-118m 51 118 2.17E+08 3.15 In-128 49 128 1.87E+07 10.28 Sb-117 51 117 3.12E+08 3.79 In-127m 49 127 5.63E+07 5.65 Sb-116 51 116 5.66E+07 6.28 In-127 49 127 5.38E+07 5.82 Sb-116m 51 116 5.02E+07 6.58 In-126m 49 126 1.26E+08 4.43 Sb-115 51 115 4.16E+07 10.23 In-126 49 126 9.13E+07 4.84 Sb-114 51 114 1.20E+07 18.28 In-125 49 125 2.71E+08 2.91 Sn-134 50 134 2.41E+06 28.09 In-125m 49 125 2.41E+08 2.96 Sn-133 50 133 9.67E+06 15.02 In-124 49 124 5.06E+08 2.17 Sn-132 50 132 3.50E+07 8.53 In-124m 49 124 3.24E+08 2.35 Sn-131m 50 131 2.74E+07 8.86 In-123 49 123 9.89E+08 1.65 Sn-131 50 131 1.89E+07 9.72 In-123m 49 123 8.03E+08 1.67 Sn-130m 50 130 4.73E+07 6.11 In-122 49 122 1.39E+09 1.53 Sn-130 50 130 3.67E+07 6.88 In-122m 49 122 5.42E+08 1.6 Sn-129 50 129 7.25E+07 5.67 In-122n 49 122 5.42E+08 1.6 Sn-129m 50 129 5.90E+07 5.74 In-121m 49 121 2.00E+09 0.99 Sn-128 50 128 3.33E+08 3.56 In-121 49 121 2.25E+09 1 Sn-128m 50 128 1.59E+08 3.68 In-120 49 120 3.71E+09 0.92       32309 In-120m 49 120 9.12E+08 1.22 Cd-118 48 118 6.05E+09 0.9 In-120n 49 120 9.12E+08 1.22 Cd-117 48 117 3.79E+09 0.68 In-119m 49 119 3.69E+09 0.79 Cd-117m 48 117 3.35E+09 0.69 In-119 49 119 3.95E+09 0.8 Cd-115 48 115 4.16E+09 0.58 In-118 49 118 7.06E+09 0.8 Cd-115m 48 115 5.98E+07 0.92 In-118m 49 118 2.01E+09 1.14 Cd-113m 48 113 3.49E+05 1.2 In-118n 49 118 1.01E+09 1.14 Cd-111m 48 111 5.14E+08 2.08 In-117 49 117 7.88E+09 0.57 Cd-109 48 109 7.96E+05 3.95 In-117m 49 117 5.28E+09 0.57 Cd-109m 48 109 8.20E+07 4.12 In-116m 49 116 1.47E+09 1.41 Cd-109n 48 109 8.20E+07 4.12 In-116 49 116 7.35E+08 1.41 Cd-107 48 107 2.47E+07 14.17 In-116n 49 116 7.35E+08 1.41 Cd-105 48 105 1.29E+06 57.44 In-115m 49 115 4.75E+09 0.53 Ag-124 47 124 1.31E+07 17.86 In-114 49 114 7.54E+08 1.88 Ag-123 47 123 4.78E+07 9.29 In-114n 49 114 3.72E+08 1.88 Ag-122 47 122 4.44E+07 6.52 In-114m 49 114 1.03E+07 1.88 Ag-122m 47 122 4.64E+07 6.57 In-113m 49 113 3.95E+08 2.21 Ag-121 47 121 2.85E+08 3.81 In-112 49 112 3.17E+08 3.93 Ag-120 47 120 4.30E+08 2.61 In-112m 49 112 1.59E+08 3.93 Ag-120m 47 120 2.54E+08 2.7 In-111 49 111 6.53E+07 5.05 Ag-119 47 119 7.35E+08 1.77 In-111m 49 111 8.02E+07 5.2 Ag-119m 47 119 5.87E+08 1.85 In-110 49 110 2.68E+07 8.59 Ag-118 47 118 1.38E+09 1.41 In-110m 49 110 2.51E+07 8.59 Ag-118m 47 118 9.78E+08 1.41 In-109 49 109 2.32E+07 14.07 Ag-117 47 117 2.02E+09 0.94 In-109m 49 109 7.72E+06 14.07 Ag-117m 47 117 1.91E+09 0.94 In-109n 49 109 7.72E+06 14.07 Ag-116 47 116 3.64E+09 1.01 In-108 49 108 1.50E+06 42.38 Ag-116m 47 116 1.54E+09 1.23 In-108m 49 108 1.07E+06 44.27 Ag-115 47 115 5.30E+09 0.71 Cd-128 48 128 2.36E+06 39.09 Ag-115m 47 115 2.97E+09 0.74 Cd-127 48 127 6.58E+06 22.53 Ag-114 47 114 9.23E+09 0.71 Cd-126 48 126 3.27E+07 10.48 Ag-113 47 113 1.03E+10 0.64 Cd-125 48 125 2.20E+07 9.15 Ag-113m 47 113 3.56E+09 0.75 Cd-125m 48 125 2.20E+07 9.15 Ag-112 47 112 1.10E+10 0.56 Cd-124 48 124 1.83E+08 5.02 Ag-111 47 111 2.32E+09 0.58 Cd-123 48 123 2.31E+08 3.81 Ag-111m 47 111 1.21E+10 0.59 Cd-123m 48 123 1.22E+08 4.08 Ag-110 47 110 1.04E+09 1.49 Cd-122 48 122 8.49E+08 2.37 Ag-110m 47 110 5.78E+06 1.49 Cd-121 48 121 7.41E+08 1.97 Ag-109m 47 109 1.35E+10 0.5 Cd-121m 48 121 4.57E+08 2.18 Ag-108 47 108 3.89E+08 2.14 Cd-120 48 120 2.80E+09 1.17 Ag-108m 47 108 3.53E+03 2.14 Cd-119 48 119 1.81E+09 1.04 Ag-107m 47 107 2.53E+08 3.09 Cd-119m 48 119 1.66E+09 1.04 Ag-106 47 106 6.76E+07 5.54       33310 Ag-106m 47 106 1.02E+07 5.54 Rh-109m 45 109 4.50E+09 0.65 Ag-105 47 105 2.06E+06 8.83 Rh-108 45 108 9.59E+09 0.65 Ag-105m 47 105 3.07E+07 8.89 Rh-108m 45 108 2.28E+09 1.09 Ag-104 47 104 9.15E+06 17.41 Rh-107 45 107 1.37E+10 0.6 Ag-104m 47 104 6.87E+06 17.41 Rh-106 45 106 1.64E+09 1.19 Ag-103 47 103 1.72E+06 49.62 Rh-106m 45 106 1.60E+09 1.22 Ag-103m 47 103 8.58E+05 49.62 Rh-105 45 105 8.20E+09 0.58 Pd-120 46 120 8.43E+07 7.01 Rh-105m 45 105 4.71E+09 0.6 Pd-119 46 119 1.48E+08 5.2 Rh-104 45 104 1.44E+09 1.68 Pd-118 46 118 4.82E+08 2.99 Rh-104m 45 104 7.22E+08 1.68 Pd-117 46 117 7.66E+08 2.43 Rh-103m 45 103 9.52E+08 1.18 Pd-117m 46 117 3.12E+08 2.65 Rh-102 45 102 1.26E+06 3.23 Pd-116 46 116 2.00E+09 1.56 Rh-102m 45 102 2.47E+05 3.23 Pd-115 46 115 1.80E+09 1.35 Rh-101 45 101 1.16E+05 5.29 Pd-115m 46 115 9.51E+08 1.43 Rh-101m 45 101 2.58E+07 5.47 Pd-114 46 114 5.20E+09 0.9 Rh-100 45 100 3.39E+07 9.3 Pd-113 46 113 5.18E+09 0.86 Rh-100m 45 100 2.12E+07 9.39 Pd-113m 46 113 1.22E+09 1.08 Rh-99m 45 99 7.50E+06 18.31 Pd-113n 46 113 1.22E+09 1.08 Rh-99 45 99 6.20E+05 18.31 Pd-112 46 112 7.68E+09 0.64 Rh-98 45 98 1.72E+06 44.62 Pd-111 46 111 9.87E+09 0.66 Rh-98m 45 98 8.58E+05 49.62 Pd-111m 46 111 2.13E+09 0.98 Ru-115 44 115 6.24E+07 8.17 Pd-109 46 109 1.27E+10 0.51 Ru-114 44 114 2.01E+08 4.62 Pd-109m 46 109 1.73E+09 1 Ru-113 44 113 3.44E+08 3.69 Pd-107 46 107 8.96E+00 0.56 Ru-112 44 112 1.08E+09 1.87 Pd-107m 46 107 9.13E+08 1.5 Ru-111 44 111 1.57E+09 1.63 Pd-103 46 103 8.27E+06 6.51 Ru-110 44 110 3.30E+09 1.25 Pd-101 46 101 7.57E+06 23.88 Ru-109 44 109 2.90E+09 1.02 Pd-100 46 100 5.45E+05 49.62 Ru-109m 44 109 1.45E+09 1.22 Rh-117 45 117 1.41E+08 5.59 Ru-108 44 108 7.31E+09 0.76 Rh-116 45 116 1.24E+08 4.12 Ru-107 44 107 8.34E+09 0.78 Rh-116m 45 116 1.24E+08 4.12 Ru-106 44 106 4.18E+07 0.62 Rh-115 45 115 7.76E+08 2.5 Ru-105 44 105 1.16E+10 0.63 Rh-114 45 114 6.95E+08 1.99 Ru-103 44 103 4.53E+08 0.62 Rh-114m 45 114 4.94E+08 2.05 Ru-103m 44 103 1.33E+09 1.33 Rh-113 45 113 2.74E+09 1.21 Ru-101m 44 101 5.41E+08 2 Rh-112 45 112 2.40E+09 1.14 Ru-97 44 97 7.17E+06 15.17 Rh-112m 45 112 1.31E+09 1.43 Tc-115 43 115 6.44E+06 26.63 Rh-111 45 111 6.18E+09 0.87 Tc-113 43 113 4.89E+07 10.81 Rh-110m 45 110 5.57E+09 0.81 Tc-112 43 112 9.66E+07 6.5 Rh-110 45 110 2.27E+09 0.99 Tc-111 43 111 3.17E+08 3.64 Rh-109 45 109 1.04E+10 0.6 Tc-110 43 110 5.58E+08 2.81       34311 Tc-109 43 109 1.44E+09 1.81 Nb-103 41 103 1.82E+09 1.58 Tc-108 43 108 1.97E+09 1.39 Nb-102 41 102 1.55E+09 1.36 Tc-107 43 107 3.93E+09 1.17 Nb-102m 41 102 9.83E+08 1.49 Tc-106 43 106 4.93E+09 0.94 Nb-101 41 101 4.07E+09 1.03 Tc-105 43 105 7.47E+09 0.78 Nb-100 41 100 3.46E+09 1.1 Tc-104 43 104 8.54E+09 0.73 Nb-100m 41 100 1.55E+09 1.18 Tc-103 43 103 1.04E+10 0.69 Nb-99 41 99 3.41E+09 0.84 Tc-102 43 102 9.60E+09 0.61 Nb-99m 41 99 2.79E+09 0.85 Tc-102m 43 102 1.91E+09 1.12 Nb-98 41 98 5.33E+09 0.9 Tc-101 43 101 1.15E+10 0.6 Nb-98m 41 98 1.74E+09 1.14 Tc-100 43 100 2.19E+09 1.44 Nb-97 41 97 7.88E+09 0.63 Tc-99m 43 99 3.53E+09 0.62 Nb-97m 41 97 5.73E+09 0.65 Tc-99 43 99 5.41E+01 0.79 Nb-96 41 96 2.06E+09 1.07 Tc-97m 43 97 3.15E+06 3.44 Nb-95 41 95 5.30E+07 1.28 Tc-96m 43 96 6.39E+07 5.85 Nb-95m 41 95 3.55E+08 1.35 Tc-96 43 96 3.46E+07 5.85 Nb-94m 41 94 5.90E+08 2 Tc-95m 43 95 5.50E+05 9.51 Nb-94 41 94 2.20E+02 2 Tc-95 43 95 2.02E+07 9.57 Nb-93m 41 93 8.63E+04 2.4 Tc-94m 43 94 5.79E+06 19.42 Nb-92m 41 92 1.84E+07 3.97 Tc-94 43 94 5.79E+06 19.42 Nb-91m 41 91 1.51E+06 5.27 Tc-93 43 93 1.52E+06 49.62 Nb-91 41 91 3.89E+02 5.28 Tc-93m 43 93 8.58E+05 49.62 Nb-90 41 90 1.62E+07 14.16 Mo-110 42 110 6.82E+07 7.83 Nb-90m 41 90 9.01E+06 14.16 Mo-109 42 109 1.14E+08 6.79 Nb-89 41 89 6.44E+05 57.44 Mo-108 42 108 3.83E+08 3.3 Nb-89m 41 89 6.44E+05 57.44 Mo-107 42 107 6.62E+08 2.66 Zr-104 40 104 1.07E+08 6.81 Mo-106 42 106 1.60E+09 1.69 Zr-103 40 103 2.01E+08 4.5 Mo-105 42 105 2.18E+09 1.34 Zr-102 40 102 5.63E+08 2.85 Mo-104 42 104 4.22E+09 0.95 Zr-101 40 101 8.90E+08 2.09 Mo-103 42 103 4.97E+09 1 Zr-100 40 100 1.91E+09 1.75 Mo-102 42 102 7.65E+09 0.73 Zr-99 40 99 2.23E+09 1.42 Mo-101 42 101 7.69E+09 0.69 Zr-98 40 98 3.59E+09 1.15 Mo-99 42 99 3.64E+09 0.71 Zr-97 40 97 3.96E+09 0.93 Mo-93 42 93 6.88E+01 7.9 Zr-95 40 95 1.49E+08 0.83 Mo-93m 42 93 3.92E+07 7.98 Zr-93 40 93 1.54E+01 0.77 Mo-91 42 91 1.29E+06 49.62 Zr-90m 40 90 2.87E+08 2.85 Mo-91m 42 91 8.58E+05 49.62 Zr-89 40 89 4.25E+07 5.9 Nb-107 41 107 9.48E+07 6.5 Zr-89m 40 89 6.29E+07 5.92 Nb-106 41 106 1.58E+08 5.01 Zr-88 40 88 6.15E+05 11 Nb-105 41 105 4.81E+08 3.01 Zr-87 40 87 3.00E+06 37.22 Nb-104m 41 104 3.72E+08 2.29 Zr-87m 40 87 1.50E+06 37.22 Nb-104 41 104 4.77E+08 2.31 Zr-86 40 86 2.60E+06 37.22       35312 Y-102 39 102 3.43E+07 7.63 Sr-94 38 94 2.22E+09 1.18 Y-102m 39 102 3.01E+07 7.91 Sr-93 38 93 2.94E+09 1.19 Y-101 39 101 1.55E+08 5.11 Sr-92 38 92 4.39E+09 0.94 Y-100 39 100 1.87E+08 3.78 Sr-91 38 91 4.78E+09 0.9 Y-100m 39 100 1.44E+08 3.85 Sr-90 38 90 7.89E+05 0.87 Y-99 39 99 6.96E+08 2.39 Sr-89 38 89 1.68E+08 0.86 Y-98m 39 98 5.02E+08 2.07 Sr-87m 38 87 4.36E+08 2.01 Y-98 39 98 5.73E+08 2.11 Sr-85 38 85 3.27E+06 5.32 Y-97 39 97 1.16E+09 1.53 Sr-85m 38 85 8.05E+07 5.43 Y-97m 39 97 5.50E+08 1.55 Sr-83 38 83 1.02E+07 16.74 Y-97n 39 97 4.84E+08 1.7 Sr-83m 38 83 7.51E+06 16.92 Y-96 39 96 1.65E+09 1.41 Sr-82 38 82 1.36E+05 40.31 Y-96m 39 96 8.80E+08 1.56 Rb-100 37 100 3.86E+06 32.66 Y-95 39 95 3.90E+09 1.15 Rb-99 37 99 9.01E+06 21.77 Y-94 39 94 4.98E+09 0.86 Rb-98 37 98 8.88E+06 14.14 Y-93 39 93 5.73E+09 0.83 Rb-98m 37 98 8.88E+06 14.14 Y-93m 39 93 2.56E+09 0.85 Rb-97 37 97 5.67E+07 8.09 Y-92 39 92 6.86E+09 0.74 Rb-96 37 96 9.50E+07 6.31 Y-91m 39 91 3.50E+09 0.74 Rb-95 37 95 3.18E+08 4.05 Y-91 39 91 1.33E+08 0.75 Rb-94 37 94 5.12E+08 2.54 Y-90m 39 90 6.91E+08 1.77 Rb-93 37 93 1.12E+09 1.94 Y-90 39 90 5.38E+08 1.77 Rb-92 37 92 1.76E+09 1.53 Y-89m 39 89 6.28E+08 1.64 Rb-91 37 91 2.73E+09 1.18 Y-88 39 88 5.07E+06 3.41 Rb-90 37 90 2.32E+09 1.17 Y-87 39 87 4.79E+07 4.87 Rb-90m 37 90 1.14E+09 1.32 Y-87m 39 87 7.65E+07 4.92 Rb-89 37 89 4.46E+09 0.94 Y-86 39 86 3.93E+07 9.42 Rb-88 37 88 5.07E+09 0.93 Y-86m 39 86 2.10E+07 9.6 Rb-86m 37 86 6.80E+08 1.78 Y-85 39 85 3.86E+06 25.14 Rb-86 37 86 9.75E+07 1.78 Y-85m 39 85 3.86E+06 25.14 Rb-84m 37 84 2.00E+08 3.16 Y-84 39 84 8.58E+05 49.62 Rb-84 37 84 1.65E+07 3.16 Y-84m 39 84 8.58E+05 49.62 Rb-83 37 83 3.27E+06 4.17 Y-83 39 83 6.01E+05 70.53 Rb-83m 37 83 9.96E+07 4.21 Y-83m 39 83 4.29E+05 70.53 Rb-82 37 82 2.58E+07 9.64 Sr-102 38 102 4.49E+06 29.8 Rb-82m 37 82 2.54E+07 9.69 Sr-101 38 101 5.02E+06 29.88 Rb-81 37 81 2.03E+07 14.24 Sr-100 38 100 4.36E+07 9.28 Rb-81m 37 81 1.03E+07 14.24 Sr-99 38 99 7.50E+07 6.86 Rb-80 37 80 3.00E+06 42.38 Sr-98 38 98 2.31E+08 4.45 Rb-79 37 79 8.58E+05 70.53 Sr-97 38 97 3.33E+08 3.51 Kr-95 36 95 2.14E+07 13.93 Sr-96 38 96 7.85E+08 2.24 Kr-94 36 94 9.22E+07 6.6 Sr-95 38 95 1.15E+09 1.94 Kr-93 36 93 1.52E+08 4.99       36313 Kr-92 36 92 5.04E+08 2.73 Se-84 34 84 2.45E+09 1.4 Kr-91 36 91 8.28E+08 2.19 Se-83m 34 83 1.41E+09 1.21 Kr-90 36 90 1.53E+09 1.75 Se-83 34 83 9.53E+08 1.26 Kr-89 36 89 2.18E+09 1.17 Se-81 34 81 2.85E+09 1.36 Kr-88 36 88 3.20E+09 1.16 Se-81m 34 81 5.26E+08 2.04 Kr-87 36 87 3.61E+09 1.1 Se-79m 34 79 2.32E+09 1.32 Kr-85m 36 85 4.21E+09 0.92 Se-79 34 79 1.51E+01 1.32 Kr-85 36 85 5.30E+05 1.08 Se-77m 34 77 1.05E+08 4.35 Kr-83m 36 83 4.29E+09 0.93 Se-75 34 75 4.74E+05 10.23 Kr-81 36 81 3.53E+00 4.19 As-87 33 87 7.91E+07 7.93 Kr-81m 36 81 9.76E+07 4.5 As-86 33 86 1.49E+08 5.28 Kr-79 36 79 1.42E+07 12.23 As-85 33 85 3.80E+08 3.29 Kr-79m 36 79 1.12E+07 12.57 As-84 33 84 3.00E+08 2.98 Br-94 35 94 4.93E+06 28.37 As-84m 33 84 2.25E+08 3.02 Br-93 35 93 2.86E+07 11.12 As-83 33 83 1.15E+09 1.77 Br-92 35 92 4.74E+07 9.64 As-82 33 82 9.34E+08 1.84 Br-91 35 91 1.77E+08 4.33 As-82m 33 82 4.64E+08 2.26 Br-90 35 90 3.17E+08 3.76 As-81 33 81 1.84E+09 1.71 Br-89 35 89 7.90E+08 2.13 As-80 33 80 1.99E+09 1.4 Br-88 35 88 1.18E+09 1.81 As-79 33 79 2.08E+09 1.4 Br-87 35 87 1.91E+09 1.45 As-78 33 78 2.12E+09 1.47 Br-86 35 86 2.45E+09 1.3 As-77 33 77 1.05E+09 1.51 Br-85 35 85 3.51E+09 1.06 As-76 33 76 2.23E+08 3.71 Br-84 35 84 3.19E+09 1.13 As-74 33 74 7.83E+06 6.39 Br-84m 35 84 7.43E+08 1.77 As-73 33 73 7.92E+05 10 Br-83 35 83 3.96E+09 0.96 As-72 33 72 7.74E+06 19.59 Br-82 35 82 5.62E+08 2.23 As-71 33 71 2.06E+06 28.06 Br-82m 35 82 4.67E+08 2.23 As-69 33 69 8.58E+05 70.53 Br-80 35 80 3.68E+08 3.65 Ge-85 32 85 2.38E+07 13.86 Br-80m 35 80 1.84E+08 3.65 Ge-84 32 84 8.81E+07 6.67 Br-79m 35 79 1.23E+08 3.96 Ge-83 32 83 1.41E+08 5.3 Br-78 35 78 9.14E+07 6.59 Ge-82 32 82 4.75E+08 2.98 Br-77m 35 77 1.63E+07 10.97 Ge-81 32 81 2.69E+08 2.97 Br-77 35 77 1.46E+07 11 Ge-81m 32 81 2.55E+08 3.01 Br-76 35 76 4.48E+06 28.06 Ge-80 32 80 1.01E+09 2.11 Br-76m 35 76 2.57E+06 28.06 Ge-79 32 79 6.88E+08 2.06 Se-91 34 91 9.57E+06 20.34 Ge-79m 32 79 3.33E+08 2.47 Se-89 34 89 9.25E+07 6.6 Ge-78 32 78 1.47E+09 1.72 Se-88 34 88 2.49E+08 4.16 Ge-77m 32 77 1.01E+09 1.9 Se-87 34 87 4.46E+08 3.06 Ge-77 32 77 4.92E+08 2.05 Se-86 34 86 1.05E+09 2.04 Ge-75 32 75 1.19E+09 1.83 Se-85 34 85 1.20E+09 1.6 Ge-75m 32 75 2.02E+08 3.09       37314 Ge-73m 32 73 9.11E+08 2.07 Cu-78 29 78 3.44E+06 34.64 Ge-71 32 71 7.09E+06 8.3 Cu-77 29 77 1.37E+07 17.29 Ge-71m 32 71 3.05E+07 8.45 Cu-76 29 76 2.58E+07 12.94 Ge-69 32 69 4.92E+06 21.27 Cu-75 29 75 6.11E+07 8.86 Ge-68 32 68 4.38E+03 70.53 Cu-74 29 74 7.74E+07 7.34 Ga-84 31 84 2.36E+06 41.17 Cu-73 29 73 1.67E+08 5.27 Ga-83 31 83 1.39E+07 16.31 Cu-72 29 72 1.56E+08 5.73 Ga-82 31 82 3.30E+07 11.85 Cu-71 29 71 2.39E+08 3.96 Ga-81 31 81 1.22E+08 5.68 Cu-70 29 70 1.50E+08 4.91 Ga-80 31 80 1.65E+08 5.24 Cu-70m 29 70 6.93E+07 5.72 Ga-79 31 79 3.80E+08 3.44 Cu-69 29 69 2.65E+08 4.06 Ga-78 31 78 4.94E+08 3 Cu-68 29 68 2.53E+08 4.33 Ga-77 31 77 6.99E+08 2.47 Cu-68m 29 68 6.33E+07 5.98 Ga-76 31 76 7.36E+08 2.34 Cu-67 29 67 1.12E+08 3.95 Ga-75 31 75 8.00E+08 2.22 Cu-66 29 66 1.53E+08 4.58 Ga-74 31 74 5.93E+08 2.46 Cu-64 29 64 3.42E+07 10.49 Ga-74m 31 74 5.03E+08 2.46 Cu-62 29 62 6.42E+06 24.9 Ga-73 31 73 8.32E+08 2.24 Cu-61 29 61 2.15E+06 44.27 Ga-72 31 72 4.04E+08 2.74 Ni-74 28 74 9.84E+06 19.94 Ga-70 31 70 1.18E+08 5.8 Ni-73 28 73 1.46E+07 17.25 Ga-68 31 68 2.75E+07 11.88 Ni-72 28 72 3.52E+07 10.54 Ga-67 31 67 2.53E+06 23.26 Ni-71 28 71 4.87E+07 9.09 Ga-66 31 66 3.33E+06 34.73 Ni-70 28 70 8.11E+07 7.4 Zn-81 30 81 4.29E+06 34 Ni-69 28 69 8.07E+07 7.22 Zn-80 30 80 1.63E+07 15.1 Ni-68 28 68 1.37E+08 5.75 Zn-79 30 79 3.89E+07 10.88 Ni-67 28 67 1.30E+08 5.84 Zn-78 30 78 9.71E+07 7.05 Ni-66 28 66 6.91E+07 5.46 Zn-77 30 77 9.93E+07 6.18 Ni-65 28 65 1.43E+08 5.24 Zn-77m 30 77 5.71E+07 6.5 Ni-63 28 63 5.58E+03 5.7 Zn-76 30 76 2.91E+08 3.58 Co-71 27 71 7.93E+06 23.94 Zn-75 30 75 2.57E+08 4.15 Co-70 27 70 6.87E+06 27.11 Zn-74 30 74 4.22E+08 3.16 Co-69 27 69 1.93E+07 14.92 Zn-73 30 73 3.48E+08 3.5 Co-68 27 68 2.15E+07 15.47 Zn-73m 30 73 1.20E+08 4.62 Co-67 27 67 3.82E+07 10.41 Zn-72 30 72 2.71E+08 2.88 Co-66 27 66 3.61E+07 10.45 Zn-71 30 71 3.34E+08 3.31 Co-65 27 65 6.14E+07 7.77 Zn-71m 30 71 9.52E+07 5.12 Co-64 27 64 8.41E+07 7.65 Zn-69 30 69 3.92E+08 3.37 Co-63 27 63 9.44E+07 6.25 Zn-69m 30 69 6.10E+07 5.31 Co-62 27 62 6.81E+07 7.24 Zn-65 30 65 4.86E+04 21.27 Co-62m 27 62 2.57E+07 9.07 Zn-63 30 63 8.58E+05 70.53 Co-61 27 61 1.04E+08 6.7 Cu-79 29 79 3.00E+06 37.22 Co-60m 27 60 1.50E+07 12.28       38315 Co-60 27 60 2.16E+04 12.28 V-53 23 53 1.67E+07 15.29 Co-58m 27 58 4.80E+06 21.51 V-52 23 52 2.45E+07 13.93 Co-58 27 58 1.66E+05 21.51 V-49 23 49 2.96E+04 24.7 Co-57 27 57 1.53E+04 37.22 V-48 23 48 2.14E+05 40.31 Fe-68 26 68 3.43E+06 34.73 Ti-54 22 54 2.15E+06 44.27 Fe-67 26 67 3.86E+06 32.66 Ti-53 22 53 3.86E+06 32.66 Fe-66 26 66 8.15E+06 24.29 Ti-52 22 52 8.15E+06 21.88 Fe-65 26 65 8.15E+06 23.12 Ti-51 22 51 1.54E+07 17.51 Fe-64 26 64 2.62E+07 13.79 Ti-45 22 45 1.29E+06 57.44 Fe-63 26 63 2.32E+07 13.57 Sc-51 21 51 3.00E+06 37.22 Fe-62 26 62 4.21E+07 10.23 Sc-50 21 50 5.51E+06 29.01 Fe-61 26 61 4.98E+07 9.34 Sc-50m 21 50 2.57E+06 30.44 Fe-59 26 59 2.00E+06 8.71 Sc-49 21 49 1.54E+07 17.06 Fe-55 26 55 4.18E+03 42.38 Sc-48 21 48 4.58E+06 21.27 Mn-65 25 65 1.72E+06 49.62 Sc-47 21 47 3.42E+06 20.67 Mn-64 25 64 2.57E+06 40.31 Sc-46m 21 46 8.58E+05 49.62 Mn-63 25 63 4.29E+06 30.9 Sc-46 21 46 2.82E+04 49.62 Mn-62 25 62 9.01E+06 22.79 Sc-45m 21 45 1.72E+06 34.73 Mn-61 25 61 1.33E+07 18.35 Sc-44 21 44 1.49E+06 44.27 Mn-60 25 60 1.07E+07 16.59 Sc-44m 21 44 4.65E+05 44.27 Mn-60m 25 60 7.29E+06 17.75 Sc-43 21 43 1.72E+06 49.62 Mn-59 25 59 2.70E+07 13.23 Ca-47 20 47 1.92E+06 23.24 Mn-58 25 58 2.70E+07 11.1 Ca-45 20 45 6.85E+04 27.51 Mn-58m 25 58 1.33E+07 11.97 K-47 19 47 1.72E+06 49.62 Mn-57 25 57 3.56E+07 10.15 K-46 19 46 3.43E+06 34.73 Mn-56 25 56 4.98E+07 9.5 K-45 19 45 3.00E+06 37.22 Mn-54 25 54 3.80E+04 22.42 K-44 19 44 4.72E+06 29.38 Mn-52m 25 52 4.29E+05 70.53 K-43 19 43 5.32E+06 24.04 Mn-52 25 52 9.59E+04 70.53 K-42 19 42 4.00E+06 33.99 Cr-62 24 62 1.29E+06 57.44 Ar-44 18 44 1.72E+06 49.62 Cr-61 24 61 1.29E+06 57.44 Ar-43 18 43 2.57E+06 40.31 Cr-60 24 60 2.57E+06 40.31 Ar-42 18 42 5.45E+02 29.38 Cr-59 24 59 7.29E+06 23.26 Ar-41 18 41 6.44E+06 24.9 Cr-58 24 58 1.37E+07 17.41 Ar-39 18 39 9.53E+01 28.51 Cr-57 24 57 7.72E+06 23.88 Ar-37 18 37 2.50E+05 28.26 Cr-56 24 56 3.00E+07 11.94 Cl-42 17 42 1.29E+06 57.44 Cr-55 24 55 2.70E+07 11.6 Cl-41 17 41 3.86E+06 32.66 Cr-51 24 51 1.47E+05 37.22 Cl-40 17 40 3.86E+06 32.66 Cr-49 24 49 2.57E+06 40.31 Cl-39 17 39 4.29E+06 34 V-56 23 56 3.86E+06 32.66 Cl-38 17 38 5.58E+06 26.89 V-55 23 55 1.20E+07 18.28 Cl-38m 17 38 1.93E+06 32.66 V-54 23 54 1.54E+07 15.63 Cl-34 17 34 6.20E+05 70.53       39316 Cl-34m 17 34 4.29E+05 70.53 N-17 7 17 3.09E+07 12.61 S-40 16 40 8.58E+05 70.53 N-16 7 16 4.16E+07 9.69 S-39 16 39 8.58E+05 70.53 N-13 7 13 2.15E+06 44.27 S-38 16 38 1.72E+06 49.62 C-16 6 16 7.72E+06 22.54 S-37 16 37 3.00E+06 37.22 C-15 6 15 3.69E+07 11.12 S-35 16 35 1.35E+05 22.42 C-14 6 14 9.56E+01 5.3 P-37 15 37 1.72E+06 49.62 C-11 6 11 1.33E+07 17.17 P-35 15 35 3.00E+06 37.22 C-10 6 10 1.72E+06 49.62 P-34 15 34 5.15E+06 28.06 B-14 5 14 2.15E+06 44.27 P-33 15 33 3.16E+05 27.82 B-13 5 13 2.27E+07 13.5 P-32 15 32 2.38E+05 40.31 B-12 5 12 4.07E+07 10.01 P-30 15 30 3.86E+06 32.66 B-8 5 8 1.72E+06 49.62 Si-35 14 35 8.58E+05 70.53 Be-12 4 12 3.86E+06 32.66 Si-34 14 34 2.15E+06 44.27 Be-11 4 11 1.33E+07 17.77 Si-33 14 33 7.85E+05 70.84 Be-8 4 8 8.65E+07 6.53 Si-32 14 32 4.90E+01 42.9 Be-7 4 7 1.20E+06 9.8 Si-31 14 31 2.15E+06 44.27 Li-9 3 9 1.67E+07 16.54 Al-31 13 31 1.29E+06 57.44 Li-8 3 8 7.65E+07 7.22 Al-30 13 30 1.29E+06 57.44 He-8 2 8 4.72E+06 29.38 Al-29 13 29 1.72E+06 49.62 He-6 2 6 4.73E+08 3.05 Al-28 13 28 1.80E+06 44.49 H-3 1 3 6.41E+06 0.41 Mg-29 12 29 8.58E+05 70.53 Mg-28 12 28 1.37E+06 49.62 Mg-27 12 27 1.72E+06 49.62 Na-27 11 27 8.58E+05 70.53 Na-25 11 25 2.57E+06 40.31 Na-24 11 24 6.35E+07 7.45 Na-24m 11 24 1.42E+07 12.73 Na-22 11 22 2.50E+03 49.62 Ne-25 10 25 1.29E+06 57.44 Ne-24 10 24 4.29E+07 9.08 Ne-23 10 23 3.73E+07 10.88 F-22 9 22 2.15E+07 14.94 F-21 9 21 2.49E+07 13.07 F-20 9 20 3.86E+07 10.18 F-18 9 18 8.58E+05 70.53 O-22 8 22 8.58E+05 70.53 O-21 8 21 9.01E+06 21.77 O-20 8 20 2.27E+07 13.76 O-19 8 19 3.99E+07 10.1 O-15 8 15 8.58E+05 70.53 N-18 7 18 8.15E+06 23.12       40317NuclideOn-Site External Dose [mSv]On-Site Internal Dose [mSv]Off-Site Dose - No Filtration [mSv]Off-Site Dose - With HC1 Stack Filtration [mSv]H 3.38E-11 1.01E-06 3.20E-09 3.20E-09Cl 1.20E-05 6.29E-06 1.76E-07 8.78E-10Ar 1.25E-05 0.00E+00 6.18E-08 6.18E-08Se 2.67E-03 2.23E-03 1.82E-05 9.11E-08Br 1.09E-02 8.94E-03 8.78E-04 4.39E-06Kr 1.04E-02 0.00E+00 5.78E-05 5.78E-05I 9.13E-03 1.98E-01 1.95E-02 9.77E-05Xe 1.22E-03 0.00E+00 7.82E-06 7.82E-06Rn 8.67E-03 1.34E+01 4.50E-03 4.50E-030.0430 13.6323On-Site Exposure ParametersElements filteredFilter efficiency (99.5% HC stack and 99.5% filtration in HCExposure Time for External and Internal On-Site Dose [s]Radius of Cloud for External On-Site Dose [m]Radius of Cloud for Internal On-Site Dose [m]Inhalation Rate [L/min]Po, Cl, Se, Br, I 0.999975 1800 30 15 12Nuclide A Z Activity (Bq)DCFA (Sv/Bq s/m3)External Dose from Airbourne Cloud (mSv)DCFI_a (Sv/Bq)Inhalation Dose (mSv)SDRL (Bq/mSv)Maximum Offsite Dose - Unfiltered (mSv)Maximum Offsite Dose - Filtered (mSv)Gaseous and Volatile Alpha IsotopesRn-223 223 86 8.58E+05 6.09E-15 8.32E-08 1.20E-07 2.62E-03 4.52E+13 1.90E-08 1.90E-08Rn-222 222 86 9.14E+05 1.91E-17 2.78E-10 7.09E-06 1.65E-01 3.47E+12 2.63E-07 2.63E-07Rn-221 221 86 8.15E+06 5.55E-15 7.20E-07 3.64E-07 7.56E-02 1.99E+09 4.09E-03 4.09E-03Rn-220 220 86 1.38E+09 1.85E-17 4.07E-07 9.20E-10 3.23E-02 3.06E+14 4.51E-06 4.51E-06Rn-212 212 86 4.09E+09 0.00E+00 0.00E+00 6.71E-09 6.99E-01 4.79E+13 8.54E-05 8.54E-05Rn-211 211 86 2.54E+09 9.44E-14 3.82E-03 1.31E-07 8.48E+00 1.44E+13 1.76E-04 1.76E-04Rn-210 210 86 3.64E+09 2.79E-15 1.62E-04 3.67E-08 3.40E+00 3.01E+14 1.21E-05 1.21E-05Rn-209 209 86 2.35E+09 4.76E-14 1.78E-03 1.71E-09 1.02E-01 5.80E+13 4.05E-05 4.05E-05Rn-208 208 86 2.36E+09 1.10E-14 4.13E-04 4.89E-09 2.94E-01 3.00E+13 7.86E-05 7.86E-05Rn-207 207 86 1.66E+09 3.96E-14 1.05E-03 2.30E-09 9.73E-02 3.25E+14 5.11E-06 5.11E-06Rn-206 206 86 1.38E+09 6.57E-14 1.44E-03 2.10E-09 7.38E-02 1.55E+14 8.88E-06 8.88E-06Total Rn Dose: 8.67E-03 Total Rn Dose: 1.34E+01 Total Rn Dose: 4.50E-03 4.50E-03Gaseous and Volatile Non-Alpha IsotopesH-3 3 1 6.41E+06 3.31E-19 3.38E-11 6.2E-12 1.01E-06 2.00E+15 3.20E-09 3.20E-09Total H Dose: 3.38E-11 Total H Dose: 1.01E-06 Total H Dose: 3.20E-09 3.20E-09Cl-36 36 17 7.04E-02 2.23E-17 2.50E-17 3.3E-10 5.92E-13 7.43E+09 9.48E-12 2.37E-16Cl-38 38 17 5.58E+06 7.87E-14 6.99E-06 2.5E-11 3.55E-06 6.48E+13 8.61E-08 2.15E-12Cl-39 39 17 4.29E+06 7.29E-14 4.98E-06 2.5E-11 2.73E-06 4.79E+13 8.96E-08 2.24E-12Total Cl Dose: 1.20E-05 Total Cl Dose: 6.29E-06 Total Cl Dose: 1.76E-07 4.39E-12Ar-41 41 18 6.44E+06 6.5E-14 6.67E-06 0 0.00E+00 1.59E+14 4.05E-08 4.05E-08Summary0.0047Filtration ParametersTotal [mSv]0.025013.6753   41   318Ar-42 42 18 5.45E+02 9E-18 7.81E-14 0 0.00E+00 1.18E+15 4.62E-13 4.62E-13Ar-43 43 18 2.57E+06 7.69E-14 3.15E-06 0 0.00E+00 3.44E+14 7.46E-09 7.46E-09Ar-44 44 18 1.72E+06 9.82E-14 2.69E-06 0 0.00E+00 1.24E+14 1.39E-08 1.39E-08Total Ar Dose: 1.25E-05 Total Ar Dose: 0.00E+00 Total Ar Dose: 6.18E-08 6.18E-08Se-73m 73 34 2.15E+05 1.17E-14 4.01E-08 9.2E-12 5.04E-08 3.39E+14 6.33E-10 1.58E-14Se-81 81 34 2.85E+09 5.24E-16 2.38E-05 8E-12 5.81E-04 2.83E+15 1.01E-06 2.51E-11Se-81m 81 34 5.26E+08 6.18E-16 5.18E-06 1.6E-11 2.14E-04 6.79E+14 7.75E-07 1.94E-11Se-83 83 34 9.53E+08 1.21E-13 1.84E-03 1.8E-11 4.37E-04 6.38E+13 1.49E-05 3.74E-10Se-84 84 34 2.45E+09 2.07E-14 8.08E-04 1.6E-11 9.99E-04 1.65E+15 1.49E-06 3.71E-11Total Se Dose: 2.67E-03 Total Se Dose: 2.23E-03 Total Se Dose: 1.82E-05 4.55E-10Br-75 75 35 0.00E+00 5.84E-14 0.00E+00 2.9E-11 0.00E+00 3.27E+13 0.00E+00 0.00E+00Br-76 76 35 4.48E+06 1.34E-13 9.56E-06 2.4E-10 2.74E-05 1.54E+12 2.90E-06 7.25E-11Br-77 77 35 1.46E+07 1.51E-14 3.51E-06 6.2E-11 2.31E-05 3.37E+12 4.33E-06 1.08E-10Br-80 80 35 3.68E+08 3.85E-15 2.26E-05 5.9E-12 5.53E-05 1.50E+15 2.46E-07 6.15E-12Br-80m 80 35 1.84E+08 3.11E-16 9.11E-07 3.3E-11 1.55E-04 8.85E+13 2.08E-06 5.20E-11Br-82 82 35 5.62E+08 1.3E-13 1.16E-03 3.5E-10 5.01E-03 6.97E+11 8.06E-04 2.02E-08Br-83 83 35 3.96E+09 3.82E-16 2.41E-05 1.6E-11 1.61E-03 3.97E+14 9.99E-06 2.50E-10Br-84 84 35 3.19E+09 9.41E-14 4.78E-03 2.2E-11 1.79E-03 6.41E+13 4.98E-05 1.24E-09Br-85 85 35 3.51E+09 2.74E-15 1.53E-04 2.9E-12 2.59E-04 9.85E+15 3.56E-07 8.91E-12Br-87 87 35 1.91E+09 1.57E-13 4.78E-03 1.5E-13 7.30E-06 8.18E+14 2.33E-06 5.84E-11Total Br Dose: 1.09E-02 Total Br Dose: 8.94E-03 Total Br Dose: 8.78E-04 2.20E-08Kr-77 77 36 4.29E+05 4.86E-14 3.32E-07 0 0.00E+00 2.19E+14 1.96E-09 1.96E-09Kr-79 79 36 1.42E+07 1.21E-14 2.74E-06 0 0.00E+00 7.78E+14 1.82E-08 1.82E-08Kr-81 81 36 3.53E+00 2.67E-16 1.50E-14 0 0.00E+00 3.51E+16 1.01E-16 1.01E-16Kr-83m 83 36 4.29E+09 1.5E-18 1.02E-07 0 0.00E+00 6.89E+18 6.23E-10 6.23E-10Kr-87 87 36 3.61E+09 4.12E-14 2.37E-03 0 0.00E+00 2.62E+14 1.38E-05 1.38E-05Kr-88 88 36 3.20E+09 1.02E-13 5.20E-03 0 0.00E+00 8.17E+13 3.92E-05 3.92E-05Kr-89 89 36 2.18E+09 8.1E-14 2.81E-03 0 0.00E+00 4.54E+14 4.80E-06 4.80E-06Total Kr Dose: 1.04E-02 Total Kr Dose: 0.00E+00 Total Kr Dose: 5.78E-05 5.78E-05I-120 120 53 1.12E+07 1.38E-13 2.46E-05 1E-10 2.85E-05 3.04E+13 3.68E-07 9.21E-12I-121 121 53 9.23E+07 1.94E-14 2.85E-05 2.7E-11 6.35E-05 1.34E+14 6.86E-07 1.72E-11I-122 122 53 1.65E+08 4.56E-14 1.20E-04 0 0.00E+00 6.38E+14 2.58E-07 6.46E-12I-123 123 53 3.87E+08 7.28E-15 4.49E-05 7.4E-11 7.30E-04 2.47E+13 1.57E-05 3.91E-10I-124 124 53 1.31E+08 5.38E-14 1.12E-04 4.4E-09 1.47E-02 9.14E+10 1.43E-03 3.58E-08I-125 125 53 2.19E+07 5.22E-16 1.82E-07 5.1E-09 2.85E-03 3.72E+10 5.88E-04 1.47E-08I-126 126 53 8.81E+07 2.15E-14 3.02E-05 9.8E-09 2.20E-02 2.08E+10 4.24E-03 1.06E-07I-128 128 53 1.09E+09 4.16E-15 7.22E-05 1.3E-11 3.61E-04 1.02E+15 1.07E-06 2.67E-11I-129 129 53 6.67E-01 3.8E-16 4.04E-15 0.000000036 6.12E-10 3.05E+09 2.18E-10 5.46E-15I-130 130 53 1.02E+09 1.04E-13 1.69E-03 6.7E-10 1.74E-02 2.51E+12 4.07E-04 1.02E-08I-131 131 53 3.78E+08 1.82E-14 1.10E-04 7.4E-09 7.13E-02 3.41E+10 1.11E-02 2.77E-07I-132 132 53 1.37E+09 1.12E-13 2.44E-03 9.4E-11 3.28E-03 2.43E+13 5.65E-05 1.41E-09I-132m 132 53 5.73E+08 1.53E-14 1.40E-04 7.9E-11 1.15E-03 1.05E+14 5.45E-06 1.36E-10I-133 133 53 1.45E+09 2.94E-14 6.79E-04 1.5E-09 5.54E-02 9.31E+11 1.56E-03 3.89E-08I-134 134 53 1.22E+09 1.3E-13 2.53E-03 4.5E-11 1.40E-03 4.92E+13 2.48E-05 6.20E-10I-135 135 53 8.78E+08 7.98E-14 1.12E-03 3.2E-10 7.16E-03 7.70E+12 1.14E-04 2.85E-09Total I Dose: 9.13E-03 Total I Dose: 1.98E-01 Total I Dose: 1.95E-02 4.89E-07Xe-120 120 54 8.58E+05 1.94E-14 2.65E-07 0 0.00E+00 1.86E+14 4.61E-09 4.61E-09Xe-121 121 54 6.87E+06 9.14E-14 1.00E-05 0 0.00E+00 1.26E+14 5.44E-08 5.44E-08Xe-122 122 54 1.74E+07 2.46E-15 6.82E-07 0 0.00E+00 1.73E+14 1.01E-07 1.01E-07Xe-123 123 54 4.81E+07 3.03E-14 2.32E-05 0 0.00E+00 3.05E+14 1.58E-07 1.58E-07Xe-125 125 54 1.80E+08 1.19E-14 3.41E-05 0 0.00E+00 3.29E+14 5.46E-07 5.46E-07Xe-127 127 54 2.11E+07 1.25E-14 4.20E-06 0 0.00E+00 7.50E+14 2.81E-08 2.81E-08Xe-129m 129 54 5.01E+07 1.06E-15 8.46E-07 0 0.00E+00 8.85E+15 5.66E-09 5.66E-09Xe-131m 131 54 4.80E+07 3.89E-16 2.97E-07 0 0.00E+00 2.41E+16 1.99E-09 1.99E-09Xe-133 133 54 3.83E+08 1.56E-15 9.51E-06 0 0.00E+00 6.01E+15 6.37E-08 6.37E-08Xe-133m 133 54 2.83E+08 1.27E-15 5.72E-06 0 0.00E+00 7.40E+15 3.82E-08 3.82E-08Xe-135 135 54 2.10E+09 1.19E-14 3.98E-04 0 0.00E+00 8.04E+14 2.61E-06 2.61E-06Xe-137 137 54 7.86E+08 9.46E-15 1.18E-04 0 0.00E+00 3.82E+15 2.06E-07 2.06E-07Xe-138 138 54 6.71E+08 5.77E-14 6.17E-04 0 0.00E+00 1.68E+14 4.00E-06 4.00E-06Total Xe Dose: 1.22E-03 Total Xe Dose: 0.00E+00 Total Xe Dose: 7.82E-06 7.82E-06   42319D Safety Analysis Report forChemical Processing of Tho-rium Targets320Safety ReportL125: Isolation of Medical Isotopes from Irradiated Thorium Metal Targetsauthored by Andrew K. H. RobertsonJuly 26, 2019contents1 Identification 22 Introduction 23 Description 33.1 Location of Experiment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.2 Overview of Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3 Target Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.4 Target Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.5 Opening of Target Capsule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.6 Processing of Irradiated Target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.7 Testing of 225Ac Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.8 212Pb Generator and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Definition of Hazards 94.1 Methods Used for Estimation of Radiation Hazards . . . . . . . . . . . . . . . . . . . . . . 94.2 Radiation Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114.3 Chemical Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114.4 Industrial Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Safety Measures 125.1 Summary of Radiation Safety Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125.2 Target Irradiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.3 Target Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.4 Opening of the Target Capsule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195.5 Dissolution of Thorium Foil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.6 Purification of 225Ac and 225Ra from Dissolved Thorium . . . . . . . . . . . . . . . . . . . 235.7 Testing of 225Ac Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255.8 212Pb Generator and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.9 Chemical Safety Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315.10 Industrial Safety Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 Definition of Responsibilities 316.1 Thorium Inventory Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327 Decommissioning and Disposal 327.1 Disposal of the Target Capsule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327.2 Disposal of Liquid Waste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327.3 Disposal of Compactable Solid Waste . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337.4 Decommissioning of the Experiment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33References 33a Single-event Derived Release Limits Used for Off-Site Dose Estimates 36b Radioactive Inventory of Thorium Foil 7 Days After EOB 38c Airborne Dose Calculations 42d Semi-Automated Chemistry System Flowchart 441321identification 2e Contents of the Solution Containing Isolated Radium Isotopes 24.5 Days After EOB 45f Contents of the Solution Containing Isolated Actinium Isotopes 7 Days After EOB 46g Modified L125 process for shipment of irradiated thorium 471 identificationExperiment L125: Isolation of Medical Isotopes from Irradiated Thorium Metal TargetsThe experiment spokespersons are Andrew Robertson and Paul Schaffer. The experiment safety coor-dinator is Andrew Robertson. Vicky Hanemaayer is the RCR1 Lab Manager. The experimental userswith access to all aspects of L125 are exclusively limited to Andrew Robertson and Hua Yang. Ad-ditional users of the 212Pb generator include Brooke McNeil, Tom Kostelnik, Neil Weatherall, IsabelRodrigo, and Lily Southcott. Stefan Zeisler and Ellard Portman are assisting with 225Ac productionruns and upgrades of the L125 hot cell equipment.Andrew Robertson TRIUMF Life Sciences4004 Wesbrook Mall, Vancouver BCarobertson@triumf.ca604 222 1047 ext. 6733 (office)778 228 7471 (cell)2 introductionSummary of changes in this versionAppendix G has been added, which describes a modified process for L125 in which targets are irradi-ated at IPF to an integrated current of 360 µA*h and thorium foils are shipped from the TRIUMF site.This 360 µA*h irradiation represents 13.6% of the 2640 µA*h irradiation that is assumed in all othersections of this document.No other changes have been made.BackgroundTargeted alpha therapy (TAT) shows high potential as an effective treatment option for small tumoursand metastases [1]. Actinium-225 (t1/2 = 9.92 d) is a promising TAT radionuclide, which can be useddirectly in combination with biomolecules or as generator source of the shorter TAT radionuclide,bismuth-213 (t1/2 = 45.6 min). Development of 225Ac and 213Bi radiopharmaceuticals has progressedslowly due to the limited availability and the resulting high cost of these isotopes. Global annual 225Acproduction is approximately 63 GBq (1.7 Ci) [2–6].ScopeIn coordination with L124 [7], experiment L125 aims to develop regular production and processing ofclinically relevant quantities of 225Ac (100 mCi, or 3.7 GBq) and 213Bi and potentially other valuablemedical radionuclides at TRIUMF using irradiation facilities at the BL1A Isotope Production Facility(IPF) and processing facilities in the MHESA RCR1 lab. While the scope of L124, Irradiation of ThoriumTargets at the TRIUMF 500 MeV Isotope Production Facility, will be limited to the production of 225Ac (in-cluding target fabrication and irradiation at IPF), L125 will encompass the post-irradiation processingof the targets (including target transfer to RCR1, target opening, and processing of targets in the RCR1hot cell). In other terms, L125 begins when targets leave the IPF hot cell.These experiments are distinct so as to separate the safety review process for each stage of theproject. In this manner, safety approval for irradiating thorium targets for possible shipment and322description 3processing off-site will be independent of safety approval for processing the targets on site. Whilemultiple isotopes of interest (e.g. 223Ra, 224Ra, 212Bi, 212Pb) will be produced in the target, 225Ac and213Bi are the isotopes of present focus.From the perspective of the safety report, the scope of L125 also includes the applications of L125-produced isotopes that will occur at the TRIUMF site. A description of experiments using L125-produced isotopes that occur off-site is not included in this report.Current Experimental Objectives1. Establish methods for the isolation of clinically relevant quantities of actinium (100 mCi, or 3.7GBq)1and radium isotopes from thorium metal irradiated with high energy protons, using andimproving upon published methods2. Quantify 225Ac production yields and the presence of any radioactive or stable impurities in thefinal isolated 225Ac product3. Test ability to use this 225Ac as generators of 213Bi4. Test abilities of 225Ac and 213Bi products for radiolabeling of common 225Ac or 213Bi biomolecules5. Collect relevant safety data and establish protocols for 225Ac and 213Bi production that will guideTRIUMF’s proposed future larger-scale 225Ac production and processing efforts (including com-mercially on BL1A or at ARIEL under the recently awarded CFI grant)Impact StatementThis project leverages unique TRIUMF infrastructure to produce understudied and sought-after iso-topes with potential to significantly aid the treatment of aggressive cancers. However, much remainsto be understood about the chemistry and biology needed to attach 225Ac or 213Bi to biomolecules thatspecifically target and treat cancer. As a result, the use of 225Ac and 213Bi in TAT is an area of researchthat has great interest.This work therefore has high translational potential, with the ability to enable other experimentsat TRIUMF and other institutions that are otherwise impractical due to the high cost and limitedavailability of 225Ac and 213Bi (current cost is a minimum purchase of 0.75 GBq (20 mCi) of 225Ac for$35000). As such, this effort is expected to enable new collaborations between TRIUMF and other TATresearch centres. A recent survey of experimenters in the TAT field suggests that demand for 225Acfrom researchers within Canada is at minimum 5.6 GBq (150 mCi) per month and growing.The knowledge and experience with thorium target irradiation, target processing, and waste man-agement that will be developed through L124 and L125 will directly support any future efforts atTRIUMF to scale up production to commercial quantities, as well as the future larger-scale 225Acproduction at ARIEL.3 description3.1 Location of ExperimentThe experiment will begin at the BL1A IPF hot cell, located in TRIUMF’s Meson Hall. The irradiatedtarget will be removed from the rear of this hot cell within a lead flask and then transported to theRCR1 lab, located on the B1 level of TRIUMF’s MHESA building. The target will then be placed insidehot cell #1 (HC1), one of the RCR1 lab’s four hot cells. The remainder of the experiment will take placewithin HC1, except for some samples that must be brought to the QC room on the RadiochemistryAnnex (RCA1) ground floor for analysis, and except for some samples that may be shipped off site.1 While the long-term experimental objective is to produce 100 mCi (3.7 GBq) of 225Ac per irradiation, the first irradiationdescribed in this review is for the production of ∼12 mCi (440 MBq) of 225Ac.323description 4Table 1: Possible modes in which RCR1 hot cells can be operated.Hot Cell Mode Shielded GloveboxModeGlovebox Mode Fume Hood ModeFull shielding withall doors closed. Ac-tions inside hot cellperformed only withmanipulators.Ports open so thatarms can be inserted inglovebox mode whilethe torso is still fullyshielded. Actions insidethe hot cell performedby hand, using thickrubber gloves.Glovebox mode with-out any shielding pro-vided by the hot celldoors. Actions insidethe hot cell performedby hand, using thickrubber gloves.Front door of hot cellopened such that it canbe used in a mannersimilar to a fume hood.No shielding of thebody. Actions insidethe hot cell performedby hand while wearingdisposable gloves andsleeves.HC1 has four different modes in which it can be used that offer varying levels of radiation shielding,contamination control, and airflow control. These modes, defined in Table 1, are referred to throughoutthis document.3.2 Overview of Experimental ProceduresThis subsection provides a brief overview of the experimental procedures. A more detailed descriptionof each stage of the experiment is provided Sections 3.3 through 3.7.Targets containing 8.3 g of Th (>99.5% purity) metal hermetically sealed within an Inconel R© capsulewill be irradiated at IPF and allowed to cool for at least one week before removal of the target from theIPF hot cell. Irradiation conditions will use typical high-current BL1A beam parameters (480 MeV, ∼100µA at extraction or ∼450 MeV, ∼85 µA at IPF) so that use of IPF can occur independent of the needs ofother BL1A users. While the experiment ultimately aims to produce 3.7 GBq (100 mCi) quantities, forthis first initial production run the duration of the irradiation will be chosen such that approximately440 MBq (12 mCi) of 225Ac will remain in the target at 1 week after end of bombardment (EOB). Thisduration is expected to be 2600 µA*h. Additional details of the initial irradiation can be found inCommissioning Plan for Irradiation of L124 Thorium Metal Targets at IPF (Document-148095) [8].Targets will be transferred from the IPF hot cell to RCR1 hot cell #1 (HC1) using a custom transferflask. Once inside HC1, the hermetic seal of the target will be broken, the thorium metal removed anddissolved in concentrated acids. Chemical processing of the irradiated targets using two or more chro-matography columns will then be performed using a semi-automated system consisting of remotelycontrolled pumps and valves. After processing, solutions containing isolated 225Ac isotopes will beremoved from the hot cell and transferred to a fume hood (or a second hot cell operated in fume hoodmode) for radiolabelling experiments.3.3 Target DesignThe target material consists of a thorium metal foil (60 mm diameter, 0.25 mm thickness, or 0.293g/cm2) supplied by IBI Labs (Boca Raton, Florida). The supplied foils currently have a significantoxide layer that will be removed before the targets are fabricated. The thorium metal foil is hermeticallysealed within a target capsule consisting of a steel, ring-shaped body and 0.13 mm thick Inconel R©-718entrance and exit windows2. The outer dimensions of the target are approximately 10 cm diameterand 1 cm thickness. Design iterations of the L124 thorium targets are shown in Fig. 1. The target324description 5Figure 1: Exterior (left) and cross-sectional view (right) the target showing the outer capsule and target interiorand thorium foil.body is shaped to centre the thorium foil radially within the target and to also press it against theentrance window, facilitating improved cooling of the thorium foil via conduction through the window.Windows are attached to the target body by electron-beam welding, the process of which also sealsthe thorium within the target capsule.Sealing of the target with an electron-beam weld – which is conducted under vacuum – will ensurethat the interior volume of the fabricated target is under vacuum. After manufacturing, leak tests ofthe target will be conducted following standard ATG procedures for leak testing IPF targets.The design review process for the first thorium metal prototype target has been completed [10,11],and two successful irradiations of this target have been completed. Design and safety approval of thenew thorium metal target is currently underway. For the most up-to-date and complete informationon L124 target, the reader is referred to the design note, L124 Thorium Metal Target for IPF (Document-148097) [12].3.4 Target TransferAfter irradiation, the target will remain inside the IPF hot cell for one week to allow shorter-livedisotopes to decay before transferring the target to the RCR1 hot cell. This limits the external radiationdose that will be received by workers conducting the target transfer.The custom transfer flask designed for this experiment is shown in Fig. 2. A new flask was requiredfor this project as load limits on the MHESA elevator (1800 kg) prevented use of the flask previouslyused to transfer hot targets from the IPF hot cell to Nordion hot cells (2250 kg). The new transfer flask(214 kg) and the IPF hot cell interface such that the flask lid can be opened and closed from within thehot cell. As such, the targets are removed from the IPF hot cell within a sealed flask. The flask willthen be craned onto a cart near the doorway between the Meson Hall and the MHESA building. Thecart will then be brought to the RCR1 lab.With the flask positioned in front of the HC1 port door, a small hoist will be used to lift the flask lid,exposing the target that is sitting on a shelf attached to the bottom of the flask lid (as shown in Fig. 2).The target (approximately 250 g) will then be lifted manually by means of an long pole (>1 m length)into the HC1 port. Once the HC1 port door is closed, the target is behind the shielding of the hot cell.2 The composition of Inconel R©-718 is as follows: 50.00-55.00% Ni, 17.00-21.00% Cr, 4.75-5.50% Nb, 2.80-3.30% Mo, 0.65-1.15% Ti,<1.00% Co, 0.20-0.80% Al, <0.35% Mn, <0.35% Si, <0.30%Cu, <0.08% C, <0.015% S, <0.015% P, <0.006% B, Fe remainder [9].325description 6Figure 2: Drawing of the transfer flask, which includes space for up to two targets that sit on shelves attached tothe bottom of the flask lid. The flask has at least 7 cm of lead and 3 cm of steel shielding in all directions.More details on the transfer flask design can be found in L125 Target Transfer Flask (Document-148098)and L125 Target Transfer Flask Requirements (Document-148102) [13, 14]. The design review process forthis flask has been completed [10,11].3.5 Opening of Target CapsuleUsing the hot cell manipulators, the target will be inserted into a semi-automated device that willremotely open the target capsule and remove the thorium foil. Shown in Fig. 3, this device uses bladesfrom pipe cutters to cut through the target window so that the thorium foil can be removed. A designreview of the target opener has been completed [15].3.6 Processing of Irradiated TargetModifications of previously published methods will be employed for dissolution of irradiated tho-rium metal and subsequent purification of actinium and radium isotopes, mostly notably techniquesdescribed by Radchenko et al [3, 16]. Similar methods requiring the use of different resins, acids, oracid concentrations may also be employed, since such minor changes do not pose any additional safetyconsiderations.Using the manipulators, the thorium foil will be placed inside a 500 mL beaker. A solution of 10 MHNO3 and 12.5 mM HF3(approximately 60 mL) will be added to the beaker and heated to <90 ◦C. Thishas been shown to dissolve similar amounts of thorium within 30 minutes. The solution containingthe dissolved target will then be evaporated to dryness and redissolved in 80.0 mL of 1 M HNO3, towhich 56 mL of H2O2 will be added to precipitate out bulk thorium as thorium peroxide. The chalkymixture will then be passed through a filter to remove the precipitate (which is later redissolved in10 M HNO3). The filtrate will then be washed with water, diluting the filtrate to appoximately 0.5 MHNO3, which is then passed through a cation exchange column (roughly 10 mL DOWEX 50x8, 100-200mesh). Under these conditions, elements such as Ra, Ac, and Th will be absorbed onto the resin. Theresin is then washed with 450 mL of 1 M citric acid (pH 2.0-2.2) to remove trace thorium quantities,as well as other spallation products. The resin is then washed with an additional 50 mL of 0.5 MHNO3. Ra and Ac are then eluted from the resin using 60 mL of 8 M HNO3, which is passed througha column containing 2 mL of DOWEX1X8 resin (200-400 mesh) which will filter out remaining traceTh quantities. The solution is then diluted to approximately 4 M HNO3 and loaded onto a columncontaining 200 mg of DGA resin. Under loading conditions, Ra and Ba will pass through the columnwithout sorption and actinium and lanthanides will be retained on the column. The column will bewashed with 5 mL of 4 M HNO3 to remove residual radium and barium impurities. Actinium will be326description 7Figure 3: Design of target opener.separated from lanthanides by eluting with 10-12 M HNO3 (5-20 mL) from DGA column. A flowchartof this separation process is shown in Fig. 4.3.7 Testing of 225Ac ProductsSmall aliquots of each solution produced during target processing will be removed from the hot cellso that their composition can be determined using gamma spectroscopy, alpha spectroscopy, or induc-tively coupled plasma mass spectrometry (ICP-MS). Products containing 225Ac will also be removedin small quantities to test the ability of the 225Ac product for labelling with chelates or biomoleculesrelevant to the TAT field. In general, these reactions involve combining 225Ac and the chelate in abuffer solution (total volume < 1 mL), with heating below 80 ◦C. The radiolabeling yield of thesereactions is then tested using iTLC plates, where 1-10 µL of the labelled product is placed on the platebefore a mobile phase is added. The plates are then counted on a plate reader in the RCA1 QC room.The RCR1 HPLC may also be used to characterize radiolabeling reaction products, provided that noorganic solvents are used (see Section 7). The use of TLC plates and HPLC for characterization of225Ac-radiolabeled biomolecules is already approved as part of experiment L122 [17].As the 225Ac progeny isotope 213Bi (t1/2 = 45.6 min) is itself a TAT isotope of interest, a 213Bigenerator from the 225Ac fraction may also be produced. In a manner similar to the chromatographydescribed in Section 3.6, the solution containing 225Ac will be loaded onto an ion exchange (AG-MP50) resin (100-200 mesh, hydrogen form) in 4 M HNO3, binding 225Ac to the resin. The column isthen washed with additional 4 M HNO3 before 213Bi is eluted by passing a solution containing 0.1 MNaI/0.1 M HCl through the resin [5]. Other similar methods using different resins or acids may beapplied.Use of the solution containing isolated Ra isotopes will be used as a second source of 225Ac. Be-ginning >17.5 days after initial thorium target purification, the entire solution (<50 mL) will be once3 A small amount of fluoride is required to catalyze the dissolution.327description 8Figure 4: Flowchart describing the thorium target dissolution and 225Ac purification process. Yield results fortests using non-irradiated thorium are shown.again passed through the a DGA column (as described in Section 3.6) to separate out 225Ac producedvia the decay of 225Ra, this time without the need to remove other spallation products.Radiopharmaceuticals labelled with clinically relevant quantities of 225Ac (∼37 MBq) or preclinicallyrelevant quantities of 213Bi (∼440 MBq) may also be produced.Finally, aliquots of the dissolved target solution (after evaporation of HCl and HF acids and conver-sion to citric acid) may also be taken such that new chromatography methods for the purification ofmedical isotopes from irradiated thorium metal can be tested.3.8 212Pb Generator and ApplicationsIn addition to 225Ac, spallation of 232Th also results in production of significant 228Th quantities. Asillustrated by the decay scheme in Figure 5, 228Th (t1/2 = 1.91 y) is a parent isotope of the medicalisotope 212Pb (t1/2 = 10.64 h). Therefore, isolation of thorium isotopes from L125 targets presents theopportunity to develop a long-lived generator of 212Pb, ensuring a reliable supply of this isotope forresearch. Fortunately, the selective precipitation of thorium employed by the revised 225Ac purificationprocess thus also provides a source of 212Pb. If repurposed as part of 212Pb generators, this thoriumfraction would otherwise be long-lived radioactive waste.Thorium hydroxide precipitates isolated as part of 225Ac purification will be redissolved in 10 Mnitric acid and allowed to decay for a period of at least 4 months. At this point, the thorium solutionwill be evaporated to dryness and redissolved in 40 to 100 mL of 1 M nitric acid, forming the 228Thgenerator solution. 212Pb will be periodically isolated from the generator stock by passing the solutionthrough a column containing 30-200 mg of Pb extraction resin (purchased from Eichrom). This resinis known to be a highly selective extractor of lead [18], a fact already demonstrated by other TRIUMFexperiments (L128). After the 212Pb binds to the resin, the resin will be washed with approximately2 mL of 1 M nitric acid. 212Pb will then be eluted from the resin using a variety of potential aqueoussolvents, such as 0.15 M ammonium acetate.The isolated 212Pb will then be used in radiolabelling or in vivo studies, which are already describedin detail in Section 3.7.328definition of hazards 9Figure 5: 228Th decay scheme. Emissions useful for identification and quantification of isotopes are shown in red.4 definition of hazards4.1 Methods Used for Estimation of Radiation HazardsEstimates of the radioisotope inventory of the irradiated thorium targets were obtained using FLUKAsimulations. These simulations were performed by Andrew Robertson with guidance from MinaNozar.Given the estimated radioisotope inventory, dose rate estimates of the target were calculated usingan Excel-based calculator developed by the TRIUMF Radiation Protection Group (RPG) that calculatesgamma radiation dose rates – both with or without shielding – from a given isotope assuming a pointsource geometry. Comparison with dose rates determined via FLUKA simulation show these methodsagree within <10% for unshielded dose rates at 1 m from the target. Note that the accuracy of theseFLUKA simulations is limited due to the limited understanding beam parameters at the end of BL1A,since the nearest diagnostics are many metres upstream. Simulated radioactivity values and resultingdose estimates presented in this document were based off of a 454 MeV, 55 µA, 48 hour irradiation,which produces 432 MBq of 225Ac one week after EOB.Similar simulations and calculations conducted as part of L124 in 2016 using a thorium oxide testtarget were within 20% of all measurements of 225Ac radioactivity and dose rate at 1 m from the target.This supports the reliability of these FLUKA simulations and dose calculations for approximating theradiation hazards associated with this experiment.While some changes to the target design have been made since the FLUKA simulations were run,the changes are expected to negligibly affect the isotope inventory and resulting dose rates since thetotal mass and approximate radial distribution of thorium and steel (the components producing >99%of the dose from the target) has changed by <1%.Internal and external dose estimates resulting from the worst case release of volatile radioisotopeswere calculated as described in TRIUMF Safety Analysis Reports (SARs) for ISAC targets: ActinideTarget Safety Analysis Report (Document-12972) and Actinide Target SAR Addendum for Thorium Oxide(Document-110961) [19, 20]. These documents contain dose estimates resulting from a worst caserelease of volatile radioisotopes from ISAC actinide targets. These calculations assume all volatile ra-dioactive isotopes within the target become uniformly distributed within a sphere of 15 m radius andthat a worker wearing no respiratory protection is located at the centre of the sphere for a duration of30 minutes. This scenario (“Scenario C” described in Document-110961) assumes that all the radioac-tive air released through the ventilation systems is somehow drawn into an office building. Decayof short-lived isotopes during the 30 minute exposure time is neglected as is the dispersion of theseradioactive gasses during this time. It should be noted that this is an extremely conservative model.Off-site dose estimates to members of the public resulting from a worst case release of volatileradioisotopes were also calculated using the methods described the ISAC actinide target SARs [19,20].When considering airborne radiation doses resulting from an accidental release of radioactivity, one329definition of hazards 10must consider which elements have the potential to become airborne. In the ISAC actinide targetSARs, the volatile elements with potential to become airborne are: hydrogen, chlorine, argon, selenium,bromine, krypton, iodine, xenon, radon, and polonium. This document uses the same definition ofpotentially volatile or gaseous isotopes. Note that while the L124 Safety Report (Document-148928) doesnot treat polonium as volatile [7], this report does. This is because of the potential for polonium to bein a volatile chemical or physical form during some L125 activities.While Actinide Target Safety Analysis Report (Document-12972) and Actinide Target SAR Addendumfor Thorium Oxide (Document-110961) guide the methodology for on-site and off-site airborne doseestimates described in this document, the following modifications were made to these methods toincorporate additional information gained in the years following their publication:1. The ISAC SARs used a 1 minute half-life cut-off of for isotopes used in the calculations. However,220Rn (t1/2 = 55.6 s) has since been shown to be a real potential airborne dose hazard [21]. Dosecalculations herein include 220Rn. This results in a <1% change to the dose estimates.2. TRIUMF is currently in the process of updating its Derived Release Limits (DRLs) – annuallimits for radioactivity released into the environment – and defining Single-event Derived ReleaseLimits (SDRLs) – limits for a single accidental release of radioactivity into the environment. Theold SDRLs used in the ISAC actinide target SARs are considered outdated. SDRLs used in thisdocument to estimate the off-site dose to members of the public resulting from a worst caserelease of radioisotopes were provided by RPG [22]. These SDRLs are listed in Appendix A.All values for Annual Limits on Intake (ALI) used in this document were obtained from the ActinideTarget SAR Addendum for Thorium Oxide (Document-110961), unless otherwise specified [20].330definition of hazards 114.2 Radiation HazardsTable 2: Activity and ALI of the non-radon alpha-emitting radionuclides produced within the thorium foil andpresent one week after EOB. These ALI values were obtained from the Actinide Target SAR Addendum forThorium Oxide (Document-110961) [20].Nuclide ALI [Bq] Activity [Bq] A/ALIPo-204 7.41E+05 0 0.00E+00Po-205 2.25E+08 0 0.00E+00Po-206 4.20E+06 4.35E+08 1.03E+02Po-207 1.33E+08 3.97E+05 2.99E-03Po-208 8.33E+03 7.81E+06 9.37E+02Po-209 8.33E+03 2.66E+05 3.20E+01Po-210 9.09E+03 7.72E+07 8.50E+03At-207 1.05E+07 0 0.00E+00At-209 1.68E+06 0 0.00E+00At-211 1.82E+05 1.26E+06 6.92E+00Ra-223 3.51E+03 2.32E+08 6.61E+04Ra-224 4.17E+03 4.18E+08 1.00E+05Ra-226 9.09E+03 2.93E+03 3.23E-01Ac-224 2.02E+05 1.89E+04 9.37E-02Ac-225 3.08E+03 4.32E+08 1.40E+05Ac-226 2.00E+04 5.14E+07 2.57E+03Ac-227 4.26E+02 8.46E+05 1.99E+03Th-227 2.63E+03 3.40E+08 1.29E+05Th-228 6.25E+02 2.83E+07 4.53E+04Pa-228 3.92E+05 8.88E+05 2.26E+00Pa-229 5.26E+04 7.67E+06 1.46E+02Pa-230 3.51E+04 5.78E+07 1.65E+03U-230 1.67E+03 1.33E+06 7.94E+02U-232 7.69E+02 1.40E+04 1.82E+01Total: 4.98E+05The irradiation of the thorium metal targets is expected to produce significant quantities of hazardousradioisotopes. The simulated radioactive composition of isotopes present within the thorium foil atone week after EOB is shown in Appendix B. This inventory includes gamma-, beta-, and alpha-emitting isotopes. Some of these isotopes are also volatile halogens, noble gases, and elements thatare potentially volatile depending on their chemical form (the definition of the relevant volatile andgaseous isotopes used in this document is provided in Section 4.1). As such, the irradiated thoriumpresents significant external and internal radiation hazards, including airborne radiation hazards.Table 2 lists the activity at EOB + 1 week and the ALI of the non-radon alpha-emitting radionuclideswith half-lives >1 hour. The selection of isotopes for this table was copied from Actinide Target SARAddendum for Thorium Oxide (Document-110961) [20].The non-thorium components of the target capsule will also become radioactive. However, theseisotopes are non-volatile and are not alpha-emitters. These components of the target present significantexternal radiation hazards as well as surface contamination hazards.Dose estimates and worst-case release estimates for different stages in the experiment are providedin Section 5.4.3 Chemical HazardsThe strong acids used in various stages of the experiment are corrosive, with potential to cause chemi-cal burns if they come in contact with skin.331safety measures 12The use of small quantities of dilute HF or (NH4)2SiF6 are particularly hazardous. Small quantitiesof HF are potentially fatal if they come in contact with the skin. (NH4)2SiF6 is potentially fatal ifinhaled or ingested.4.4 Industrial HazardsLifting hazards are mainly associated with the movement of the transfer flask by the Meson Hall crane.Fire hazards are associated with the accumulation of flammable waste inside the hot cell (ex. dis-posable gloves).5 safety measures5.1 Summary of Radiation Safety MeasuresStandard safety practices associated with working in TRIUMF radiochemistry labs will be followed,including wearing proper PPE, routinely monitoring oneself for contamination, and routinely swipingthe floor. In addition, additional zone control near HC1 will be employed: additional tacky mats willbe placed on the surrounding HC1, the area will be marked off with tape, and a pancake probe andalpha contamination monitor will be available at the boundary of this zone, along with additional PPEand decontamination supplies.Safety measures specific to this experiment will also be followed. Table 3 summarizes the radiationrelated risks and hazards for each task discussed in Sections 5.3 through 5.7. For each of these tasksthe maximum credible estimated risk after considering all planned safety measures is compared withan existing similar or greater radiation hazard at TRIUMF.332safetymeasures13Table 3: Task-based risk and dose summary.Task Hazard or Risk Maximum Credible EstimateGiven All Safety MeasuresExample of Comparable orLarger Existing RiskTarget Transfer from IPF toHC1 (Section 5.3)External Whole Body Dose 23 µSv <500 µSv daily dose guidelineInternal Dose or Contamination Minimal risk given PPE andexposure only to metalactivation contaminants ontarget outer surfaceContamination from handlingof irradiated metals is acommon hazard at TRIUMFAccidental Release of VolatileRadioisotopes668 µSv on-site, 5 µSv off-site Off-site dose from accidentalrelease from an ISAC U or Thtarget is 150 µSv or 836 µSv,respectively [20]Target Opening and ThoriumDissolution (Section 5.5.4)External Dose <2 µSv/h - performed in hotcell modeDose rate outside HC4 after99mTc target irradiationInternal Dose or Contamination None – performed in hot cellmoden/aExpected Release of VolatileRadioisotopes58 µSv on-site, 0.02 µSv off-site After filtration this dose ismostly due to radon isotopes.This can be compared to therelease of xenon isotopes bymedical isotope production atNordion, which in 2016contributed a total off-site doseof 1.46 uSv when calculatedusing methods listed in Section4.1 and using measured valuesstated in the TRIUMF 2016Annual Compliance Report (Table9-3) [23].Ac and Ra Purification (Section5.5)External Dose <2 µSv/h - performed in hotcell modeDose rate outside HC4 after99mTc target irradiationInternal Dose or Contamination None – performed in hot cellmoden/a333safetymeasures14Release of VolatileRadioisotopesNone – any volatile isotopes areexpected to be released duringthe target opening or thoriumdissolutionn/aSampling of PurificationProducts (Section 5.7)External Whole Body Dose <3.5 µSv/h Dose rates from these samplesare much lower than from othersamples that TRIUMFradiochemists routinelymanipulate by hand (ex. 2.8mSv/h at 1 m from C-11produced during experimentL4 [24])External Extremity Dose Not estimated See above cellInternal Dose or Contamination Handling <5000 ALI ofnon-volatile alpha-emittingisotopes in aqueous form whileoperating the hot cell in fumehood modeHandling of up to 16000 ALI ofnon-volatile alpha-emittingisotopes in aqueous form isapproved for experiment L122Handling of 225Ra \225Ac and225Ac \213Bi Generators(Section 5.7)External Whole Body Dose <15 µSv/h Dose rates from these samplesare much lower than from othersamples that TRIUMFradiochemists routinelymanipulate by hand (ex. 2.8mSv/h at 1 m from C-11produced during experimentL4 [24])External Extremity Dose Not estimated See above cellInternal Dose or Contamination None – handling of thismaterial, representing 29000ALI, is performed in gloveboxmoden/a334safetymeasures15Radiolabeling Studies with225Ac or 213Bi (Section 5.7)External Whole Body Dose <3.5 µSv/h These studies are alreadyapproved and performed aspart of experiment L112. Theadditional presence of 227Ac inthis experiment increases theALI of a sample containing225Ac by ∼1%External Extremity Dose Not estimated See above cellInternal Dose or Contamination < ALI of Ac isotopes See above cellPreparation ofRadiopharmaceuticalsContaining ClinicallyRelevant Quantities of 225Acor 213Bi (Section 5.7)External Whole Body Dose <15 µSv/h These studies are alreadyapproved and performed aspart of experiment L112, withthe exception of handling up to400 MBq of 213Bi. However, 400MBq of 213Bi represents only 40ALI. Compared to L112, theadditional presence of 227Ac inthis experiment increases theALI of a sample containing225Ac by ∼1%External Extremity Dose Not estimated See above cellInternal Dose or Contamination 40 ALI for 213Bi , 12000 ALI for225Ac with contaminantsSee above cellTesting of New PurificationMethods (Section 5.7)External Whole Body Dose <2.6µSv/h Dose rates from these samplesare much lower than from thosethat TRIUMF radiochemistsroutinely manipulate by hand(ex. 2.8 mSv/h at 1 m fromC-11 produced duringexperiment L4 [24])External Extremity Dose Not estimated See aboveInternal Dose or Contamination None – performed in gloveboxmoden/a335safetymeasures16Waste Disposal (Section 7)External Whole Body Dose <2.6µSv/h Dose rates from these samplesare much lower than from thosethat TRIUMF radiochemistsroutinely manipulate by hand(ex. 2.8 mSv/h at 1 m fromC-11 produced duringexperiment L4 [24])External Extremity Dose Not estimated See aboveInternal Dose or Contamination None – performed in gloveboxmoden/a336safety measures 175.2 Target IrradiationTarget irradiation will be conducted under the purview of L124 [7]. A comprehensive discussion ofsafety concerns related to target irradiation is therefore outside the scope of this safety report. However,a brief description of the irradiation is provided herein.Targets will be irradiated at IPF under typical high-current BL1A beam parameters (480 MeV, ∼100µA at extraction or ∼450 MeV, ∼85 µA at IPF). The duration of the irradiation will be chosen such thatapproximately 440 MBq (12 mCi) of 225Ac will exist in the target at 1 week after end of bombardment(EOB). After removal from beam, targets will be raised from the beam level and into the IPF hot cellwhere they will be left for at least one week before transfer to RCR1. This cooldown period allowsshort-lived isotopes to decay such that the dose rate from the target can be reduced before the targettransfer occurs. During this cool-down period, radiation fields from the target will be contained by theIPF hot cell shielding. Monitoring of the integrity of the target capsule during this period will be doneusing the hot cell stack monitors, which may detect airborne contamination that would result fromthe release of volatile radioisotopes from inside the target capsule. Visual confirmation of the targetcapsule’s integrity will also be done; the windows on the target will be deformed inwards as long asvacuum is maintained inside the target.5.3 Target Transfer5.3.1 Procedure and Safety MeasuresThe transfer of targets from the IPF hot cell to the RCR1 hot cell will be governed by an active TRIUMFWork Permit at the time of the transfer. The planned work will be reviewed and approved by RPGpersonnel before being conducted.Targets will be removed from the IPF hot cell one week after EOB. Only one target will be transferredat a time. At one week after EOB, the target is expected to present an external gamma radiation fieldof 3.52 mSv/h at 1 m without shielding. The target will be removed from the IPF hot cell within ashielded transfer flask (see Section 3.4). This flask contains a minimum of 7 cm of lead and 3 cm ofsteel shielding in all directions, reducing the external dose rate to an estimated 0.03 mSv/h at 1 m.Note that this dose rate estimate – determined via FLUKA – matches measurements of dose rates fromprevious target irradiations. After removal from the IPF hot cell, the outer surface of the flask will beswiped for loose contamination and decontaminated if necessary.The Meson Hall crane will be used to lift the 214 kg flask from the IPF hot cell area and place it ona cart located in the Meson Hall Extension. The flask will then be pushed to the MHESA building andtransferred to the RCR1 lab on the B1 level via the MHESA elevator (1800 kg capacity).Once in RCR1, the flask will be opened and the target inserted into the hot cell access port. PPE forthis part of the work will include a disposable full-body suit, elbow sleeves, cover shoes, gloves, and arespirator. Plastic sheeting will be placed on the floor and nearby surfaces to help contain the spreadof any contamination present inside the flask or on the surface of the target. The flask lid will be liftedusing a hoist until the target can be picked up by a >1 m pole and immediately inserted into the hotcell access port, at which point radiation fields will be reduced by 10 cm of lead shielding to below 5µSv/h. Fig. 6 shows the the hand- or drill-powered hoist that is used to lift the flask lid and also showshow the pole securely attaches to the target such that it can be reliably picked up without dropping.Once the target is behind shielding, the area will be checked for contamination and decontaminated ifnecessary. A high-volume air sample will also be taken to check for airborne contamination. Note thatafter the first two L125 target transfers (April and May 2018), no removable contamination was foundon surfaces other than the inside of the transfer flask (<10 kcpm).5.3.2 Gamma Radiation Exposure During Target TransferDuring the transport of the flask to the RCR1 lab the target is contained in the flask and the resulting0.03 mSv/h field at 1 m will result in a dose of 0.003 mSv assuming a minimum distance from thetarget of 1 m and an estimated exposure time of 5 minutes during the transfer of the flask to RCR1.During the transfer of the target from the flask and into the RCR1 hot cell, the target is not behindany shielding. This portion of the job is expected to expose two workers to gamma radiation fields337safety measures 18of 3.52 mSv/h (at 1 m from the target) for a duration of 30 seconds, resulting in a dose of 0.03 mSvper worker. Note that this estimate is higher than personnel doses measured during the first two L125target transfers (April and May 2018).5.3.3 Contamination of Workers During Target TransferThe exterior surface of the target is expected to be contaminated with metal activation products pro-duced in the steel or Inconel R© components of the target. Such contaminated metals are routinelyencountered at TRIUMF. However, since workers will be wearing full PPE (including tank suit, gloves,and shoe covers) and will not be directly contacting the target, the risk of contaminating personnel isminimal. Contaminants from the thorium foil will be contained within the capsule.5.3.4 Possibility of Target Capsule Rupture During Target TransferWhile alpha-emitting and volatile radioisotopes are expected to be sealed inside the target duringthe target transfer, rupture of the target hermetic seal during the transfer has the potential to releasevolatile radioisotopes into the surrounding air. Of these, the most hazardous are the alpha-emittingisotopes. During the transfer the target is not contained within a nuclear ventilation system and anyrelease of volatile radioisotopes during this time would not be contained.The release of all volatile isotopes within the target would be most hazardous during the portionof the transfer occurring in RCR1 when the target is lifted from the flask into the hot cell. At thispoint, the target is contained in neither the flask nor the hot cell. The risk of a target rupture releasingvolatile radioisotopes will be minimized by the following factors:• the interior of the target capsule is below atmospheric pressure• the target securely attaches to the extendable pole shown in Fig. 6• this portion of the target transfer will be rehearsed with cold targetsHowever, given a rupture of the hermetic seal of the target capsule in RCR1, dose calculationsdescribed in Section 4.1 suggest that the release of all volatile isotopes within the target during thattime could expose a worker to an external dose of 0.23 mSv and an internal dose (due to inhalation ofradioactive isotopes) of 66.8 mSv4. However, this dose will be reduced due to three factors:• All workers in RCR1 at the time of the target transfer will be wearing respirators that provide aprotection factor of 10• The target is expected to be outside of both the flask and the RCR1 hot cell for less than oneminute, after which an air sample will be immediately taken. If significant levels of airbornecontamination were detected, all workers would immediately leave RCR1, having only beenexposed to the airborne radioactivity for under 3 minutes. This provides a reduction factor of 10since calculations described in Section 4.1 assume a 30 minute exposure.• While this document assumes polonium to be a volatile isotope, it is unlikely to be volatile inthis circumstance and it is known to stick to metal surfaces below 100 ◦C, meaning it is veryunlikely to leave the thorium foil and target capsule.These factors combine to reduce the maximum external dose by a factor of 10 to 23 µSv and reducethe maximum internal dose by a factor of 100 to 668 µSv.Following the methods of Section 4.1, the maximum off-site dose to a member of the public due therelease of volatile isotopes during the target transfer in RCR1 is 0.92 mSv, assuming that none of thisair is filtered. However, ventilation for the RCR1 lab is controlled by the fume hood, which draws airout of RCR1. The charcoal and HEPA filters on this stack filter out 99.5% of bromine, selenium, iodine,and polonium isotopes [20], which reduces this maximum possible dose to 5 µSv.A breakdown of the airborne dose estimates by isotope is shown in Appendix C. Section 5.1 providesa comparison of the dose estimates in this section to dose estimates from similar hazards existing atTRIUMF.4 The calculation described in Section 4.1 was modified to account for the actual volume of RCR1. A 400 m3 volume was usedinstead of the standard 15 m radius sphere.338safety measures 19Figure 6: Photos showing how the flask lid will be raised and the targets pickup up when the target is moved fromthe transfer flask and into HC1. Note that the flask pictured is not the one that will be used, however,the hoist and extendable pole will interface with the actual flask and targets in the same manner.5.4 Opening of the Target Capsule5.4.1 Procedure and Safety MeasuresAfter the target capsule has been opened, as described in Section 3.5, the thorium foil will be removed.The remaining components of the target capsule will be placed behind a lead bunker (walls >7.5 cmthickness) at the back of HC1. This removes the largest contribution to the external radiation fieldemanating from the entire target (3.52 mSv/h at 1 m), as the dose rate from the thorium foil aloneis expected to be only 0.86 mSv/h at 1 m. The target capsule will be allowed to decay for at least 6months (or until radiation fields have been sufficiently reduced) before it is removed from the hot celland given to RPG for disposal (see Section 7.1). One year after EOB, the target body is expected toemit a dose rate of 33 µ Sv/h at 1 m.5.4.2 External Doses to Workers During Opening of the Target CapsuleThis work will be conducted within the RCR1 hot cell shielding. The resulting dose rate outside of thehot cell is expected to be less than 5 µSv/h before the components of the target body are placed in theshielding bunker. After the target body is placed behind shielding the dose rate outside of the hot cellis expected to be less than 2 µSv/h.5.4.3 Contamination of Workers During Opening of Target CapsuleThis work will be conducted within the RCR1 HC1 hot cell, operated in hot cell mode. All work willbe carried out using the manipulators or remotely controlled systems. Therefore, there is no risk ofcontamination of personnel during this portion of the experiment.5.4.4 Release of Volatile or Gaseous Isotopes During Opening of Target CapsuleThe opening of the target capsule is not expected to result in the release of volatile radioisotopes thatwere produced within the thorium during the irradiation, as these isotopes will remain trapped within339safety measures 20Figure 7: Stack monitor readings during processing of first thorium metal target at 1 week after EOB.the thorium metal. This is supported by RCR1 stack radiation monitor readings during the processingof the first two L124/L125 metal targets, shown in Figure 7. However, the release of volatile andgaseous isotopes is expected to occur during target dissolution and evaporation (see Section 5.5.4.The release of these volatile isotopes will be further controlled by use of an additional air contain-ment and filtration system that will be built inside HC1. While initially designed to trap and filter airduring both the target opening and the dissolution, results from the first runs (Figure 7) indicate thisis only necessary during the dissolution. Additionally, due to the large volume of the target opener,providing sufficient air flow to trap any gases released during target opening is challenging. Therefore,trapping and filtering air during opening of the target is not necessary and is no longer done. Theupdated internal air containment system is described in Section 5.5.4.5.5 Dissolution of Thorium Foil5.5.1 Procedure and Safety MeasuresThe irradiated thorium foil will be placed in a 500 mL beaker for the dissolution, which is capped witha large custom stopper, shown in Fig. 9. This stopper contains three ports: one for airflow into thebeaker from the hot cell, a second for airflow out of the beaker, and a third for remotely adding theacids used for the dissolution. As described in Section 3.6, the solution of dissolved thorium will alsobe evaporated to near dryness after the dissolution.Shown in Fig. 8, a system for trapping acidic vapours as well as volatile or gaseous radioactiveisotopes is employed during the dissolution and evaporation. This systems pumps air out of the beakerand through a liquid trap, a soda lime column for neutralization of any acidic vapour, then a filterconsisting of activated charcoal and tellurium. This filter is expected to further reduce the release ofchlorine, bromine, selenium, iodine, and polonium isotopes by an additional 99.5%. Work at TRIUMF340safety measures 21Figure 8: Diagram of system that will be employed to capture and filter acidic and radioactive gases that may bereleased during opening of the target capsule and dissolution of the thorium foil. Blue arrows indicatedirection of airflow. Not shown: manipulator-controlled valves, flow indicators.and elsewhere has shown that tellurium is an effective trap for polonium isotopes, the element thatcontributes the most to airborne dose estimates [25]. This will allow any volatile radioisotopes trappedwithin the thorium and released during the dissolution to be captured and filtered before the air isreleased through the hot cell stack.Contamination surveys conducted during the first two L125 runs show that this system effectivelyprevents the release of volatile and gaseous isotopes into the hot cell, as very little contaminationwas found on surfaces inside the hot cell after the run (<200 cpm on swipes of surfaces) or on liquidsamples removed from the hot cell during the run (<1000 cpm on swipes, mostly due to the contents ofthe samples themselves). Measurements conducted using air sampling filters during the first two L125runs also show that the charcoal filter traps >99.5% of volatile halogen isotopes (based off of gammaspectroscopy measurements that quantified the amount of 125I or 131I on sampling filters upstreamand downstream of the charcoal filter) before they are released into the hot cell stack. With this dataacquired, these sampling filters have now been removed, as they are highly susceptible to corrosionand are prone to leaking, reducing the efficiency of the rest of the air containment system.After dissolution and evaporation, the thorium nitrate salts are redissolved in approximately 80 mLof 1 M HNO3. This solution is then removed from the beaker by using the manipulators to insert a thintubing line in through the larger air inlet. This is necessary as the tubing is only rated for concentratedacids at temperatures below 50 ◦C and therefore cannot be in contact with the solutions during thedissolution or evaporation.5.5.2 External Doses to Workers During Thorium DissolutionThis work will be conducted within the RCR1 hot cell shielding. The resulting dose rate outside of thehot cell is expected to be less than 2 µSv/h.5.5.3 Contamination of Workers During Thorium DissolutionThis work will be conducted within the RCR1 HC1 hot cell, operated with the shielding doors closed.All work will be carried out using the manipulators or remotely controlled systems. Therefore, thereis no risk of contamination of personnel during this portion of the experiment.5.5.4 Release of Volatile or Gaseous Isotopes During Thorium DissolutionVolatile and gaseous isotopes within the target are expected to be released during the dissolution andevaporation. Calculations of the dose resulting from the release of these isotopes assume the entirevolatile inventory (as defined in Section 4.1).Isotopes of these elements with half-lives greater than 50 seconds are listed in Appendix C alongwith the estimated maximum amount released. This selection of isotopes is identical to those usedin the Actinide Target SAR Addendum for Thorium Oxide, with the addition of 220Rn [20]. Withoutany mitigation, this release is estimated to result in a maximum on-site internal dose of 1.80 mSv(calculated as defined in Section 4.1). However, the presence of charcoal and HEPA filters on thehot cell exhaust nominally filters out 99.5% of chlorine, bromine, selenium, iodine, and polonium341safety measures 22Figure 9: Image of the beaker (with stopper) that will be used for the thorium dissolution and evaporation. Notethat an ETFE stopper is used instead of the rubber stopper shown.isotopes [20], which reduces this maximum possible dose to 0.06 mSv. The off-site dose to membersof the public from this release is estimated at 0.92 mSv without accounting for the hot cell stack filtersand 4.6 µSv when filtration is considered. Calculation details and a breakdown of these airborne doseestimates by isotope are shown in Appendix C. Assuming the air containment system captures all ofthe radioactive isotopes within the target and that the filters remove airborne contaminants with theexpected 99.5% efficiency, this results in lower the maximum expected on-site internal dose to 0.05mSv and the off-site dose to members of the public to 0.02 µSv. Details of these calculations can befound in Appendix C. After filtration, polonium isotopes dominate the dose contribution.It is also important to keep in mind that these calculations are conservative and are in practiceexpected to be lower for reasons that include:• As shown in Appendix C, the isotope that contributes >99% to unfiltered airborne internalradiation doses both on- and off-site is 206Po. However, polonium is known to not be 100%volatile and despite the production of large quantities of Po isotopes during ISAC actinide targetirradiation, no measurable release of Po isotopes through ISAC stacks has been detected [20]• The alpha-emitting volatile isotopes are radon isotopes and while methods defined in Section 4.1and the Actinide Target SAR Addendum for Thorium Oxide Report [20] assume that radon isotopesare not filtered, work both within and outside of TRIUMF has demonstrated that charcoal filterscan trap radon to some extent [21,26].During target dissolution, the hot cell stack can also be monitored by existing radiation detectorsmonitored in the Main Control Room. It is also possible to make arrangements with RPG to sampleand analyze the air released from the hot cell stack using existing RPG systems. This will ensure thatactual releases can be quantified.Section 5.1 provides a comparison of the dose estimates in this section to dose estimates from similarhazards existing at TRIUMF.342safety measures 235.6 Purification of 225Ac and 225Ra from Dissolved Thorium5.6.1 Procedures and Safety MeasuresChemical separation of actinium and radium isotopes from the dissolved thorium target requiresthe use of multiple chromatography columns. First attempts will use the columns and proceduredescribed in Section 3.6, but other columns or similar chemical procedures may also be explored.However, the general methods and tools used to perform this process while minimizing the spread ofcontamination will not change.The isolation of actinium and radium isotopes will be done within the hot cell with the shieldingdoors closed. A system of pumps and valves that can be controlled from outside the hot cell will beused to pass the necessary solutions through the required steps of the process. The same system isused to control the dissolution and evaporation steps described in Section 5.5.1. The components ofthis system are described in Table 4. To perform the procedure described in Section 3.6, 20 valves and5 pumps are planned. A schematic of this setup is shown in Appendix D.This procedure will first be tested with thorium metal that has not been irradiated. If available, asmall amount (<1 MBq) of 225Ac and 225Ra will be added to the initial solution of dissolved thoriumas tracers. The results of these tests will be documented.5.6.2 External Doses to Workers During Chemical ProcessingThis work will be conducted within the RCR1 hot cell shielding. The resulting dose rate outside of thehot cell is expected to be less than 2 µSv/h.5.6.3 Contamination of Workers During Chemical ProcessingThis work will be conducted within the RCR1 HC1 hot cell, operated with the shielding doors closed.All work will be carried out using the manipulators or remotely controlled systems. Therefore, thereis no risk of contamination of personnel during this portion of the experiment.5.6.4 Release of Volatile or Gaseous Isotopes During Chemical ProcessingAll volatile radioisotopes produced in the thorium metal are expected to have already been releasedduring the dissolution and evaporation steps. Following this single release of volatile and gaseousisotopes, the continuous production of any alpha-emitting volatile or gaseous isotopes listed in Ap-pendix C from a long-lived parent isotope will be limited to the progeny of 226Ra, 222Rn (t1/2 = 3.8d), of which a maximum of 3 kBq is expected and the progeny of 228Th, 220Rn, of which 28.3 MBq isexpected. However, after processing of the target, the container containing these isotopes will be keptsealed. Therefore, a continuous release of 226Ra or 228Th progeny through the hot cell ventilation isnot expected.Since the solution of isolated radium isotopes will act as a secondary generator of 225Ac via 225Ra(t1/2 = 14.9 d), the container will be opened approximately every 17.5 days to remove additionalquantities of 225Ac. This could be expected to release a maximum of 3 kBq of 222Rn every 17.5 days.5.6.5 Contamination Control During Chemical ProcessingWhile performing the chemical process within a hot cell protects workers from contamination, mea-sures will still be taken to prevent the hot cell from becoming contaminated. The semi-automatedsystem using components shown in Fig. 4 as well as those employed for the dissolution and evap-oration (Section 5.5.1) are expected to contain radioactive liquids within sealed containers or tubing,as has been demonstrated during the first two L125 runs. Personnel conducting the purification willvisually monitor the system via the hot cell window throughout the process for any unexpected leaksof radioactive liquids and will immediately turn off all pumps if one is observed.As a secondary measure of contamination control, all components and containers involved in open-ing, dissolving, and processing the thorium target will be placed on spill trays lined with absorbentpaper to prevent any liquid spills or leaks from irreparably contaminating the hot cell surfaces. Thisapplies to all work described in this document that includes the handling of radioactive liquids.343safety measures 24Table 4: Components of semi-automated system for controlling thorium target processing.ContainersContainers used to hold stock acid solutions, radioactive solutions,waste products, and desired 225Ac or 225Ra products will glass solventcontainers (50 - 500 mL) compatible with GL45 solvent caps. Thesecontainers will be reused between separate production runs. plasticcontainers are compatible with all acids used in the experiment.Container SealsSolvent caps with inlets for tubing are employed to provide a tight sealon each container. These caps are equipped with inlet and outlet airvalves to prevent pressure build up when liquid is pumped in or outof a container. designed to provide tight seals epta caps are used toseal all nalgene and Falcon tube containers. The only containers thatdon’t use these caps are the glass beakers used for the dissolution andevaporation stages, described in Section 5.5.1 – these are sealed withthe large stoppers shown in Fig. 9.ValvesPinch valves will be used to open and close tubing to and from dif-ferent solutions at various stages in the process. The image to the leftshows the valve in the default closed state. The valve opens with theapplication of a 24 VDC potential. The use of pinch valves preventsacid or alpha-radiation damage to the pinch valve, since the valve onlycontacts the outer surface of the tubing.PumpsPeristaltic pumps will be used to pump solutions at different stages ofthe process. Pump speed is controlled between approximately 2 and16 mL/min by varying the input voltage between 8 and 24V. The stateof pinch valves upstream or downstream will determine to and fromwhere liquids will be pumped.Tubing and FittingsTubing used will be either ETFE tubing or BioChem CFlex tubing, bothof which are compatible with all solvents and other components usedin the setup. Fitting components that contact the solvents are all ETFEplastic and compatible.ControlsA control box consisting of switches dedicated to each pump and valvewill be used to control the processing of the thorium targets. Theseswitches, located outside the hot cell, are directly wired to each pumpand valve through the built-in hot cell wire ports. The controls arefurther wired such that no pump can be turned on unless at least oneupstream and downstream valve is open, this prevents the buildup ofpressure within the flexible tubing.344safety measures 25Table 5: Comparison of directly- and indirectly-produced 225Ac products by both yield and contaminants. Iso-lation of Ra and Ac isotopes 1 week after EOB gives the directly-produced 225Ac product. Allowingthe Ra fraction to sit for 17.5 days and then once again separating Ra and Ac isotopes provides theindirectly-produced 225Ac product via 225Ra decay.Directly-Produced 225Ac Indirectly-Produced 225Ac225Ac [MBq] 432 17228Ac/225Ac [%] 0.040 0.974227Ac/225Ac [%] 0.196 3.2×10−13226Ac/225Ac [%] 11.900 0.000At least one of the manipulators is expected to become contaminated by typical metal activationproducts on the outer surface of the target when it is picked up before opening the target and removingthe thorium. Contamination of the manipulators by thorium spallation products will be minimizedby using a suction tube to pick up the foil (thus avoiding direct manipulation of the foil with amanipulator) and placing it the dissolution beaker. However, some contamination to the manipulatorsfrom thorium spallation products may be unavoidable.Again, contamination surveys after the first two L125 runs show that contamination control mea-sures in place are effective, as very little contamination was found on surfaces inside the hot cell afterthe run (<200 cpm on swipes, mostly radon progeny) or on liquid samples removed from the hot cellduring the run (<1000 cpm on swipes, mostly due to the contents of the samples themselves).5.7 Testing of 225Ac Products5.7.1 Radioactive Composition of 225Ac ProductsThe purification of Ac and Ra isotopes from the irradiated thorium will result in two 225Ac products:directly-produced 225Ac isolated in the Ac fraction one week after EOB, and indirectly-produced 225Acextracted 17.5 days later from the isolated Ra isotopes after the decay of 225Ra to 225Ac [27]. Since thesetwo products are expected to contain different radioactive contaminants, it is scientifically crucial tothe experiment that both are assessed for their utility as a supply for 225Ac-radiopharmaceuticals. Themost notable difference is in the amount of 227Ac co-produced. Concern exists within the TAT fieldthat the presence of 227Ac – a long-lived (t1/2 = 21.8 y) and toxic alpha-emitter – may prevent theregulatory approval of an 225Ac-radiopharmaceutical. For this experiment, 227Ac is also challengingfrom a waste management perspective.Table 5 contains details regarding the anticipated quantities of Ac contaminants in each 225Ac prod-uct. These values were determined using the FLUKA simulation results and modelling of the purifi-cation process that assumes perfect chemistry (i.e. no breakthrough of 227Ac into the initially isolatedRa fraction, for example). The directly-produced 225Ac product is expected to contain ∼0.2% 227Ac byactivity at EOB + 1 week and a total of 1.45×105 ALI of Ac isotopes.While the indirectly-produced 225Ac is expected to have a ∼25 times lower yield, it is also expectedto be 227Ac-free, and contain 5.8×103 ALI of Ac isotopes.5.7.2 Procedures and Safety MeasuresSampling of Purification ProductsTo gather information about the process of purifying 225Ac and 225Ra from the thorium, it is necessaryto remove samples of all solutions produced during the 225Ac purification process so that their com-position can be determined by gamma spectroscopy, alpha spectroscopy, and ICP-MS. To do this, leadbrick shielding will be employed inside the hot cell such that a worker can put their hands inside thefront area of the hot cell (in either glove box or fume hood mode) without exposing the worker to highwhole body or extremity (hand) doses. A diagram of this shielding setup is shown in Fig. 11. Twosliding doors made of 10 cm of lead and capable of being opened and closed by the manipulators willbe built. With these shielding doors open, the semi-automated purification process can be visuallymonitored through the shielding of the hot cell door. With these shielding doors closed, the hot cell345safety measures 26Figure 10: Diagram illustrating how radioactive solutions will be sampled from behind shielding. Pre-positionedsampling lines with syringe fittings will be used to remove up to 100 µL (<1% of total volume) of aradioactive solution. Increased shielding and distance to the bulk volume of radioactive liquid willreduce worker’s hand dose during the process.front door can be lowered to permit use of the hot cell in fume hood or glove box mode without expos-ing the worker to the high radiation fields from the purification products. The 10 cm of lead shieldingis expected to lower the dose rate from the purification products from 820 µSv/h to 2.5 µSv/h at 1 m(at the front of the hot cell).Sampling lines pre-positioned in each container will allow small aliquots of the highly radioactivesolutions to be sampled from behind this shielding. The diagram of this is shown in Fig. 10. The sy-ringe adapter on the end of the sampling line will allow up to 100 µL (<0.1% of radioactive inventory)of a radioactive solution to be removed. These adapters will be plugged when not in use. The 100µL sample will then be transferred to a vial and diluted to a concentration suitable for gamma spec-troscopy, alpha spectroscopy, or ICP-MS measurements. The collection and dilution of these sampleswill be conducted in fume hood mode. All samples removed from the hot cell will first be swipedfor removable contamination. A conservative maximum possible dose rate expected from a 100 µLsample of any of the purification products is 1 µSv/h at 1 m without shielding. Using values fromTable 2, a <100 µL sample of any of the purification products would contain <4.98×103 ALI.Secondary Production of 225Ac from Isolated Radium IsotopesUse of the solution containing isolated Ra isotopes will be used as a second source of 225Ac. Begin-ning >17.5 days after initial thorium target purification, the entire solution (<50 mL) will be passedthrough an extraction chromatography column to purify additional 225Ac quantities. The anticipatedradioactive composition of this solution at the time this task will be performed and the resulting doserate from each isotope is shown in the table of Appendix E, including Ra isotopes and their decayproducts in equilibrium as well as barium (Ba) isotopes that are known to follow Ra isotopes throughthe thorium purification process [3]. This inventory represents a total of 2.9×104 ALI. The total ex-pected dose rate at 1 m from this vial is 8.18 µSv/h. Since this dose rate is well below the dose rate ofhigh activity solutions routinely handled by hand by TRIUMF’s radiochemists, this work will not besemi-automated but will be done in the hot cell by hand. However, due to the relatively large volumesof liquid anticipated (<50 mL) and the presence of long-lived alpha-emitting isotopes such as 226Ra,this work will be performed in glovebox mode.225Ac Radiolabeling Test ReactionsSmall aliquots (<100 µL containing <200 kBq of 225Ac and <72 ALI of Ac isotopes) of the two iso-lated 225Ac products will also be used to perform radiolabeling experiments. These simple reactions346safety measures 27are described in Section 3.7 and will be performed inside the hot cell in fume hood mode, as willpreparation of iTLC plates. These plates will then be sealed with parafilm before they are checked forremovable contamination and transferred to the RCA1 QC room for readout. This process of labelingbiomolecules with similar amounts of 225Ac in RCR1 hot cells and measuring the resulting iTLC plateson the QC room plate reader has already been subject to safety review under L122 and has been per-formed many dozens of times [17]. The RCR1 HPLC may also be used to characterize radiolabelingreaction products, provided that no organic solvents are used (see Section 7).The additional presence of 227Ac does not significantly increase the hazards associated with thiswork. As can be seen in Table 2, in terms of ALIs, 225Ac is produced at two orders of magnitudemore than 227Ac. However, the presence of 227Ac does significantly increase waste management issues,which are described in Section 7.Preparation of an 225Ac Generator of 213BiAs the 225Ac progeny isotope 213Bi (t1/2 = 45.6min) is itself a TAT isotope of interest, a 213Bi generatorfrom the directly-produced 225Ac fraction may also be produced. This work may involve the entiretyof the directly produced 225Ac (<440 MBq in <30 mL, <1.45×105 ALI), which will be loaded ontoan ion exchange (AG-MP 50) resin. Once loaded, Ac isotopes (dominantly 225Ac and 227Ac) willremain on the resin, within which 213Bi is continuously produced and can be removed as needed. Theanticipated radioactive composition of this loading solution at the time this task will be performedand the resulting dose rate from each isotope is shown in the table F, including Ac isotopes and theirdecay products in equilibrium. The total expected dose rate at 1 m from this vial is 11.11 µSv/h.Since this dose rate is well below the dose rate of high activity solutions routinely handled by handby TRIUMF’s radiochemists, this work will not be semi-automated but will be done in the hot cell byhand. However, due to the presence of hazardous amounts of 227Ac , the loading of the column will beperformed in glovebox mode. Since 227Ac will remain bound to the column throughout the lifetime ofthe generator’s use, eluting of the generator will be done within the hot cell, operating in fume hoodmode.Alone, 213Bi has an ALI of 1.11×107 Bq [28]. Radiolabelling of the collected 213Bi (<440 MBq, <40ALI) may also be performed in the hot cell by hand, operating in fume hood mode. This wouldproduce 213Bi-radiopharmaceuticals with activities great enough for preclinical trials.Preparation of Clinically Relevant Quantities of 225Ac-RadiopharmaceuticalsA clinical dose of 225Ac-TAT requires approximately 37 MBq (1 mCi) of 225Ac in the final radiolabeledproduct. Preparation of such compounds may also be conducted within the hot cell and is alreadyapproved as part of L122 [17]. When using the directly-produced 225Ac, the work will be done inglovebox mode due to the presence of 227Ac. When using the indirectly-produced (and 227Ac-free)225Ac product, this work will be conducted in fume hood mode. L122 is already approved to handleup to 37 MBq of 225Ac in solution (without 227Ac) within the RCR1 hot cells in fume hood mode [17].Low-Level Testing of Other Irradiated Thorium Purification MethodsSince the investigation of novel processes for purification of 225Ac from irradiation thorium is also ofinterest, small samples (<10 µL and <0.01% of the target’s total radioactive inventory) of the dissolvedtarget solution (after evaporation of HCl and HF acids and conversion to citric acid) may also be takensuch that new chromatography methods can be tested. These tests will be conducted with the hot celloperating in fume hood mode. The dose rate expected from 0.01% of the thorium target is <0.1 µSv/h.Similarly, the purification method that will be implemented for full processing of the irradiatedtarget will be practiced before introducing the irradiated target into the hot cell. This tests will usereadily available tracers of key isotopes as tracers for the elements that must be separated. Thesetracers will include <2 MBq 225Ra and 225Ac from CNL, <2 MBq 89Zr from the TR13, <2 MBq 177Lufrom BC Caner Agency (originally purchased from ITG), and potentially 227Th sourced from the USDOE. Additionally, since limited thorium metal is available for such tests, in some cases, thoriumnitrate already available at TRIUMF may be used in place of non-irradiated thorium metal. The usesof these tracers does not change the hazard assessment and safety precautions outlined in previous347safety measures 28Figure 11: Aerial view of hot cell setup, illustrating how shielding will be used to surround containers of radioac-tive liquids produced during the purification process. Two sliding lead doors capable of being openedand closed by the manipulators will be built. With these shielding doors open, the semi-automatedpurification process can be visually monitored through the shielding of the hot cell door. With theseshielding doors closed, the hot cell front door can be lowered to permit use of the hot cell in fumehood or glove box mode without exposing the worker to the high radiation fields from the purificationproducts.parts of this document since the anticipated co-production of these isotopes in the irradiated targetshas already been considered.Summary of Activities Performed Outside the Hot CellWith a few exceptions, all work described in Section 5.7 will be conducted in HC1, operating inglovebox mode or fume hood mode, as indicated. Activities performed in fume hood mode maybealso be conducted in HC2, in which 225Ac samples are already regularly handled in fume hood modeas part of L122 [17].However, some samples must be removed from the hot cell entirely for analysis, since the requiredequipment is located outside the hot cell. This includes:• Vials containing liquid samples for gamma spectroscopy will be removed from the hot cell andcounted in the RCR1 HPGe detector.• Samples prepared for alpha spectroscopy will be removed from the hot cell and counted on thealpha spectroscopy detector in RCR1. These samples consist of a small metal disk on top ofwhich a drop of a radioactive solution has been evaporated. Due to the sensitivity of the alphaspectroscopy detector, the total activity of these samples will be on the order of 102 Bq.• As described in Section 3.7, TLC plates spotted with a drop of a solution from the purified 225Acproducts and developed inside an RCR1 hot cell, will be sealed in a plastic bag and removedfrom the hot cell. These plates typically contain 102-104 Bq. These samples will be brought tothe RCA1 QC room, where the TLC plate reader is located. Plates will remain inside a plasticbag while they are counted.348safety measures 29• Vials containing liquid samples of radiolabeling reaction products may be removed from the hotcell and analyzed on the RCR1 HPLC.• Vials containing samples prepared for ICP-MS will be removed from the hot cell and shippedoff-site for analysis.• Prepared 225Ac-radiopharmaceuticals will be removed from the hot cell and shipped off-site foranimal studies.All samples removed from the hot cell will be in a sealed container (ex. vial or plastic bag) withan exterior surface verified (via swipes) to be free of removable contamination. Alpha spectroscopysamples must be removed from their container before being placed in the detector.5.7.3 External Doses to Workers During Testing of 225Ac ProductsWhole Body Dose EstimatesWith the exception of the operation of 225Ra\225Ac and 225Ac\213Bi generators, all tasks described inSection 5.7 involve handling samples having dose rates of <1.2 µSv/h at 1 m without shielding. Theworker’s body may be closer to the samples during the work, increasing the dose rate to <5 µSv/h ifa 0.5 m distance is assumed, plus an additional 2.5 µSv/h from other contents of the hot cell (behindthe shielding shown in Fig. ??). Since it is unlikely a worker will spend more than 4 hours in one daywithin 0.5 m from these samples, an estimated upper limit of dose received conducting these tasks is30 µSv per day.While the dose rates are higher for the operation of 225Ra\225Ac and 225Ac\213Bi generators (8.18and 11.11 µSv/h at 1 m, respectively), these tasks take less time. If an upper limit of one hour spentby a worker at 0.5 m from the generator is assumed, doses of up to 33 µSv for the elution of the 225Ra-225Ac generator and 47 µSv for the 225Ac-213Bi generator can be expected, including the additional 2.5µSv/h from other contents of the hot cell.Extremity Dose EstimatesThe radioactive samples described in Section 5.7 that will be manipulated by hand present dose rateswell below those of other materials frequently handled by TRIUMF’s radiochemists. Therefore, nosignificant extremity doses are expected. Wherever possible, workers will use shielding (ex. lead pigs)and distance (ex. tools such as tongs) to limit the dose received by their hands.5.7.4 Risk of Contamination During Testing of 225Ac ProductsWorkers performing tasks described in Section 5.7 with the hot cell operated in glovebox mode willwear a lab coat, safety glasses, cover shoes, hydrophobic elbow sleeves, and gloves. Since all unsealedradioactive samples containing long-lived alpha-emitters such as 227Ac or 226Ra that are handled infume hood mode are also <100 µL in volume, the risk of an accident resulting in the spill of activityout of the hot cell or the penetration of activity through the worker’s PPE is reduced. Using valuesfrom Table 2, a <100 µL sample of any of the purification products would contain <4.98×103 ALI.Given the handling of such small volumes, the ease of use gained by working in fume hood modeis expected to help reduce the spread of contamination within the hot cell, an important concernconsidering that some samples must leave the hot cell for analysis. While working in glovebox modeprovides a higher level of protection to the worker from direct contamination, these thick gloveboxgloves can be awkward and difficult to cover with disposable gloves. This contrasts with the use offume hood mode, where a worker wearing multiple layers of disposable gloves can easily remove pairsof gloves when touching different surfaces, reducing the spread of contamination.Whenever the hot cell front door will be opened for operations in fume hood mode, swipes of thefront interior area of the hot cell will first be taken in glovebox mode. Surfaces swiped will also includethe inner surface of the hot cell door and the hot cell gloves themselves.Still, tasks described in Section 5.7 that involve handling larger volumes of radioactive solutions orlarger quantities of 227Ac will be performed in glovebox mode, the risk of contaminating a worker tothese isotopes is controlled.349safety measures 30Protection of hot cell surfaces from contamination is described in Section 5.6.5.A comparison of the contamination or internal dose hazard for this experiment with similar hazardsfrom other TRIUMF experiments or activities is further provided in Section 5.1Prior Experience Handling Liquid 225Ac and 225Ra SamplesThe users of L125 (Andrew Robertson and Hua Yang), along with other TRIUMF workers, have pre-viously handled liquid sources of both 225Ac and 225Ra isotopes in RCR1 hot cells under the purviewof L122. L122 has safety approval to handle up to 37 MBq of 225Ac and 37 MBq of 225Ra (or a total of1.2×104 ALI) [17]. Two years of experience during these experiments has shown that 225Ac and 225Racontamination does not spread easily once in liquid form and at no point has contamination spreadoutside the hot cell or onto workers.227Ac Contamination227Ac is the isotope with the most restrictive ALI and is produced in significant quantities in thisexperiment. While 227Ac, as an alpha-emitter with few gamma emissions, may present challenges interms of direct detectability, any substances containing 227Ac are also expected to contain 225Ac, 226Ac,and/or 228Ac, which themselves are easily detectable by all contamination monitors, as are 227Ac decayproducts 227Th and 223Ra. Though 227Ac will outlive these isotopes, once 225Ac has decayed there isno motivation to handle these substances. As shown in Table 2, nearly 100 times more ALIs of 225Acwill be produced than ALIs of 227Ac, and experiments involving similar 225Ac quantities are alreadyconducted in RCR1 hot cells in fume hood mode. Proposed tasks involving larger 225Ac quantitieswill be performed in glovebox mode.5.8 212Pb Generator and ApplicationsAt 6 months after EOB, the 228Th stock solution from the first L125 target (irradiated in December 2017and processing in April 2018), has an external dose rate of 2.5 µSv/h at 1 m. The main contributionto this dose rate is a 2.61 MeV gamma emission (99.8% branching ratio) emitted by the 228Th progeny208Tl. The radioactive inventory of this solution has been measured, and is shown in Table 6. Inaddition to this, the solution also contains approximately 8 g of natural thorium. In total, this inventorycontains 1973 ALI of radioactivity if inhaled, and 35.43 ALI of activity if ingested. However, since 228This a non-volatile metal in an aqueous solution, inhalation of 228Th is not considered a credible exposurescenario.To minimize handling of the generator stock solution, an automatic apparatus for loading the 212Pbonto the extraction resin will be built. This apparatus will meet the following safety-related require-ments:1. retain the 228Th solution in a closed loop, such that the user does not have to handle it by hand2. for each use of the generator, the user is only required to exchange the single-use resin, and towash and elute the resin using a syringe3. a peristaltic pump for moving the solution through the resin will be placed downstream fromresin, such that liquid is pulled through the resin, not pushed. This prevents build-up of backpressure and also prevents a spill in the event that the user does not properly attach the column4. house the stock 228Th solution within 3-5 cm of a steel shielding that is expected to reduce theexternal dose rate to below 1 µSv/h at 1 mBy using this apparatus, the user is only required to handle the 228Th progeny isotopes, namely 212Pb(t1/2 = 10.6 h), which will decay within days in the event of any spills or generation of contaminatedwaste.The generator apparatus will be placed on an acid resistant spill tray and absorbent spill paper willalso be utilized. Due to the release of 220Rn from the generator, the generator will be kept insidethe RCR1 fume hood. Note that this does not introduce any new airborne radioactivity releases,350definition of responsibilities 31as the hazard assessment for this 220Rn is already included in the hazard assessment for the 225Acpurification.Handling of the 212Pb produced from the generator will expose the user to a dose rate of <2.5 µSv/hat 1 m. This activity will be handled in a fume hood or hot cell operating in fume hood mode. Smallsealed quantities may be removed from the fume hood for analysis (ex. gamma spectroscopy, TLCplate reading etc.).Table 6: Radionuclide inventory of 228Th solution produced as by-product of the first processed L125 targetNuclide half-life Activity [Bq] ALIing. [Bq] ALIinh. [Bq] A/ALIing.Th-228* 1.91 y 9.78E+06 2.78E+05 5.00E+02 35.21*including decay products (not listed)Th-227 18.7 d 3.37E+05 2.27E+06 2.00E+03 0.15Ag-110m 250 d 4.20E+05 7.14E+06 1.67E+06 0.06Se-75 120 d 1.37E+05 7.69E+06 1.54E+07 0.02Total: 35.435.9 Chemical Safety MeasuresChemical safety hazards described in Section 4.3 are commonly found in TRIUMF’s radiochemistrylabs. Equipment and spill kits required for dealing with chemicals spills are available in the lab.Workers have also completed chemical safety training and are aware of the location of SDS for thechemicals involved.The use, handling, and storage of HF will be conducted in accordance with UBC Risk ManagementServices guideline for the handling of HF (UBCV-RMS-OHS-GDL 14-006)5.5.10 Industrial Safety MeasuresIndustrial hazards described in Section ?? are limited to the lifting of heavy objects, notably the transferflask. Craning of the flask will be conducted by the Meson Hall crane operators, not the experimenters.The workers will wear safety boots when transporting heavy objects and will wear hard hats if nearthe Meson Hall crane while it’s in use.The accumulation of flammable material within the hot cell – notably disposable solid waste – willbe limited to one bag (∼12”x15”) of disposables at a time.6 definition of responsibilitiesAndrew Robertson is the experimental Safety Coordinator and is responsible for ensuring the overallsafety of the experiment and that all actions taken comply with this safety report. Due to the presenceof long-lived isotopes with low ALI values (ex. 227Ac) and the level of care that must be taken toprevent contamination of surfaces inside the hot cell with these isotopes, Andrew Robertson and HuaYang will be the only users of HC1 and this experiment and the 225Ac materials it produces. BrookeMcNeil will also be a user of the 228Th-212Pb generator and the resulting 212Pb. Stefan Zeisler andEllard Portman are assisting with 225Ac production runs and upgrades of the L125 hot cell equipment.Other groups outside of the Life Science Division also have specific responsibilities related to thisexperiment. As the Applied Technology Group (ATG) has ownership of the IPF, ATG Operators willbe responsible for removing the transfer flask from IPF; Meson Hall Crane Operators will then beresponsible for lifting the flask as necessary. RPG and Operators in the 500 MeV Control Room areresponsible for monitoring stacks from the IPF, RCR1 fume hood, and HC1 during the experiment andfor collecting any required air samples from these stacks. The L125 Safety Coordinator will coordinatewith RPG regarding the timing of any required air sampling of the ventilation stacks. RPG is also5 http://riskmanagement.sites.olt.ubc.ca/files/2016/05/UBCV-RMS-OHS-GDL-14-006-Handling-Hydrofluoric-Acid.pdf351decommissioning and disposal 32responsible for receiving waste generated in this experiment that is prepared according to this safetyapproval.6.1 Thorium Inventory ManagementThe 232Th that makes up the target material is a controlled nuclear substance, the inventory of whichTRIUMF reports in detail to the Canadian Nuclear Safety Commission (CNSC). Only thorium that hasbeen exempted from restrictions on its modification will be used in the experiment. The spokespersonsare also responsible for ensuring that items containing thorium are appropriately labelled, that thequantity of thorium therein is recorded, and for reporting on a monthly basis to the RadioactiveMaterials Coordinator any changes to the location, mass, chemical form, or physical form of anythorium materials.7 decommissioning and disposalIn the scope of this experiment, less than 10 targets (including those irradiated since 2017) will beirradiated. It’s anticipated this number is sufficient to develop TRIUMF’s 225Ac production processesthat in the future could support routine (i.e. non-experimental) production.7.1 Disposal of the Target CapsuleAfter the experiment, the target capsule will consist of activated and contaminated metal waste, pri-marily steel. This type of activated metal waste is common at TRIUMF. The target capsule will beallowed to decay inside HC1 for at least 6 months (or until radiation fields have been sufficiently re-duced) before it is removed from the hot cell, sealed in an 8 mil plastic bag, and given to RPG fordisposal, probably in the vault tunnel at the discretion of RPG. One year after EOB, the target body isexpected to emit a dose rate of 33 µSv/h at 1 m.7.2 Disposal of Liquid WasteAll liquid waste products are expected to be in the form of acidic aqueous solutions. No organicsolvent waste containing radioisotopes will be generated, until a waste management stream for suchmaterials at TRIUMF is defined by the RPG and the RCR1 Lab Manager. At the time that disposalof this waste will occur (at least two weeks after EOB), the dose rate from liquid waste products isexpected to be approximately 600 µSv/h at 1 m without shielding (as determined by measurementsof previous runs). The following procedure will be used prepare this waste for removal from RCR1:1. Liquid waste will be pumped into a 1 L glass solvent bottle with a GL45 cap. These bottle capsare also compatible with caps that have inserts for tubing so that the bottle can be easily attachedto any future waste processing (avoids having to pour liquid out the bottle).2. The pH of the waste will be adjusted to between 4 and 10 by addition of NaOH.3. The cap on the bottle will be closed and sealed with parafilm.4. The bottle will be placed in a 4L pail (or similar), along with absorbent material capable ofabsorbing any liquids in the event of a spill.5. All info (pH, volume, solvents, radioactive inventory, dose rate, and date) will be recorded onthe outside of the pail and also in the RCR1 waste log. The waste log is kept by the RCR1 LabManager and documents waste transferred to RPG for temporary storage or disposal.6. The user will prepare the waste, and the RCR1 Lab Manager will verify this was done correctlyand then coordinate with RPG to transfer the waste into temporary storage.352references 33Liquid waste will remain in temporary storage until it has decayed to the point that the externaldose rate is low enough that the waste can be processed for final disposal without accruing significantpersonnel doses.7.3 Disposal of Compactable Solid WasteIn order to minimize the volume of solid waste contaminated with long-lived isotopes with low dispos-ability limits (most notably 227Ac) 6and in the spirit of sorting radioactive waste at the source [29], allsolid waste produced by activities associated with this experiment will be segregated from other solidradioactive waste routinely produced in RCR1. Solid waste from L125 will be further separated intomultiple streams including: 1) unlikely but potentially contaminated waste; 2) low-level contaminatedwaste; and 3) highly contaminated waste.Solid waste produced by this experiment will include items such as empty containers, tubing, andfittings associated with the purification process, as well as other items such as pipette tips, disposablePPE (gloves and elbow sleeves), cleaning supplies (i.e. paper towels), and small 1.5 mL vials. This iswaste that is typically produced in TRIUMF’s radiochemistry labs. These items are bagged and givento RPG, who then characterizes each bag by total count rate [31,32]. Bags of similar radioactivity levelare then compacted into metal barrels. Each barrel is then assayed using gamma spectroscopy [33] andstored on site for decay until its radioactive contents are below the limit for which they can be disposedof via the landfill. This waste management program is described in Radioactive Waste Management forthe TRIUMF Site (Document-5330) [34]. With the exception of the target capsule and the glass bottles,filter, and beakers required for the dissolution and storage of liquids produced during the purificationprocess, all solid wastes associated with this work can be compacted. Disposal of this waste will occurin coordination with the RPG.7.4 Decommissioning of the ExperimentDecommissioning of the experiment will involve removal of all equipment from inside the hot cell.Compactable items may be deposed of as described in Section 7.3, while non-compactable objects willbe first swiped for removable contamination, decontaminated if possible, and then given to RPG fordisposal. There is currently no anticipated timeline for the decommissioning of the experiment.references[1] Clemens Kratochwil, Frank Bruchertseifer, Frederik L Giesel, Mirjam Weis, Frederik A Ver-burg, Felix Mottaghy, Klaus Kopka, Christos Apostolidis, Uwe Haberkorn, and Alfred Morgen-stern. 225Ac-PSMA-617 for PSMA targeting alpha-radiation therapy of patients with metastaticcastration-resistant prostate cancer. J. Nucl. Med., 57(12):1941–4, jul 2016.[2] B L Zhuikov. Successes and problems in the development of medical radioisotope production inRussia. Physics-Uspekhi, 59(5):481–486, 2016.[3] V Radchenko, J W Engle, J J Wilson, J R Maassen, F M Nortier, W A Taylor, E R Birnbaum, L AHudston, K D John, and M E Fassbender. Application of ion exchange and extraction chromatog-raphy to the separation of actinium from proton-irradiated thorium metal for analytical purposes.J. Chromatogr. A, 1380:55–63, feb 2015.[4] R. A. Aliev, S. V. Ermolaev, A. N. Vasiliev, V. S. Ostapenko, E. V. Lapshina, B. L. Zhuikov, N. V.Zakharov, V. V. Pozdeev, V. M. Kokhanyuk, B. F. Myasoedov, and S. N. Kalmykov. Isolation ofMedicine-Applicable Actinium-225 from Thorium Targets Irradiated by Medium-Energy Protons.Solvent Extr. Ion Exch., 32(5):468–477, 2014.6 227Ac is of particular concern since the criteria for disposal of waste containing 227Ac via the landfill is limited to an activityconcentration of <0.1 Bq/g or a total activity of <1 kBq [30]. A total of 0.85 MBq of 227Ac is expected to be produced duringthis experiment.353references 34[5] Alfred Morgenstern. Bismuth-213 and actinium-225–generator performance and evolving ther-apeutic applications of two generator-derived alpha-emitting radioisotopes. Curr. Radiopharm.,5(3):221–227, 2012.[6] International Atomic Energy Agency. Technicial Meeting on Alpha emitting radionuclides andradiopharmaceuticals for therapy. Technical report, International Atomic Energy Agency, Vienna,2013.[7] A. K. H. Robertson. Safety Report for L124: Irradiation of Thorium Targets at the TRIUMF500 MeV Isotope Production Facility (Document-148928). Technical report, TRIUMF, Vancouver,Canada, 2017.[8] Andrew K H Robertson. Commissioning Plan for Irradiation of L124 Thorium Metal Targets atIPF (Document-148095). Technical report, TRIUMF, Vancouver, Canada, 2017.[9] Inconel 718, Alloy 718, UNS N07718 - MEGA MEX.[10] Anders Mjos. L124 Design Review 2017-10-27 (Document-148948). Technical report, TRIUMF,Vancouver, Canada, 2017.[11] Anders Mjos. L124 Design Review 2017-11-09 (Document-148946). Technical report, TRIUMF,Vancouver, Canada, 2017.[12] L. Moskven and AKH. Robertson. L124 Thorium Metal Target for IPF (Document-148097). Tech-nical report, TRIUMF, Vancouver, Canada, 2017.[13] Andrew K H Robertson. L125 Target Transfer Flask Requirements (Document-148102). Technicalreport, TRIUMF, Vancouver, Canada, 2017.[14] L. Moskven. L125 Target Transfer Flask (Document-148098). Technical report, TRIUMF, Vancouver,Canada, 2017.[15] Sam Varah. Design Review of L214 Remote Thorium Target Opener (Document-146024). Technicalreport, TRIUMF, Vancouver, Canada, 2017.[16] Valery Radchenko, Jonathan W. Engle, Justin J. Wilson, Joel R. Maassen, Meiring F. Nortier,Eva R. Birnbaum, Kevin D. John, and Michael E. Fassbender. Formation cross-sections andchromatographic separation of protactinium isotopes formed in proton-irradiated thorium metal.Radiochim. Acta, 104(5):291–304, 2016.[17] C. F. Ramogida. Safety Report for L122: Alpha-emitter studies using the ISAC implantationstation. Technical report, TRIUMF, Vancouver, Canada, 2017.[18] E Philip Horwitz, Mark L Dietz, Susan Rhoads, Claudia Felinto, Noel I Gale, and JudithHoughton. A lead-selective extraction chromatographic resin and its application to the isolationof lead from geological samples. 292:263–273, 1994.[19] A Trudel and J Mildenberger. Actinide Target Safety Analysis Report (Document-12972). Technicalreport, TRIUMF, Vancouver, Canada, 2011.[20] J Mildenberger and A Trudel. Actinide Target SAR Addendum for Thorium Oxide (Document-110961). Technical report, TRIUMF, Vancouver, Canada, 2014.[21] J Mildenberger. Rn-220 from ISAC target pits (Document-130951). Technical report, TRIUMF,Vancouver, Canada, 2016.[22] Joe Mildenberger. personal communication.[23] J Mildenberger and A. Trudel. Annual Compliance Report 2016. Technical Report February,TRIUMF, Vancouver, Canada, 2016.[24] Trevor Uittenbosch. personal communication.354references 35[25] Jason R Crawford, Hua Yang, Peter Kunz, Scott Wilbur, Paul Schaf-Fer, Thomas J Ruth, CrawfordJason, Yang Hua, Kunz Peter, Schaffer Paul, Ruth Thomas, D Scott Wilbur, and Paul Schaffer.Development of a preclinical At generator system for targeted alpha therapy research with 211At. Nucl. Med. Biol., 48:31–35, 2017.[26] John P Greene, Jerry Nolen, and Sam Baker. Nickel-backed Bi targets for the production of 211At.J. Radioanal. Nucl. Chem., pages 1–4, 2015.[27] A. K. H. Robertson, K. Ladouceur, M. Nozar, L. Moskven, C. F. Ramogida, J. D’Auria, V. Sossi,and P. Schaffer. Design and Simulation of Thorium Target for Ac-225 Production. AIP Conf. Proc.,1845(1):020019–1 —- 020019–5, 2017.[28] United States Nuclear Regulatory Commission.[29] M Kinakin. Sorting Radioactive Waste at the Source (Document-5816). Technical report, TRIUMF,Vancouver, Canada, 2012.[30] Nuclear substances and radiation devices regulations (2000). Retrieved from the Justice Lawswebsite: http://laws-lois.justice.gc.ca/eng/regulations/SOR-2000-207/.[31] M Kinakin. Characterization of radioactive waste (Document-5815). Technical Report August,TRIUMF, Vancouver, 2012.[32] J Mildenberger. Radioactive waste area sorting cave sensitivity. Technical report, TRIUMF, Van-couver, Canada, 2012.[33] M Kinakin. Assaying Radioactive Waste (Document-8000). Technical report, TRIUMF, Vancouver,2012.[34] M Kinakin. Radioactive Waste Management for the TRIUMF Site (Document-5330). Technicalreport, TRIMF, Vancouver, 2016.355Nuclide SDRL [TBq] Nuclide SDRL [TBq] Nuclide SDRL [TBq] Nuclide SDRL [TBq]H-3 2.00E+03 FE-55 3.01E-01 KR-75 5.10E+02 SN-113 1.44E-01BE-7 9.23E-01 FE-52 3.42E+00 KR-76 4.67E+02 SB-122 4.37E-01C-11 2.68E+02 FE-59 3.44E-02 KR-77 2.19E+02 SB-124 2.00E-02C-14 1.69E+02 CO-55 1.41E+00 KR-79 7.78E+02 SB-125 7.09E-03N-13 4.02E+02 CO-56 1.01E-02 KR-81 3.51E+04 TE-121 2.29E-01O-14 5.78E+02 CO-57 8.39E-02 KR-83M 6.89E+06 TE-121M 3.93E-02O-15 1.18E+03 CO-58 3.80E-02 KR-85 7.87E+04 TE-123M 6.11E-02F-17 1.73E+03 CO-60 7.16E-04 KR-85M 1.31E+03 TE-132 1.68E-01F-18 3.56E+01 CO-61 2.11E+02 KR-87 2.62E+02 I-120 3.04E+01NE-24 1.42E+03 NI-56 2.21E-01 KR-88 8.17E+01 I-120M 2.45E+01NA-22 1.57E-03 NI-57 7.69E-01 KR-89 4.54E+02 I-121 1.34E+02NA-24 1.22E+00 CU-64 1.63E+01 RB-81 2.35E+01 I-122 6.38E+02MG-28 8.76E-01 CU-67 2.07E-01 RB-82M 4.05E+00 I-123 2.47E+01Al-26 3.47E-05 ZN-65 1.57E-02 RB-83 4.29E-02 I-124 9.14E-02SI-31 1.29E+02 GA-67 2.61E+00 RB-84 4.52E-02 I-125 3.72E-02P-32 8.70E-02 GA-68 5.50E+01 RB-86 6.78E-02 I-126 2.08E-02P-33 6.74E-01 GE-68 9.29E-02 RB-88 2.43E+02 I-128 1.02E+03S-35 9.71E-01 GE-75 4.71E+02 RB-89 1.01E+02 I-129 3.05E-03CL-34M 5.60E+01 AS-71 1.08E+00 SR-82 2.98E-02 I-130 2.51E+00CL-36 7.43E-03 AS-72 6.99E-01 SR-85 7.29E-02 I-131 3.41E-02CL-38 6.48E+01 AS-73 4.22E-01 SR-85M 2.67E+02 I-132 2.43E+01CL-39 4.79E+01 AS-74 1.01E-01 SR-89 5.28E-02 I-132M 1.05E+02AR-37 7.38E+07 AS-76 1.09E+00 Y-88 1.10E-02 I-133 9.31E-01AR-39 1.03E+06 SE-73 7.61E+00 ZR-88 7.88E-02 I-134 4.92E+01AR-41 1.59E+02 SE-73M 3.39E+02 ZR-89 4.93E-01 I-135 7.70E+00AR-42 1.18E+03 SE-75 3.31E-02 ZR-95 4.79E-02 XE-118 1.99E+03AR-43 3.44E+02 SE-79 2.37E-02 ZR-97 1.49E+00 XE-119 4.33E+02AR-44 1.24E+02 SE-81 2.83E+03 NB-95 8.84E-02 XE-120 1.86E+02K-43 2.68E+00 SE-81M 6.79E+02 NB-95M 1.08E+00 XE-121 1.26E+02K-44 6.83E+01 SE-83 6.38E+01 NB-97 7.59E+01 XE-122 1.73E+02CA-45 1.60E-01 SE-84 1.65E+03 MO-99 1.43E+00 XE-123 3.05E+02CA-47 2.63E-01 BR-74 3.19E+01 TC-96 2.20E-01 XE-125 3.29E+02SC-43 1.39E+01 BR-75 3.27E+01 TC-99M 8.19E+01 XE-127 7.50E+02SC-44 7.26E+00 BR-76 1.54E+00 RU-103 9.74E-02 XE-129M 8.85E+03SC-44M 3.90E-01 BR-77 3.37E+00 PD-100 8.87E-01 XE-131M 2.41E+04SC-46 1.65E-02 BR-80 1.50E+03 PD-103 9.94E-01 XE-133 6.01E+03SC-47 1.12E+00 BR-80M 8.85E+01 AG-105 1.10E-01 XE-133M 7.40E+03TI-44 1.76E-03 BR-82 6.97E-01 AG-108M 9.13E-05 XE-135 8.04E+02V-48 4.72E-02 BR-83 3.97E+02 AG-110M 4.40E-03 XE-135M 7.74E+02CR-51 2.14E+00 BR-84 6.41E+01 AG-111 2.77E-01 XE-137 3.82E+03MN-52 1.18E-01 BR-85 9.85E+03 CD-109 6.06E-02 XE-138 1.68E+02MN-54 1.19E-02 BR-87 8.18E+02 IN-111 1.57E+00 CS-127 2.68E+01MN-56 1.43E+01 KR-74 3.25E+02 IN-114M 2.93E-02 CS-129 6.96E+00single-event derived release limits used for off-site dose estimates 36a single-event derived release limits used for off-sitedose estimates356Nuclide SDRL [TBq] Nuclide SDRL [TBq]CS-130 4.28E+00 RN-207 3.25E+02CS-131 4.80E+00 RN-208 3.00E+01CS-132 4.90E-01 RN-209 5.80E+01CS-134 2.30E-03 RN-210 3.01E+02CS-137 1.79E-02 RN-211 1.44E+01CS-138 4.65E+01 RN-212 4.79E+01BA-128 6.44E-01 RN-220 3.06E+02BA-131 3.24E-01 RN-221 1.99E-03BA-137M 6.36E-04 RN-222 3.47E+00Eu-152 6.67E-04 RN-223 4.52E+01TA-182 1.77E-02 RA-223 1.73E-03Re-182 3.99E+00 RA-224 7.06E-03Re-182 3.40E-01 RA-225 1.33E-03Re-184 6.33E-02 RA-226 4.36E-04RE-184M 3.12E-02 RA-228 9.33E-05RE-186 4.15E-01 AC-225 8.85E-03AU-195 1.49E-01 AC-227 6.42E-05AU-198 6.69E-01 AC-228 8.77E-01AU-199 1.53E+00 TH-227 1.45E-02HG-197 3.24E+00 TH-228 8.70E-04HG-199M 6.72E+01 TH-232 3.63E-04HG-203 1.40E-01 U-234 3.82E-03TL-200 2.01E+00 U-235 5.13E-04TL-201 5.46E+00 U-238 4.26E-03TL-202 3.40E-01 NP-237 9.53E-04PB-203 2.65E+00 PU-238 6.63E-04PB-212 4.52E-01 PU-239 6.10E-04BI-203 2.31E+00 PU-240 6.08E-04BI-205 9.53E-02 PU-241 3.27E-02BI-207 2.12E-04 PU-242 6.34E-04BI-210 3.66E-01 AM-241 6.35E-04BI-212 3.69E+00PO-203 5.79E+01PO-204 1.00E+00PO-205 2.46E+01PO-206 3.12E-01PO-207 9.00E+00PO-208 1.18E-04PO-209 1.08E-04PO-210 9.05E-05PO-211 2.05E+05PO-212M 9.41E+10PO-218 1.34E+01RN-206 1.55E+02single-event derived release limits used for off-site dose estimates 37357Nuclide Z A Activity [Bq] +- [%] Nuclide Z A Activity [Bq] +- [%]U-233 92 233 3.99E+01 0.51 Po-210 84 210 7.72E+07 0.68U-232 92 232 1.40E+04 4.02 Po-209 84 209 2.66E+05 0.71U-230 92 230 1.33E+06 2.06 Po-208 84 208 7.81E+06 0.79Pa-233 91 233 3.78E+08 0.51 Po-207 84 207 3.97E+05 1.27Pa-232 91 232 4.15E+06 4.03 Po-206 84 206 4.35E+08 0.87Pa-231 91 231 2.47E+03 0.43 Bi-214 83 214 2.61E+05 36.93Pa-230 91 230 5.78E+07 2.06 Bi-213 83 213 4.33E+08 0.84Pa-229 91 229 7.67E+06 3.54 Bi-212 83 212 4.77E+08 0.9Pa-228 91 228 8.88E+05 4.53 Bi-211 83 211 2.32E+08 0.89Th-231 90 231 1.58E+08 0.44 Bi-210 83 210 3.48E+08 1.06Th-230 90 230 1.08E+03 0.46 Bi-208 83 208 3.08E+01 1.22Th-229 90 229 7.50E+03 0.58 Bi-207 83 207 6.98E+05 0.75Th-228 90 228 2.83E+07 0.57 Bi-206 83 206 3.18E+08 0.87Th-227 90 227 3.40E+08 0.79 Bi-205 83 205 1.48E+08 1.09Th-226 90 226 4.48E+07 0.98 Bi-204 83 204 1.09E+05 1.1Th-224 90 224 2.98E+02 4.53 Bi-203 83 203 6.43E+04 1.21Ac-228 89 228 1.72E+05 4.1 Pb-214 82 214 2.60E+05 36.92Ac-227 89 227 8.46E+05 0.87 Pb-212 82 212 4.71E+08 0.89Ac-226 89 226 5.14E+07 1 Pb-211 82 211 2.32E+08 0.89Ac-225 89 225 4.32E+08 0.84 Pb-210 82 210 1.55E+06 0.6Ac-224 89 224 1.89E+04 4.53 Pb-209 82 209 4.39E+08 0.84Ra-228 88 228 1.72E+05 4.1 Pb-207m 82 207 6.49E+05 0.75Ra-226 88 226 2.93E+03 1.45 Pb-203 82 203 8.30E+07 1.22Ra-225 88 225 3.96E+07 2.61 Pb-202 82 202 1.08E+02 1.48Ra-224 88 224 4.18E+08 0.89 Pb-201 82 201 3.01E+03 1.9Ra-223 88 223 2.32E+08 0.89 Pb-200 82 200 2.08E+06 2.22Ra-222 88 222 4.48E+07 0.98 Tl-210 81 210 5.23E+01 36.93Ra-221 88 221 4.32E+05 0.84 Tl-209 81 209 9.05E+06 0.84Ra-220 88 220 3.04E+02 4.53 Tl-208 81 208 1.71E+08 0.9Fr-223 87 223 1.17E+04 0.87 Tl-207 81 207 2.31E+08 0.89Fr-222 87 222 3.11E+03 1 Tl-206 81 206 4.53E+02 1.06Fr-221 87 221 4.32E+08 0.84 Tl-202 81 202 1.93E+05 35.39Fr-220 87 220 1.70E+03 4.53 Tl-201 81 201 5.63E+07 1.93Rn-222 86 222 2.59E+05 36.92 Tl-200 81 200 1.82E+07 2.22Rn-220 86 220 4.18E+08 0.89 Tl-199 81 199 1.04E+02 2.29Rn-219 86 219 2.32E+08 0.89 Hg-197 80 197 1.74E+07 3.38Rn-218 86 218 4.48E+07 0.98 Hg-197m 80 197 8.48E+03 37.22Rn-217 86 217 4.75E+05 0.84 Hg-195 80 195 1.40E+05 19.2Rn-216 86 216 3.04E+02 4.53 Hg-195m 80 195 1.94E+05 19.42Rn-211 86 211 8.75E+05 1.27 Hg-194 80 194 1.90E+03 4At-218 85 218 5.18E+01 36.92 Hg-193 80 193 7.22E+01 11.39At-217 85 217 4.32E+08 0.84 Hg-193m 80 193 6.90E+02 11.39At-216 85 216 1.69E+03 4.53 Au-196 79 196 1.61E+05 49.62At-215 85 215 5.33E+02 0.89 Au-196n 79 196 3.38E+00 49.62At-211 85 211 1.26E+06 1.27 Au-195 79 195 1.40E+06 4.21At-210 85 210 1.42E+03 1.24 Au-194 79 194 7.20E+04 39.26At-209 85 209 2.29E+00 0.95 Au-193 79 193 2.83E+05 4.52Po-218 84 218 2.59E+05 36.92 Pt-193 78 193 1.21E+04 4.47Po-216 84 216 4.18E+08 0.89 Pt-193m 78 193 3.83E+04 70.53Po-215 84 215 2.32E+08 0.89 Pt-191 78 191 6.15E+06 6.61Po-214 84 214 4.50E+07 0.99 Pt-189 78 189 1.35E+03 8.11Po-213 84 213 4.25E+08 0.84 Pt-188 78 188 4.77E+06 7.93Po-212 84 212 3.05E+08 0.9 Ir-190 77 190 6.50E+04 57.44Po-211 84 211 1.38E+06 0.77 Ir-189 77 189 4.42E+06 8.01radioactive inventory of thorium foil 7 days after eob 38b radioactive inventory of thorium foil 7 days after eob358Ir-188 77 188 5.36E+06 7.91 Gd-159 64 159 4.10E+04 12.28Ir-187 77 187 7.81E+02 10.17 Gd-153 64 153 1.70E+05 11.38Ir-186 77 186 3.54E+04 10.43 Gd-151 64 151 2.00E+05 16.18Ir-185 77 185 9.40E+03 11.88 Gd-149 64 149 7.68E+05 23.08Os-185 76 185 4.51E+05 11.87 Gd-148 64 148 3.50E+02 24.03Os-183 76 183 2.57E+03 14.41 Gd-147 64 147 1.06E+05 32.45Os-183m 76 183 1.29E+01 34.73 Gd-146 64 146 4.39E+04 49.62Os-182 76 182 8.67E+04 14.11 Eu-157 63 157 3.04E+04 7.53Re-183 75 183 3.93E+05 14.15 Eu-156 63 156 7.88E+06 5.27Re-182 75 182 2.13E+06 14 Eu-155 63 155 1.40E+05 4.77Re-181 75 181 4.54E+04 16.25 Eu-154 63 154 7.95E+03 14.94W-181 74 181 1.99E+05 16.3 Eu-152 63 152 3.05E+03 16W-178 74 178 3.62E+05 24.7 Eu-152m 63 152 1.86E+01 16Ta-179 73 179 1.81E+04 21.24 Eu-150 63 150 8.42E+02 15.83Ta-178 73 178 3.63E+05 24.7 Eu-150m 63 150 8.23E+02 15.83Ta-177 73 177 3.78E+05 24.89 Eu-149 63 149 3.55E+05 13.28Ta-176 73 176 5.54E+00 23.42 Eu-148 63 148 3.55E+05 17.06Ta-175 73 175 9.05E+01 27.76 Eu-147 63 147 7.91E+05 15.84Hf-175 72 175 1.26E+05 25.62 Eu-146 63 146 9.26E+05 20.93Hf-173 72 173 2.88E+04 32.17 Eu-145 63 145 5.99E+05 26.33Hf-172 72 172 1.38E+04 25.62 Sm-156 62 156 4.09E+02 5.79Hf-171 72 171 1.89E+02 37.23 Sm-153 62 153 1.29E+07 3.78Hf-170 72 170 1.31E+03 44.27 Sm-151 62 151 2.48E+04 2.85Lu-173 71 173 1.42E+04 30.3 Sm-145 62 145 9.86E+04 13.02Lu-172 71 172 2.02E+05 42.53 Pm-151 61 151 6.36E+06 2.98Lu-171 71 171 4.96E+05 26.9 Pm-149 61 149 4.68E+07 2.37Lu-170 71 170 2.93E+05 27.47 Pm-148 61 148 3.06E+06 7.7Lu-169 71 169 9.65E+04 29.38 Pm-148m 61 148 9.64E+05 7.7Yb-169 70 169 2.53E+05 25.58 Pm-147 61 147 8.59E+05 1.75Yb-166 70 166 3.18E+05 26.89 Pm-146 61 146 4.20E+04 7.83Tm-170 69 170 1.33E+04 57.44 Pm-145 61 145 1.33E+04 7.97Tm-168 69 168 3.01E+04 44.27 Pm-144 61 144 1.82E+05 9.27Tm-167 69 167 6.37E+05 22.54 Pm-143 61 143 3.14E+05 8.61Tm-166 69 166 3.68E+05 26.89 Nd-147 60 147 1.01E+08 1.69Tm-165 69 165 9.00E+04 24.9 Nd-140 60 140 5.25E+06 8.54Er-165 68 165 1.37E+05 24.89 Pr-145 59 145 6.26E+00 1.45Er-160 68 160 7.03E+04 27.75 Pr-144 59 144 9.06E+06 1.44Ho-166m 67 166 1.36E+00 70.53 Pr-144m 59 144 1.36E+05 1.44Ho-163 67 163 1.18E+01 18.11 Pr-143 59 143 1.75E+08 1.21Ho-160 67 160 7.14E+04 27.75 Pr-142 59 142 2.89E+05 5.46Dy-159 66 159 1.39E+05 17.39 Pr-140 59 140 5.25E+06 8.54Dy-157 66 157 8.61E+00 17.6 Ce-144 58 144 9.06E+06 1.44Dy-155 66 155 7.18E+01 21.53 Ce-143 58 143 4.07E+07 1.28Tb-161 65 161 1.28E+06 16.52 Ce-141 58 141 9.94E+07 1.22Tb-160 65 160 9.14E+04 28.06 Ce-139 58 139 3.52E+06 3.69Tb-158 65 158 2.17E+02 20.08 Ce-137 58 137 2.03E+06 5.15Tb-157 65 157 9.38E+02 13.01 Ce-137m 58 137 1.51E+06 5.15Tb-156 65 156 1.01E+06 18.97 Ce-135 58 135 9.73E+04 7.15Tb-156m 65 156 2.52E+04 18.97 Ce-134 58 134 4.43E+06 9.03Tb-155 65 155 2.14E+06 13.24 La-140 57 140 1.84E+08 1.23Tb-154 65 154 1.36E+04 26.35 La-137 57 137 3.71E+01 2.54Tb-154m 65 154 1.04E+01 26.35 La-135 57 135 1.45E+06 4.65Tb-154n 65 154 1.17E+04 26.35 La-134 57 134 4.44E+06 9.03Tb-153 65 153 9.69E+05 15.67 Ba-140 56 140 1.51E+08 1.35Tb-152 65 152 1.03E+04 20.34 Ba-137m 56 137 3.05E+05 1.17Tb-151 65 151 9.38E+03 21.55 Ba-136m 56 136 7.80E+06 1.84radioactive inventory of thorium foil 7 days after eob 39359Ba-135m 56 135 2.92E+06 2.75 Sb-118 51 118 6.98E+06 7.48Ba-133 56 133 1.67E+05 3.27 Sn-126 50 126 4.33E+01 1.97Ba-133m 56 133 4.57E+06 3.93 Sn-125 50 125 6.32E+07 1.59Ba-131 56 131 1.70E+07 4.2 Sn-123 50 123 1.01E+07 1.48Ba-128 56 128 2.08E+06 10.82 Sn-121 50 121 4.93E+07 0.83Cs-137 55 137 3.22E+05 1.17 Sn-121m 50 121 1.01E+05 1.11Cs-136 55 136 6.97E+07 1.84 Sn-119m 50 119 4.86E+06 1.27Cs-135 55 135 5.77E+00 1.07 Sn-117m 50 117 4.23E+07 1.8Cs-134 55 134 1.47E+06 2.23 Sn-113 50 113 9.37E+05 7.14Cs-132 55 132 5.41E+07 2.84 In-115m 49 115 5.18E+08 0.58Cs-131 55 131 5.44E+07 2.5 In-114 49 114 8.90E+06 1.88Cs-129 55 129 7.41E+06 3.24 In-114m 49 114 9.31E+06 1.88Cs-128 55 128 2.08E+06 10.82 In-113m 49 113 9.37E+05 7.14Cs-127 55 127 1.21E+00 5.43 In-111 49 111 1.16E+07 5.05Xe-135 54 135 1.28E+04 1.54 Cd-115 48 115 4.74E+08 0.58Xe-135m 54 135 2.84E+00 2.08 Cd-115m 48 115 5.37E+07 0.92Xe-133 54 133 3.24E+08 1.14 Cd-113m 48 113 3.56E+05 1.18Xe-133m 54 133 3.38E+07 1.72 Cd-111m 48 111 5.88E+06 5.05Xe-131m 54 131 3.31E+07 2 Cd-109 48 109 7.97E+05 3.95Xe-129m 54 129 2.90E+07 2.76 Ag-113 47 113 3.95E+00 0.64Xe-127 54 127 1.94E+07 2.82 Ag-112 47 112 3.55E+07 0.64Xe-125 54 125 1.85E+05 4.11 Ag-111 47 111 1.26E+09 0.58Xe-122 54 122 5.29E+04 14.39 Ag-111m 47 111 1.33E+00 0.98I-135 53 135 1.76E+01 2.08 Ag-110 47 110 7.71E+04 1.49I-133 53 133 5.44E+06 1.46 Ag-110m 47 110 5.67E+06 1.49I-132 53 132 7.37E+07 2.17 Ag-109m 47 109 3.39E+06 1.01I-131 53 131 2.35E+08 1.17 Ag-108 47 108 3.07E+02 2.14I-130 53 130 8.30E+04 1.86 Ag-108m 47 108 3.53E+03 2.14I-126 53 126 6.09E+07 2.05 Ag-106m 47 106 5.76E+06 5.54I-125 53 125 2.21E+07 1.92 Ag-105 47 105 1.84E+06 8.83I-124 53 124 4.11E+07 3.44 Pd-112 46 112 3.02E+07 0.64I-123 53 123 6.13E+04 3.33 Pd-111 46 111 1.07E+00 0.98I-122 53 122 5.31E+04 14.39 Pd-111m 46 111 1.36E+00 0.98Te-132 52 132 7.15E+07 2.17 Pd-109 46 109 2.59E+06 0.51Te-131 52 131 1.28E+06 2.15 Pd-107 46 107 9.06E+00 0.56Te-131m 52 131 5.70E+06 2.15 Pd-103 46 103 6.22E+06 6.51Te-129 52 129 1.48E+07 1.74 Pd-101 46 101 8.10E+00 23.88Te-129m 52 129 2.32E+07 1.74 Pd-100 46 100 1.43E+05 49.62Te-127 52 127 1.75E+08 1.34 Rh-106 45 106 4.12E+07 0.62Te-127m 52 127 1.17E+07 1.38 Rh-105 45 105 3.68E+08 0.58Te-125m 52 125 1.55E+07 1.72 Rh-103m 45 103 4.06E+08 0.61Te-123m 52 123 5.56E+06 2.11 Rh-102 45 102 1.23E+06 3.23Te-121 52 121 1.97E+07 2.97 Rh-102m 45 102 2.45E+05 3.23Te-121m 52 121 2.00E+06 3.1 Rh-101 45 101 1.22E+05 5.3Te-119 52 119 5.22E+04 5.28 Rh-101m 45 101 8.42E+06 5.47Te-119m 52 119 6.87E+06 5.54 Rh-100 45 100 3.11E+05 29.77Te-118 52 118 6.98E+06 7.48 Rh-99 45 99 4.59E+05 18.31Sb-128 51 128 1.12E+03 2.07 Ru-106 44 106 4.12E+07 0.62Sb-127 51 127 1.78E+08 1.4 Ru-103 44 103 4.00E+08 0.62Sb-126 51 126 4.58E+07 1.68 Ru-97 44 97 1.35E+06 15.17Sb-126m 51 126 4.33E+01 1.97 Tc-99 43 99 1.71E+02 0.62Sb-125 51 125 4.73E+06 1.06 Tc-99m 43 99 5.99E+08 0.71Sb-124 51 124 3.30E+07 1.61 Tc-97m 43 97 2.98E+06 3.44Sb-122 51 122 1.15E+08 1.56 Tc-96 43 96 1.13E+07 5.85Sb-120m 51 120 5.00E+07 2.21 Tc-95 43 95 7.97E+04 9.54Sb-119 51 119 3.95E+07 2.18 Tc-95m 43 95 5.08E+05 9.51radioactive inventory of thorium foil 7 days after eob 40360Mo-99 42 99 6.22E+08 0.71 Ge-69 32 69 2.50E+05 21.27Mo-93 42 93 7.66E+01 7.9 Ge-68 32 68 4.30E+03 70.53Mo-93m 42 93 1.62E+00 7.98 Ga-72 31 72 3.18E+07 2.88Nb-97 41 97 4.34E+06 0.93 Ga-68 31 68 4.31E+03 70.53Nb-97m 41 97 3.82E+06 0.93 Ga-67 31 67 5.71E+05 23.26Nb-96 41 96 1.41E+07 1.07 Ga-66 31 66 1.62E+01 34.91Nb-95 41 95 8.82E+07 1.05 Zn-72 30 72 2.21E+07 2.88Nb-95m 41 95 9.36E+07 1.33 Zn-69 30 69 1.38E+04 5.31Nb-94 41 94 2.20E+02 2 Zn-69m 30 69 1.29E+04 5.31Nb-93m 41 93 8.62E+04 2.4 Zn-65 30 65 4.76E+04 21.27Nb-92m 41 92 1.14E+07 3.97 Cu-67 29 67 1.71E+07 3.95Nb-91 41 91 4.15E+02 5.27 Cu-66 29 66 8.20E+06 5.46Nb-91m 41 91 1.40E+06 5.27 Cu-64 29 64 3.57E+03 10.49Nb-90 41 90 5.56E+03 14.16 Ni-66 28 66 8.19E+06 5.46Zr-97 40 97 4.03E+06 0.93 Ni-63 28 63 5.58E+03 5.7Zr-95 40 95 1.39E+08 0.83 Co-60 27 60 2.16E+04 12.28Zr-93 40 93 1.98E+01 0.75 Co-58 27 58 1.79E+05 21.51Zr-89 40 89 9.65E+06 5.91 Co-58m 27 58 1.43E+01 21.51Zr-88 40 88 5.81E+05 11 Co-57 27 57 1.50E+04 37.22Zr-86 40 86 2.24E+03 37.22 Fe-59 26 59 1.79E+06 8.71Y-93 39 93 6.21E+04 0.83 Fe-55 26 55 4.16E+03 42.38Y-91 39 91 1.54E+08 0.74 Mn-54 25 54 3.74E+04 22.42Y-91m 39 91 1.47E+04 0.9 Mn-52 25 52 4.03E+04 70.53Y-90 39 90 9.41E+07 1.75 Cr-51 24 51 1.23E+05 37.22Y-89m 39 89 9.65E+06 5.9 V-49 23 49 2.94E+04 24.71Y-88 39 88 4.87E+06 3.39 V-48 23 48 1.58E+05 40.31Y-87 39 87 1.47E+07 4.87 Sc-48 21 48 3.18E+05 21.27Y-87m 39 87 1.26E+04 4.92 Sc-47 21 47 1.60E+06 16.9Y-86 39 86 2.70E+04 18.52 Sc-46 21 46 2.66E+04 49.62Sr-91 38 91 2.68E+04 0.9 Sc-44 21 44 6.75E+04 44.25Sr-90 38 90 7.90E+05 0.87 Sc-44m 21 44 6.37E+04 44.27Sr-89 38 89 1.54E+08 0.86 Ca-47 20 47 6.60E+05 23.24Sr-85 38 85 3.10E+06 5.32 Ca-45 20 45 6.67E+04 27.52Sr-83 38 83 2.80E+05 16.74 K-43 19 43 2.88E+04 24.04Sr-82 38 82 1.12E+05 40.31 K-42 19 42 8.69E+02 21.83Rb-86 37 86 7.52E+07 1.78 Ar-42 18 42 5.45E+02 29.38Rb-84 37 84 1.43E+07 3.16 Ar-39 18 39 9.69E+01 28.52Rb-83 37 83 3.24E+06 4.22 Ar-37 18 37 2.17E+05 28.26Rb-82 37 82 1.12E+05 40.31 S-35 16 35 1.28E+05 22.42Kr-85 36 85 5.72E+05 1.05 P-33 15 33 2.61E+05 27.82Kr-81 36 81 3.58E+00 4.17 P-32 15 32 1.70E+05 40.3Kr-79 36 79 5.12E+05 12.23 Si-32 14 32 4.90E+01 42.9Br-82 35 82 2.08E+07 2.23 Al-28 13 28 5.22E+03 49.62Br-77 35 77 1.90E+06 11 Mg-28 12 28 5.21E+03 49.62Br-76 35 76 3.38E+03 28.06 Na-24 11 24 2.65E+04 7.45Se-79 34 79 1.52E+01 1.32 Na-22 11 22 2.49E+03 49.62Se-77m 34 77 1.33E+05 1.51 C-14 6 14 9.56E+01 5.3Se-75 34 75 4.55E+05 10.23 Be-7 4 7 1.10E+06 9.8As-77 33 77 6.22E+07 1.51 H-3 1 3 6.40E+06 0.41As-76 33 76 2.67E+06 3.71As-74 33 74 5.96E+06 6.39As-73 33 73 7.47E+05 9.98As-72 33 72 8.79E+04 19.59As-71 33 71 3.45E+05 28.06Ge-77 32 77 1.65E+04 2.05Ge-71 32 71 4.95E+06 8.06radioactive inventory of thorium foil 7 days after eob 41361NuclideOn-Site External Dose [mSv]On-Site Internal Dose [mSv]Off-Site Dose - No Filtration [mSv]Off-Site Dose - With HC1 Stack Filtration [mSv]Off-Site Dose - With Additional Filtration in HC [mSv]H 3.13E-11 9.38E-07 2.97E-09 2.97E-09 2.97E-09Cl 2.31E-17 5.46E-13 8.75E-12 4.37E-14 2.19E-16Ar 7.38E-14 0.00E+00 4.36E-13 4.36E-13 4.36E-13Se 1.40E-58 3.43E-57 5.93E-60 2.97E-62 1.48E-64Br 5.36E-05 2.32E-04 3.75E-05 1.88E-07 9.38E-10Kr 9.92E-08 0.00E+00 6.61E-10 6.61E-10 6.61E-10I 2.77E-04 7.00E-02 1.12E-02 5.62E-05 2.81E-07Xe 1.40E-05 0.00E+00 9.46E-08 9.46E-08 9.46E-08Rn 2.06E-06 5.78E-02 1.52E-06 1.52E-06 1.52E-06Po 4.32E-04 1.67E+00 9.12E-01 4.56E-03 2.28E-050.001 1.803On-Site Exposure ParametersElements filteredFilter efficiency (99.5% HC stack and 99.5% filtration in HCExposure Time for External and Internal On-Site Dose [s]Radius of Cloud for External On-Site Dose [m]Radius of Cloud for Internal On-Site Dose [m]Inhalation Rate [L/min]Po, Cl, Se, Br, I 0.999975 1800 30 15 12Nuclide A Z Activity (Bq)DCFA (Sv/Bq s/m3)External Dose from Airbourne Cloud (mSv)DCFI_a (Sv/Bq)Inhalation Dose (mSv)SDRL (Bq/mSv)Maximum Offsite Dose - Unfiltered (mSv)Maximum Offsite Dose - Filtered (mSv)Gaseous and Volatile Alpha IsotopesRn-223 223 86 0.00E+00 6.09E-15 0.00E+00 1.20E-07 0.00E+00 4.52E+13 0.00E+00 0.00E+00Rn-222 222 86 2.42E+05 1.91E-17 7.36E-11 7.09E-06 4.37E-02 3.47E+12 6.97E-08 6.97E-08Rn-221 221 86 0.00E+00 5.55E-15 0.00E+00 3.64E-07 0.00E+00 1.99E+09 0.00E+00 0.00E+00Rn-220 220 86 4.18E+08 1.85E-17 1.23E-07 9.20E-10 9.80E-03 3.06E+14 1.37E-06 1.37E-06Rn-212 212 86 0.00E+00 0.00E+00 0.00E+00 6.71E-09 0.00E+00 4.79E+13 0.00E+00 0.00E+00Rn-211 211 86 1.29E+06 9.44E-14 1.94E-06 1.31E-07 4.30E-03 1.44E+13 8.94E-08 8.94E-08Rn-210 210 86 6.27E-12 2.79E-15 2.78E-25 3.67E-08 5.86E-21 3.01E+14 2.08E-26 2.08E-26Rn-209 209 86 0.00E+00 4.76E-14 0.00E+00 1.71E-09 0.00E+00 5.80E+13 0.00E+00 0.00E+00Rn-208 208 86 0.00E+00 1.10E-14 0.00E+00 4.89E-09 0.00E+00 3.00E+13 0.00E+00 0.00E+00Rn-207 207 86 0.00E+00 3.96E-14 0.00E+00 2.30E-09 0.00E+00 3.25E+14 0.00E+00 0.00E+00Rn-206 206 86 0.00E+00 6.57E-14 0.00E+00 2.10E-09 0.00E+00 1.55E+14 0.00E+00 0.00E+00Total Rn Dose: 2.06E-06 Total Rn Dose: 5.78E-02 Total Rn Dose: 1.52E-06 1.52E-06Po-218 218 84 2.42E+05 4.48E-19 1.73E-12 8.40E-09 5.18E-05 1.34E+13 1.81E-08 4.52E-13Po-212 212 84 3.36E+08 0.00E+00 0.00E+00 5.20E-18 4.45E-11Po-211 211 84 1.71E+06 3.81E-16 1.03E-08 7.60E-12 3.30E-07 2.05E+17 8.34E-12 2.08E-16Po-210 210 84 7.62E+07 4.16E-19 5.05E-10 6.10E-07 1.18E+00 9.05E+07 8.42E-01 2.11E-05Po-209 209 84 2.64E+05 2.20E-16 9.24E-10 2.40E-06 1.61E-02 1.08E+08 2.45E-03 6.11E-08Po-208 208 84 7.75E+06 0.00E+00 0.00E+00 2.40E-06 4.74E-01 1.18E+08 6.59E-02 1.65E-06Po-207 207 84 5.85E+05 6.50E-14 6.06E-07 5.80E-11 8.65E-07 9.00E+12 6.50E-08 1.63E-12Po-206 206 84 4.54E+08 5.97E-14 4.32E-04 1.10E-11 1.27E-04 3.12E+11 1.46E-03 3.64E-08Po-205 205 84 2.02E-21 7.80E-14 2.51E-33 3.30E-11 1.70E-33 2.46E+13 8.23E-35 2.06E-39Po-204 204 84 2.52E-05 5.68E-14 2.28E-17 2.70E-08 1.74E-14 1.00E+12 2.52E-17 6.30E-22Total Po Dose: 4.32E-04 Total Po Dose: 1.67E+00 Total Po Dose: 9.12E-01 2.28E-05Gaseous and Volatile Non-Alpha IsotopesH-3 3 1 5.94E+06 3.31E-19 3.13E-11 6.2E-12 9.38E-07 2.00E+15 2.97E-09 2.97E-09Summary0.00462Filtration ParametersTotal [mSv]0.921.8040.00002airborne dose calculations 42c airborne dose calculations362Total H Dose: 3.13E-11 Total H Dose: 9.38E-07 Total H Dose: 2.97E-09 2.97E-09Cl-36 36 17 6.50E-02 2.23E-17 2.31E-17 3.3E-10 5.46E-13 7.43E+09 8.75E-12 2.19E-16Cl-38 38 17 1.53E-11 7.87E-14 1.92E-23 2.5E-11 9.77E-24 6.48E+13 2.37E-25 5.92E-30Cl-39 39 17 0.00E+00 7.29E-14 0.00E+00 2.5E-11 0.00E+00 4.79E+13 0.00E+00 0.00E+00Total Cl Dose: 2.31E-17 Total Cl Dose: 5.46E-13 Total Cl Dose: 8.75E-12 2.19E-16Ar-41 41 18 1.83E-21 6.5E-14 1.89E-33 0 0.00E+00 1.59E+14 1.15E-35 1.15E-35Ar-42 42 18 5.15E+02 9E-18 7.38E-14 0 0.00E+00 1.18E+15 4.36E-13 4.36E-13Ar-43 43 18 0.00E+00 7.69E-14 0.00E+00 0 0.00E+00 3.44E+14 0.00E+00 0.00E+00Ar-44 44 18 0.00E+00 9.82E-14 0.00E+00 0 0.00E+00 1.24E+14 0.00E+00 0.00E+00Total Ar Dose: 7.38E-14 Total Ar Dose: 0.00E+00 Total Ar Dose: 4.36E-13 4.36E-13Se-73m 73 34 0.00E+00 1.17E-14 0.00E+00 9.2E-12 0.00E+00 3.39E+14 0.00E+00 0.00E+00Se-81 81 34 1.68E-44 5.24E-16 1.40E-58 8E-12 3.43E-57 2.83E+15 5.93E-60 1.48E-64Se-81m 81 34 0.00E+00 6.18E-16 0.00E+00 1.6E-11 0.00E+00 6.79E+14 0.00E+00 0.00E+00Se-83 83 34 0.00E+00 1.21E-13 0.00E+00 1.8E-11 0.00E+00 6.38E+13 0.00E+00 0.00E+00Se-84 84 34 0.00E+00 2.07E-14 0.00E+00 1.6E-11 0.00E+00 1.65E+15 0.00E+00 0.00E+00Total Se Dose: 1.40E-58 Total Se Dose: 3.43E-57 Total Se Dose: 5.93E-60 1.48E-64Br-75 75 35 3.58E-26 5.84E-14 3.33E-38 2.9E-11 2.65E-38 3.27E+13 1.10E-39 2.74E-44Br-76 76 35 4.98E+03 1.34E-13 1.06E-08 2.4E-10 3.04E-08 1.54E+12 3.22E-09 8.06E-14Br-77 77 35 2.71E+06 1.51E-14 6.51E-07 6.2E-11 4.28E-06 3.37E+12 8.03E-07 2.01E-11Br-80 80 35 1.44E-03 3.85E-15 8.84E-17 5.9E-12 2.17E-16 1.50E+15 9.64E-19 2.41E-23Br-80m 80 35 1.35E-03 3.11E-16 6.67E-18 3.3E-11 1.13E-15 8.85E+13 1.52E-17 3.80E-22Br-82 82 35 2.56E+07 1.3E-13 5.30E-05 3.5E-10 2.28E-04 6.97E+11 3.67E-05 9.17E-10Br-83 83 35 7.12E-12 3.82E-16 4.33E-26 1.6E-11 2.90E-24 3.97E+14 1.80E-26 4.49E-31Br-84 84 35 0.00E+00 9.41E-14 0.00E+00 2.2E-11 0.00E+00 6.41E+13 0.00E+00 0.00E+00Br-85 85 35 0.00E+00 2.74E-15 0.00E+00 2.9E-12 0.00E+00 9.85E+15 0.00E+00 0.00E+00Br-87 87 35 0.00E+00 1.57E-13 0.00E+00 1.5E-13 0.00E+00 8.18E+14 0.00E+00 0.00E+00Total Br Dose: 5.36E-05 Total Br Dose: 2.32E-04 Total Br Dose: 3.75E-05 9.38E-10Kr-77 77 36 2.82E-35 4.86E-14 2.18E-47 0 0.00E+00 2.19E+14 1.29E-49 1.29E-49Kr-79 79 36 5.15E+05 1.21E-14 9.92E-08 0 0.00E+00 7.78E+14 6.61E-10 6.61E-10Kr-81 81 36 3.59E+00 2.67E-16 1.53E-14 0 0.00E+00 3.51E+16 1.02E-16 1.02E-16Kr-83m 83 36 3.00E-11 1.5E-18 7.16E-28 0 0.00E+00 6.89E+18 4.35E-30 4.35E-30Kr-87 87 36 1.23E-30 4.12E-14 8.06E-43 0 0.00E+00 2.62E+14 4.70E-45 4.70E-45Kr-88 88 36 1.00E-08 1.02E-13 1.63E-20 0 0.00E+00 8.17E+13 1.23E-22 1.23E-22Kr-89 89 36 0.00E+00 8.1E-14 0.00E+00 0 0.00E+00 4.54E+14 0.00E+00 0.00E+00Total Kr Dose: 9.92E-08 Total Kr Dose: 0.00E+00 Total Kr Dose: 6.61E-10 6.61E-10I-120 120 53 8.87E-31 1.38E-13 1.95E-42 1E-10 2.26E-42 3.04E+13 2.92E-44 7.30E-49I-121 121 53 2.99E-16 1.94E-14 9.23E-29 2.7E-11 2.06E-28 1.34E+14 2.22E-30 5.55E-35I-122 122 53 6.79E+04 4.56E-14 4.93E-08 0 0.00E+00 6.38E+14 1.06E-10 2.66E-15I-123 123 53 9.38E+04 7.28E-15 1.09E-08 7.4E-11 1.77E-07 2.47E+13 3.79E-09 9.48E-14I-124 124 53 4.61E+07 5.38E-14 3.95E-05 4.4E-09 5.17E-03 9.14E+10 5.04E-04 1.26E-08I-125 125 53 2.24E+07 5.22E-16 1.86E-07 5.1E-09 2.91E-03 3.72E+10 6.02E-04 1.50E-08I-126 126 53 6.08E+07 2.15E-14 2.08E-05 9.8E-09 1.52E-02 2.08E+10 2.93E-03 7.32E-08I-128 128 53 0.00E+00 4.16E-15 0.00E+00 1.3E-11 0.00E+00 1.02E+15 0.00E+00 0.00E+00I-129 129 53 7.22E-01 3.8E-16 4.37E-15 0.000000036 6.62E-10 3.05E+09 2.36E-10 5.91E-15I-130 130 53 1.32E+05 1.04E-13 2.19E-07 6.7E-10 2.26E-06 2.51E+12 5.27E-08 1.32E-12I-131 131 53 2.45E+08 1.82E-14 7.11E-05 7.4E-09 4.63E-02 3.41E+10 7.20E-03 1.80E-07I-132 132 53 7.95E+07 1.12E-13 1.42E-04 9.4E-11 1.90E-04 2.43E+13 3.28E-06 8.19E-11I-132m 132 53 4.09E-28 1.53E-14 9.97E-41 7.9E-11 8.24E-40 1.05E+14 3.89E-42 9.73E-47I-133 133 53 7.54E+06 2.94E-14 3.53E-06 1.5E-09 2.88E-04 9.31E+11 8.10E-06 2.03E-10I-134 134 53 0.00E+00 1.3E-13 0.00E+00 4.5E-11 0.00E+00 4.92E+13 0.00E+00 0.00E+00I-135 135 53 3.27E+01 7.98E-14 4.15E-11 3.2E-10 2.66E-10 7.70E+12 4.24E-12 1.06E-16Total I Dose: 2.77E-04 Total I Dose: 7.00E-02 Total I Dose: 1.12E-02 2.81E-07Xe-120 120 54 0.00E+00 1.94E-14 0.00E+00 0 0.00E+00 1.86E+14 0.00E+00 0.00E+00Xe-121 121 54 0.00E+00 9.14E-14 0.00E+00 0 0.00E+00 1.26E+14 0.00E+00 0.00E+00Xe-122 122 54 6.77E+04 2.46E-15 2.65E-09 0 0.00E+00 1.73E+14 3.92E-10 3.92E-10Xe-123 123 54 3.97E-17 3.03E-14 1.91E-29 0 0.00E+00 3.05E+14 1.30E-31 1.30E-31Xe-125 125 54 2.64E+05 1.19E-14 5.01E-08 0 0.00E+00 3.29E+14 8.03E-10 8.03E-10Xe-127 127 54 1.93E+07 1.25E-14 3.84E-06 0 0.00E+00 7.50E+14 2.57E-08 2.57E-08Xe-129m 129 54 3.04E+07 1.06E-15 5.14E-07 0 0.00E+00 8.85E+15 3.44E-09 3.44E-09Xe-131m 131 54 3.36E+07 3.89E-16 2.08E-07 0 0.00E+00 2.41E+16 1.39E-09 1.39E-09Xe-133 133 54 3.46E+08 1.56E-15 8.59E-06 0 0.00E+00 6.01E+15 5.75E-08 5.75E-08Xe-133m 133 54 3.95E+07 1.27E-15 7.99E-07 0 0.00E+00 7.40E+15 5.33E-09 5.33E-09Xe-135 135 54 2.20E+04 1.19E-14 4.16E-09 0 0.00E+00 8.04E+14 2.73E-11 2.73E-11Xe-137 137 54 0.00E+00 9.46E-15 0.00E+00 0 0.00E+00 3.82E+15 0.00E+00 0.00E+00Xe-138 138 54 0.00E+00 5.77E-14 0.00E+00 0 0.00E+00 1.68E+14 0.00E+00 0.00E+00Total Xe Dose: 1.40E-05 Total Xe Dose: 0.00E+00 Total Xe Dose: 9.46E-08 9.46E-08airborne dose calculations 43363S0 250 mL bottle,filled 175 mL 10 M HNO3 +12.5 mM HF P1S-speedP1L1/8 ETFEJ1S7 100 mL bottle,filled 80 mL 1 M HNO3S7L 1/8 CFlexS1 500 mL bottle,filled 450 mL 1 M citric acid(pH 2.0-2.2)stockJ1L1/8 ETFEJ2T0LVT0L1/8 CFlexS0LVS7LVS1L1/8 CFlexS1LVS2 50 mL bottle,filled 50 mL 0.5 M HNO3stock, tracemetal gradeS3 100 mL bottle,filled 65 mL8M HNO3stock, trace metalgradeS3LVS3L1/8 CFlexS2LVS2L1/8 CFlex J2L1/8 ETFEP2S-speedC1P2L1/8 ETFEJ3C1-L1/8 ETFEW1 500 mL bottle C1 loadW2 500 mL bottle C1 wash 1J3L1VJ3L11/8 CFlexJ3L2VJ3L21/8 CFlex W3 100 mL bottle C1 wash 2J3L3VJ3L31/8 CFlex W1SL1/16 ETFEW2SL1/16 ETFEW3SL1/16 ETFET1 250 mL bottle,pre-filled with60 mL H2O C1 eluateT1SL1/16 ETFEJ3L41/8 CFlexJ3T1LVT1L1/8 CFlexS4 50 mL bottle,filled 5 mL4M HNO3 stock, trace metalgradeS4L1/8 CFlexS4LVS5 50 mL bottle,filled 13 mL12 M HNO3 stock, trace metalgradeS5LVS5L1/8 CFlex S6 50 mL bottle,filled 10 mL 0.05 M HNO3 stockS6L1/8 CFlex S6LVP3S-speedJ3L1/8 ETFEC3P3L1/8 ETFEJ5C3-L1/8 ETFEY1 (Ra-225) 250 mL bottle C3 loadY2 (Ac-225) 50 mL bottle C3 elute 1J5L1VJ5L11/8 CFlex J5L3VJ5L31/8 CFlex W4 50 mL bottle C3 washJ5L2V J5L21/8 CFlex W5 50 mL bottle C3 elute 2J5L4VJ5L41/8 CFlex Y2SL1/16 ETFEY1SL1/16 ETFEW4SL1/16 ETFEW5SL1/16 ETFESP2 C2C2L1/8 CFlexJ3L4VS9 250 mL bottle,filled 250 mL mQ H2OS9LVS8 100 mL bottle,filled 56 mL 30% H2O2S8LVS8L1/8 CFlexS9L 1/8 CFlex S0L1/8 CFlex D1 500 mL beaker dissolution andprecipitationHP1 HOT/STIRPLATE P0M-speedF1 filterP4M-speedT0 500 mL bottleSP1 T0SL1/16 ETFED1SL1/16 ETFEF1L1/8 ETFEP0L1/8 ETFED1L1/8 ETFEP4L1/8 ETFECHEMISTRY MODULE DISSOLUTION AND PRECIPITATION MODULE C3200-205 mg DGA-normal (TODGA)resin in 4 mL UCTreservoirpreconditioned with10 mL mQ water and10 mL 4 M nitric acidreservoir filled withexcess 4 M nitric acidC110 mL DOWEX 50WX8(200-400 mesh)) resinin yellow BioRadreservoirpreconditioned with 60mL mQ water and 60mL 0.5 M nitric acidreservoir filled withexcess 0.5 M nitric acid C22 mL DOWEX 1X8(200-400 mesh))resin in 4 mL UCTreservoirpreconditioned with15 mL mQ water and15 mL 8 M nitric acidreservoir filled withexcess 8 M nitric acidsemi-automated chemistry system flowchart 44d semi-automated chemistry system flowchart364contents of the solution containing isolated radium isotopes 24.5 days after eob 45e contents of the solution containing isolated radium iso-topes 24.5 days after eobTable 7: Anticipated radioactive contents of the isolated solution of Ra isotopes at EOB + 1 week. This list includesBa isotopes that are expected to follow Ra through the initial purification, as well as all Ra decay chainsin equilibrium.Nuclide Activity [Bq] Dose Rate at 1 m (unshielded) [µSv/h]Ba-128 1.41E+04 0.00Ba-131 5.93E+06 0.49Ba-133 1.67E+05 0.01Ba-133m 2.57E+03 0.00Ba-135m 9.29E+01 0.00Ba-140 5.82E+07 1.54Ra-223 8.00E+07 1.37Rn-219 8.00E+07 0.66Po-215 8.00E+07 0.00Pb-211 8.00E+07 0.72Bi-211 8.00E+07 0.54Tl-207 8.00E+07 0.03Ra-224 1.52E+07 0.02Rn-220 1.52E+07 0.00Po-216 1.52E+07 0.00Bi-212 1.52E+07 0.21Po-212 9.73E+06 0.09Tl-208 5.47E+06 2.18Ra-225 1.76E+07 0.06Ac-225 7.80E+06 0.01Fr-221 7.80E+06 0.03At-217 7.80E+06 0.00Bi-213 7.80E+06 0.14Tl-209 1.95E+05 0.05Ra-226 2.93E+03 0.00Rn-222 2.93E+03 0.00Po-218 2.93E+03 0.00Pb-214 2.93E+03 0.00Bi-214 2.93E+03 0.00Po-214 2.93E+03 0.00Pb-210 2.93E+03 0.00Bi-210 2.93E+03 0.00Po-210 2.93E+03 0.00Ra-228 1.71E+05 0.00Total 8.18365contents of the solution containing isolated actinium isotopes 7 days after eob 46f contents of the solution containing isolated actiniumisotopes 7 days after eobTable 8: Anticipated radioactive contents of the isolated solution of Ac isotopes at EOB + 1 week. Ac decay chainsare assumed to be in equilibrium for the purpose of determining upper limits on dose rates.Nuclide Activity [Bq] Dose Rate at 1 m (unshielded) [µSv/h]Ac-225 4.32E+08 4.74E-01Bi-213 4.33E+08 7.97E+00Fr-221 4.32E+08 1.62E+00At-217 4.32E+08 0.00E+00Po-213 4.25E+08 0.00E+00Ac-226 5.14E+07 8.71E-01Po-214 4.50E+07 0.00E+00Ra-222 4.48E+07 5.87E-02Rn-218 4.48E+07 5.04E-03Th-226 4.48E+07 4.22E-02Ac-227 8.46E+05 0.00E+00Th-227 8.34E+05 1.35E-02Ra-223 8.34E+05 1.43E-02Fr-223 1.18E+04 8.19E-05Rn-219 8.34E+05 6.93E-03Pb-211 8.34E+05 7.55E-03Bi-211 8.34E+05 5.61E-03Tl-207 8.34E+05 2.83E-04Ac-228 1.72E+05 1.96E-02Ac-224 1.89E+04 5.30E-04Total 11.11366modified l125 process for shipment of irradiated thorium 47g modified l125 process for shipment of irradiated tho-riumThis amendment to the L125 safety analysis describes an alternative process where irradiated thoriumfoils are shipped off the TRIUMF site for chemical processing at collaborating institutions. All safetyaspects of this document will be followed, with the exception of the modifications described below. Ingeneral, since the level of the irradiation will be approximately 13.6% of the total 2640 µA*h irradiationdescribed elsewhere in this document, the safety case described in this appendix is considered to beless hazardous and in most cases personnel will receive lower doses and be exposed to lower radiationhazards.Thorium targets will be irradiated at IPF to a total of 360 µA*h and allowed to decay for 7 days, asrequired by the L124 SAR [7]. Targets will then be transferred to HC1 in RCR1 as described in Section3.4 and opened as described in Section 3.5.From within the hot cell, the thorium foil will then be placed inside a plastic bag and removedthrough the hot cell’s side port. Using forceps to reduce hand dose, this bag will then be sealed withina second bag which will be swiped for loose contamination and placed inside a pig containing 11 mmof lead shielding. During this portion of the work, the foil is estimated to emit a dose rate of 484µSv/h at 0.5 m without shielding. One worker will be exposed to this radiation field for less than 2minutes, for a total whole body dose of <16 µSv. The hand dose is estimated to be <400 µSv.One day later (at least 8 days after EOB), the Type A container containing the thorium foil will beshipped off site. The total ratio of A/A2 shipping values is calculated by FLUKA at this time point tobe 0.751.When using the Croft ("yellow can") Type A shipping container, which contains 1.1 cm of leadshielding, there will be a total of 1.9 cm of lead shielding (including the pig that is also inside thecontainer). The estimated dose rate on the outside of the package is estimated to be 24 µSv/h at 1m and approximately 1553 µSv/h on the surface of the package (which has a diameter of 25 cm).Additional shielding will be provided by 0.6 cm of steel within the container, which is not included inthe shielding calculations.A TRIUMF Radioactive Material Shipping Permit will be obtained in coordination with RPG, andall Transportation of Dangerous Goods (TDG) paperwork at the time of shipment will be completedby someone with valid TDG certification.367
Thesis/Dissertation
eng
Physics
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Nuclide production and imaging applications of ²²⁵Ac for targeted alpha therapy
Text