1. Slide 1 Examples of Critical U.S. Transuranium & Uranium Registries (USTUR) Cases Involving Chelation Therapy Anthony C. James, PhD, CRadP USTUR Director, Research Professor College of Pharmacy Richland, WA 99354-4959, USA tjames@tricity.wsu.edu www.ustur.wsu.edu EURADOS WG7 Meeting Forschungszentrum Karlsruhe GmbH, Institut für Strahlenforschung (ISF) Monday, April 6 th, 2009 “Learning from Plutonium and Uranium Workers”

2. Slide 2 USTUR: Learning from Plutonium and Uranium Workers Major USTR Landmark: 1976 Hanford 241 Am Incident Explosion of ion-exchange column containing ~ 100 g 241 Am Chemical operator injured – acid burns, superficial cuts (face and upper body) From 1 to 5 Ci (~ 40 – 200 GBq!) deposited on injured worker and his clothing

3. Slide 3 USTUR Whole-body Case # 0269 [James et al., 2007 (Montpellier, 2006)]

4. Slide 4 USTUR Case #0269 – Decorporation Treatments Within a day of the accident, patient treated with i.v. Ca- EDTA:  1 g per injection – per day.  Injection regimen  1-week-on, 1-week-off.  Continued for following 6 months. Oral administration of Ca-EDTA – and various other “experimental” chelating agents – attempted over following years. Intravenous Ca-DTPA:  869 d – 0.2 g  2  870 d – 0.4 g  2  871 d – 0.6 g  2  872 → 952 d – 0.8 g  2 per day – intermittently.  954 → 963 d – 1.0 g  2 per day – intermittently.  1031 → 1642 d – 1.0 g  1 per day – intermittently.

5. Slide 5 USTUR Whole-body Case # 0269 – 239/240 Pu-in-Urine Data

6. Slide 6 USTUR Whole-body Case # 0269 – 239/240 Pu-in-Feces Data

7. Slide 7 USTUR Whole-body Case # 0269 – All 239/240 Pu Bioassay Data

8. Slide 8 USTUR Whole-body Case # 0269 – Biokinetic Modeling

9. Slide 9 USTUR Whole-body Case # 0269 – Modeling Method

10. Slide 10 USTUR Whole-body Case # 0269 – Modeling Hypotheses

11. Slide 11 USTUR Whole-body Case # 0269 – Modeling Method

12. Slide 12 USTUR Whole-body Case # 0269 – Modeling Results

13. Slide 13 USTUR Whole-body Case # 0269 – Modeling Results

14. Slide 14 USTUR Whole-body Case # 0269 – Modeling Results

15. Slide 15 Case 0269: Summary of Tissue Radiochemistry Results TissueMeasured Tissue Content, kBq Whole Body 2.280 Lungs 0.0267 Lymph Nodes 0.00019 Liver 0.937 Skeleton 1.178 Muscle, Skin, etc. 0.141 Kidneys 0.00169

16. Slide 16 USTUR Whole-body Case # 0269 – EDTA Modeling Results EDTA Flush Build-up Time Constant (Tissues) = 145 EDTA Excretion Build-up Time Constant (Urine) = 240 EDTA Excretion Enhancement Factor (to Urinary Path) = 5.100 EDTA Excretion Enhancement Factor (to Bladder) = 14.900 EDTA Tissue Uptake Factor = 1.000 EDTA Liver Clearance Factor = 1.370 EDTA Marrow Clearance Factor = 1.370 EDTA ST0 Clearance Factor = 1.370 EDTA ST1 Clearance Factor = 1.370 EDTA ST2 Clearance Factor = 1.370 EDTA Bone Surface Clearance Factor = 1.370

17. Slide 17 USTUR Whole-body Case # 0269 – DTPA Modeling Results DTPA Excretion Enhancement Factor (to Urinary Path) = 1.000 DTPA Urinary Path Flush Factor (to Bladder) = 1.000 DTPA Excretion Enhancement Factor (to Bladder) = 15.500 DTPA Tissue Uptake Factor = 0.000 DTPA Liver 2 Clearance Factor = 1.000 DTPA Liver 1 to Liver 2 Clearance Factor = 0.056 DTPA Liver 1 Fecal Factor = 0.500 DTPA Marrow Clearance Factor = 18.000 DTPA ST0 Clearance Factor = 1.440 DTPA ST1 Clearance Factor = 1.440 DTPA ST2 Clearance Factor = 1.440 DTPA Bone Surface Clearance Factor = 6.660

18. Slide 18 Autoradiographic Visualization of Bone Growth/Chelation Dynamics in the Weanling Rat From James and Taylor, 1971 Key i.v. injection of citrate- buffered (monomeric) 239 Pu(NO 3 ) 4 – 5 µCi/kg a.21 d untreated b.DTPA at 7 d c.DTPA at 30 min d.From [b] - untreated e.From [c] – DTPA 7 d f.1 d untreated

19. Slide 19 USTUR Whole-body Case # 0269 – Modeling Results

20. Slide 20 USTUR Whole-body Case # 0269 – Modeling Results

21. Slide 21 USTUR: Learning from Plutonium and Uranium Workers Web Publication of Tissue Analysis Results

22. Slide 22 SF/ICP-MS: Determination of 241 Pu 241 Pu T 1/2 = 14.1 y,  -emitter not detectable by  -spectrometry 241 Pu was detected in: 269.003 (liver) 269.031 (femur, PE) 269.052 (humerus, PE) 720.001 (lung) 720.004 (liver) ICP-MS in USTUR Program

23. Slide 23 SF/ICP-MS (at NAU) vs  -spectrometry ICP-MS in USTUR Program

24. Slide 24 The Mound Glove Box Explosion (1968)

25. Slide 25 Original Publication of Mound 238 Pu Cases

26. Slide 26 DTPA-enhanced Urinary 238 Pu Excretion (Employee ‘C’)

27. Slide 27 238 Pu Excretion in Feces (3 Employees)

28. Slide 28 Case #0682 - 238 Pu Skeletal Contents

29. Slide 29 USTUR: Learning from Plutonium and Uranium Workers FY2008 Whole-Body Donations January: 87-y-old 239 Pu-contaminated puncture wound(s) (Hanford – 1960s). March: 95-y-old 239 PuO 2 acute inhalation (Rocky Flats – 1965 Pu fire – high intake). March: 72-y-old 241 AmO 2 chronic inhalation (U.S. Radium Corporation – 1960s – very high intake – heavily chelated). September: 83-y-old U 3 O 8 -fume acute inhalation (Hanford – 1948 – up to 300 μg-U/d in urine).

30. Slide 30 USTUR: Learning from Plutonium and Uranium Workers USTUR Web Site – Case Narrative for Registrant 0846

31. Slide 31 USTUR: Learning from Plutonium and Uranium Workers USTUR Web Site – Case Narrative for Registrant 0846

32. Slide 32 USTUR: Learning from Plutonium and Uranium Workers USTUR Web Site – File Downloads for Registrant 0846

33. Slide 33 USTUR: Learning from Plutonium and Uranium Workers Case #0846 Urine Data – First Year

34. Slide 34 USTUR: Learning from Plutonium and Uranium Workers Case #0846 Urine Data – Second Year

35. Slide 35 USTUR: Learning from Plutonium and Uranium Workers Case #0846 Urine Data – Years 2-3

36. Slide 36 USTUR: Learning from Plutonium and Uranium Workers Post Mortem 241 Am External Counts (PNNL) – With and Without Lungs

37. Slide 37 USTUR: Learning from Plutonium and Uranium Workers External Counts Pre- and Post-Autopsy

38. Slide 38 USTUR: Learning from Plutonium and Uranium Workers NHRTR – FY2008: THEMIS Bar-coded Sample Inventory Chain of Custody/Database System

39. Slide 39 USTUR: Learning from Plutonium and Uranium Workers The Management Information System (THEMIS)  Assigns a unique barcode to each individual sample.  Records a sample’s mass or volume.  Tracks the sample’s current location as it is moved within the NHRTR facility (e.g., from one freezer to another).  Tracks the sample’s location (e.g., as it is ‘shipped’ for radiochemical analysis).

40. Slide 40 USTR & USUR (pre-1992) - Analyses carried out primarily by Los Alamos (LASL/LANL). USTUR (1992-2006) - Analyses carried out by Washington State University (WSU) - Nuclear Radiation Center (NRC), Pullman, WA. USTUR (2006-2008) - Limited analyses carried out in temporary (leased) laboratory at Columbia Basin College, Pasco, WA (no tissue digestion facilities). - Tried “full-service” commercial laboratories. - New separations procedures and ICP-MS. USTUR (2009+) - New (leased) “in-house” radiochemistry facilities. Radiochemistry: Tissue Sample Actinide Separation and Measurement HPA/CRCE Seminar – ACJ – April 2 nd, 2009

41. Slide 41 Radiochemistry Comparison of Analytical Performance: USTUR-150-220-310 vs. TEVA-TRU-DGA DescriptionUSTUR 150-220-310TEVA-TRU-DGA Separation technique Extraction chromatography + anion exchange (gravity fed) Extraction chromatography (vacuum-assisted) Sample loading3 timesonce Number of samples in batch1824 Reagents used345 mL/sample110 mL/sample Time for Pu/Am separation5+ days1 day

42. Slide 42 Benefits & Limitations of ICP-MS Rapid analysis (10 min vs 42 hr for  -spectrometry) Low detection limits High precision (1-3 %) 240 Pu/ 239 Pu isotopic ratio measurement 236 U and 241 Pu detection Limited for 241 Am and 238 Pu determination c.f. AS ICP-MS in USTUR Program

43. Slide 43 New Frontier: Laser Ablation ICP-MS LA-ICP-MS in USTUR Program Phillip Doble, Ph.D., Senior Lecturer, Department of Chemistry & Forensic Science, University of Technology, Sydney, Australia

44. Slide 44 Application of LA-ICP-MS to USTUR/NHRTR LA-ICP-MS: Potential Applications to USTUR/NHRTR Spatial distribution of actinides, 226 Ra and major matrix elements (Ca, Mg, Sr, P) in autopsy samples Actinide and 226 Ra concentration measurements Others?

45. Slide 45 USTUR: Learning from Plutonium and Uranium Workers Major USTR Landmark: 1st Whole Body Donation (1979) Donor (radiochemist) worked with unsealed 241 Am source in his doctoral research (1952-54) First indication of intake was detection of 241 Am in urine sample (1958 routine surveillance program) – No chelation therapy Contemporary estimate of intake 0.23 – 1.1 μCi (~ 8 – 40 kBq!)

46. Slide 46 USTUR: Learning from Plutonium and Uranium Workers Voxel Modeling of DOE 241 Am Phantom (USTUR Case #0102) George Tabatadze M.S. (UNLV Medical Physics) - ISU Ph.D. Project

47. Slide 47 USTUR: Learning from Plutonium and Uranium Workers Voxel Modeling of DOE 241 Am Phantom (USTUR Case #0102) George Tabatadze M.S. (ISU Graduate Student)

48. Slide 48 USTUR: Learning from Plutonium and Uranium Workers Voxel Modeling of DOE 241 Am Phantom (USTUR Case #0102) George Tabatadze M.S. (ISU Graduate Student)

49. Slide 49 USTUR: Learning from Plutonium and Uranium Workers Potential ‘Phantom’ Resource? - Whole Limbs from Case #0846

50. Slide 50 12 th International Congress of the International Radiation Protection Association (IRPA) Buenos Aires, Argentina October 8 th - 24 th, 2008 Uncertainty in Internal Doses: Using Bayes to Transfer Information from One Worker to Another Scenario Comprehensive bioassay follow-up of a worker who accidentally inhaled 241 AmO 2 yields knowledge of the lung absorption behavior of this material. Can this knowledge be applied rigorously to improve dose estimates for another worker inhaling same material (with relatively sparse bioassay data and unknown time of intake)? Demonstrate use of the Weighted Likelihood Monte Carlo Sampling (WeLMoS) method (Puncher and Birchall, 2008) to derive posterior probability distributions of doses for the second worker. Scenario Comprehensive bioassay follow-up of a worker who accidentally inhaled 241 AmO 2 yields knowledge of the lung absorption behavior of this material. Can this knowledge be applied rigorously to improve dose estimates for another worker inhaling same material (with relatively sparse bioassay data and unknown time of intake)? Demonstrate use of the Weighted Likelihood Monte Carlo Sampling (WeLMoS) method (Puncher and Birchall, 2008) to derive posterior probability distributions of doses for the second worker. 5-month aqueous suspension James, A.C., 1 Birchall, A. 2 and Puncher, M. 2 1 United States Transuranium and Uranium Registries, 1854 Terminal Drive, Richland, WA 99354, USA 2 Health Protection Agency-Radiation Protection Division, Chilton, Oxon OX11 0RQ, UK

51. Slide 51 USTUR: Learning from Plutonium and Uranium Workers USTUR Organization – FY2009 (Planned)

52. Slide 52 USTUR: Learning from Plutonium and Uranium Workers In Conclusion: USTUR and EURADOS WG7 USDOE/WSU’s USTUR/NHRTR are unique resources of data and tissue materials voluntarily donated by hundreds of individual workers - the measured actinide contents of tissues and major organs at autopsy provide a unique collection of scientific data which encompasses all types of accidental exposure to actinides over the history of U.S. nuclear materials production and handling. USTUR cases include lifetime follow-up of extensively chelated individuals with comprehensive medical and bioassay records. USTUR is working hard to refine and organize these (privacy- protected) data – and make them readily available for research study by collaborating scientists – in the U.S. and internationally. USTUR and DOE welcome the opportunity to work closely with EURADOS WG7 to ensure that the Registries’ data and materials resources are utilized most effectively to reduce uncertainty in the assessment, management and potential ‘treatment’ of accidental (or malevolent) exposures to actinides.

53. Slide 53 RAP/HSEP Joint Committee Meeting, Jan 8 th, 2009 - James Disclaimer: “This presentation was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, expressed or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof.”