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Canada’s National Laboratory for Particle and Nuclear Phy Laboratoire national canadien pour la recherche en physiq et en physique des particules Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada Propriété d’un consortium d’universités canadiennes, géré en co-entreprise à partir d’une contribution administrée par le Conseil national de recherches Canada World Medical Isotope Crisis: How did this happen and where are we now? Thomas J. Ruth, PhD | Senior Research Scientist Emeritus| TRIUMF/BC Cancer Agency Adjunct Professor, U. Victoria 1 A.I. Alikhanian National Science Laboratory Yerevan, Armenia 15 October 2013 ANSL

Canada’s National Laboratory for Particle and Nuclear Physics Laboratoire national canadien pour la recherche en physique nucléaire et en physique des

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Page 1: Canada’s National Laboratory for Particle and Nuclear Physics Laboratoire national canadien pour la recherche en physique nucléaire et en physique des

Canada’s National Laboratory for Particle and Nuclear Physics Laboratoire national canadien pour la recherche en physique nucléaire et en physique des particules

Owned and operated as a joint venture by a consortium of Canadian universities via a contribution through the National Research Council Canada

Propriété d’un consortium d’universités canadiennes, géré en co-entreprise à partir d’une contribution administrée par le Conseil national de recherches Canada

World Medical Isotope Crisis: How did this happen and where are

we now?

Thomas J. Ruth, PhD |

Senior Research Scientist Emeritus|

TRIUMF/BC Cancer Agency

Adjunct Professor, U. Victoria

1

A.I. Alikhanian National Science Laboratory Yerevan, Armenia

15 October 2013 ANSL

Page 2: Canada’s National Laboratory for Particle and Nuclear Physics Laboratoire national canadien pour la recherche en physique nucléaire et en physique des

• Brief Background, why are 99Mo/99mTc important• Routes to 99Mo/99mTc• Challenges associated with each route• Status of various projects for alternative

production• Future outcomes

Outline

15 October 2013 ANSL 2

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15 October 2013 3

Background• Tc-99m is most widely used radionuclide for nuclear medicine

procedures in the world and accounts for 80% of all procedures

• Major efforts expended in connecting to biological molecules to assess– Cardiac function– Blood flow– Bone metastases

• Half life & chemical properties of Mo-99 and Tc-99m are exploited to separate them in what is called a generator – Mo-99/Tc-99m generator invented at Brookhaven National Laboratory– Mo-99 half life is 66 hours, Tc-99m has a half life of 6 hours– Process of separating Mo-99 and Tc-99m called “milking”

• Generators sent around the world

ANSL

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15 October 2013 ANSL 4

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15 October 2013 ANSL

Illustrating the simplicity of the 99Mo/99mTc generator

55

Developed at BNL in 1958 it was never patented.

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Global Supply Chain of 99Mo

6Adopted from Covidien web site

ANSTOANSTO

15 October 2013 ANSL

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• US production was halted in 1989Foreign subsidies were claimed to be the cause for lower costs abroadDeemed “not worth it” to continue in US

• Low market price, risk of reactor business, and high cost of production facilities

• Half of US demand met by Canada (until 2011)

• HEU has significant security issues; future will likely require use of something else

Issues

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15 October 2013 ANSL

Fission Yield Distribution 235U(n,f)

99Mo

99Mo is produced 6% of the total fission yield

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15 October 2013 ANSL 9

Why is HEU a concern?

Why is HEU a concern?

Mass required to create a fissile device assuming a sphere

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NRU @ Chalk River

101015 October 2013 ANSL

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15 October 2013 ANSL

MAPLE Project

• MDS Nordion commissioned the AECL in 1996 to build two 10 MW reactors dedicated to radioisotope production that would each have the capacity to supply the world with Mo-99.

• In 2002, MDSN sued AECL to take back the project due to delays. As part of this settlement AECL is obligated to supply MDSN with radioisotopes for 40 years.

• In May 2008 AECL cancelled the project.• MDSN is now suing AECL for breaking the above

contract. (AECL says they cannot do this until they don’t deliver!)

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15 October 2013 ANSL 12

Maple Project

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15 October 2013 ANSL 13

National Academy Sciences Study Origin:Production of Medical Isotopes w/o HEU

Mandated by U.S. Congress in Energy Policy Act of 2005

• Reflects an effort by U.S. Congress to strike a balance between two important national interests: – Availability of reasonably priced medical isotopes in

the United States– Proliferation prevention

• Study sponsored by U.S. Department of Energy, National Nuclear Security Administration

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NAS Study Members

Would you believe anything this group says?ANSL

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Study Plan: Study Focus

• Primary focus was on Mo-99/Tc-99m supply chain• Conversion feasibility was assessed at three points in

Mo-99/Tc-99m supply chain– Costs to produce Mo-99– Costs for technetium generators – Costs for Tc-99m doses

• Potential impediments to conversion were assessed– Technical– Regulatory– Timing– Impacts on supply reliability

• Examined “large-scale” and “regional” producer experiences and capabilities

ANSL

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Reliability of Mo-99 Supply

• Mo-99 supply to the U.S. is fragile • Supply reliability is likely to become a serious problem

for the U.S. in the early part of the next decade (now) without new or refurbished reactors

• It will take time (5-10 years +) for substantial supplies of Mo-99 to become available to the U.S. from other foreign and domestic producers

• AECL’s May 2008 decision to discontinue work on the Maple Reactors is a blow to worldwide supply reliability

• NRU (AECL) to cease isotope production in 2016

ANSL

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15 October 2013 ANSL

Production routes to 99Mo

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• OPAL (Australia) Built to use LEU (2007)• OSIRIS(France) Scheduled to close in 2015• Safari (South Africa) from 50% HEU to LEU (2010)• BR2 (Belgium) >90% HEU to LEU (2013)• PALLAS (The Netherlands) to be built to use LEU

(2022?)• NRU (Canada) to cease producing Medical isotopes

(2016)

Conversion to LEU Targets

15 October 2013 ANSL 19

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15 October 2013 ANSL

What is the US trying?

NNSA Sponsoring alternatives to HEU:

• Babcock & Wilcox – Solution reactor; discontinued

• GE Hitatchi – Power reactors; discontinued

• SHINE Medical Technologies (UWisc)- (D,T) Neutron generator

• NorthStar- Photon approach.20

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15 October 2013 ANSL

Using Mo-100 with photons

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NNSA Sponsored Effort by NorthStar

- NorthStar Medical Radioisotopes irradiating 100Mo(γ,n)99Mo using an electron LINAC

- studied in depth at INL in mid-1990’s

- first production tested by NorthStar at RPI in 2008; demonstrated at mCi scale; commercial scale testing in process

- produces a specific activity of Mo-99 of ~10 Ci/g target material

- Low level Class A waste only

- licensed as an accelerator by an Agreement State; no NRC licensing role

- Mo-99 generated does not fit into current distribution stream

- requires new generating system to use product and generate Tc-99m in activity concentrations typical in nuclear pharmacies

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TechneGen™ Generating System (prototype)

2315 October 2013 ANSL

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15 October 2013 ANSL 24

TRL: (g,n), transformation of Mo-100

• Accelerator – Concept well established, requiresdevelopment for high power

• Targetry - enriched target, development work needed

• Processing –Prototype exists, in clinical trials forfor other radioisotopes

• Production of Tc-99m Generators – see above

• Waste Management – minimal waste although tracking of Tc-99g and non- moly isotopes required

• Regulatory Approval – extensive testing required

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Accelerator and Target for Subcritical Reactor

SNMMI

D(T,n)4He

ANSL

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ANSL 26

TRL: Accelerator Driven Subcritical Reactor

• Accelerator – conceptual stage

• Targetry - – extensive testing required

• Processing - – similar to existing process

• Production of Tc-99m Generators – minimal changes

• Waste Management – similar to existing fissionprocess, larger volumes?

• Regulatory Approval – similar to existing fissionprocess15 October 2013

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15 October 2013 ANSL 27

Non-reactor Isotope Supply Program (NISP)

9 months into the NSERC/CIHR, Natural Resources Canada (NRCan, announced the NISP competition (July 2010).

Secretly announced awardees in November

Officially announced awardees in January 2011

Released money the end of January 2011.

Results to be provided to Government 31 March 2012!!!

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Canadian Networks for producing 99mTc via proton irradiation of 100Mo

• 2 Networks have been funded to develop the direct production of 99mTc via the 100Mo(p,2n) reaction

• Vancouver (TRIUMF CP-42 & BCCA-TR19) London (Lawson Health Sciences & CPDC (Hamilton, both PETTrace),

• ACSI, Edmonton (Cross Cancer Institute –TR24), & Sherbrooke (TR24)

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15 October 2013 ANSL

Cyclotron-based Production of Tc-99m Radioisotopes

A Collaborative Program for the Production of Tc-99m using Canada’s Existing Medical Cyclotron Infrastructure

With support from: GE, Nordion, AAPS, others

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Canadian ITAP

15 October 2013 ANSL

ITAP Funding Announced Feb 2013 – 3 year program to: 1. Secure regulatory approval of accelerator-based products from Health Canada and

2. Address operational issues identified in Phase 1 work.

3. Establish a commercial supply chain.

CLSI to become a PIPE supplier to demonstrate that they could fulfill the key supply chain role for PIPE – Mo-99 producer.

Prairie Isotope Production Enterprise (PIPE)

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15 October 2013 ANSL 31IAEA 99Mo/99mTc CRP

• So far, we’ve looked at other ways to make Mo-99– What about making Tc-99m “directly” ?– Many moons ago, process below was validated and set aside

• NOTE: Shipping & transport of 6-hr half-life Tc-99m instead of 66-hr half-life Mo-99 (akin to present-day business using F-18/FDG for PET)

Using Mo-100 with protons…

100Mo 101Tc

99mTc

n

100Mo(p,2n)99mTc

p

n

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Technical Goals: Cyclotron-based Production

15 October 2013 ANSL 32

Establish optimal irradiation conditionsBeam (energy, current)Target characteristics (purity, plate, housing, transfer, recycle)Time (irradiation, cooling)GoalsEstablish production quantityIdentify impuritiesSpecific activity (99m/99g ratios, other long-lived Tc)Implications in radiopharmaceutical chemistry, patient doseRadionuclidic purity / other non-Tc isotopes presentImplications in production waste, recycling, patient doseIdentify/Understand regulatory space Production specifications, transport, shelf-life, etc.To meet healthcare system demands, maximize safetyEconomics

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15 October 2013 ANSL 3333

Mo-100 Recycling

Target Manufacture

Cyclotron

Irradiation

Purification

Radiopharmacy

Tc-99m Mo-100

Production cycle for 99mTc

100Mo(p,2n)99mTc

Project Elements and Workflow

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Demonstrating Proof of Concept

15 October 2013 ANSL 34Funded by NSERC/CIHR

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15 October 2013 ANSL

BCCA TR19 Target Station

Local Shield Closed

Local Shield Open

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15 October 2013 ANSL

Beam shape on target

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Low energy orthogonal target

15 October 2013 ANSL 39

100 mA16.5 MeV

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15 October 2013 40

• TR19 (vaulted), PETtrace (self-shielded, vaulted)

Demonstrated Equipment/Capabilities

40

TR1913-19 MeV, 200µA

Upgraded to 300 µA

GE PETtrace16 MeV, 100 µA

Upgraded to: 150 µA

BC Cancer Agency

Lawson CPDC

Not shown: CP42, 20-42 MeV, 200µA ANSL

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15 October 2013 4141

Theor. Calculations: Beam Energy

100Mo(p,x) reactions of highest probability

99Mo

99mTc

99gTc98Tc

PETtrace TR19 CP42 A. Celler, X. Hou, F. Bénard, T. Ruth, Phys. Med. Biol. 2011, 56, 5469

ANSL

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15 October 2013 ANSL 42

Cross Sections

42Gagnon, et al., NMB 2011

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Theoretical Calculations: Energy & Time

15 October 2013 ANSL 43

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Radionuclides Produced

15 October 2013 ANSL 44Morley, et al. NMB 39 (2012)

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Enrichment of 100Mo from different sources

Isotopes Enriched Natural

A B C92Mo 0.005 0.0060 0.09 14.8594Mo 0.005 0.0051 0.06 9.2595Mo 0.005 0.0076 0.10 15.9296Mo 0.005 0.0012 0.11 16.6897Mo 0.01 0.0016 0.08 9.5598Mo 2.58 0.41 0.55 24.13

100Mo 97.39 99.54 99.01 9.63

X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-1745

15 October 2013 ANSL

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Enrichment of 100Mo from different sources

Isotopes Enriched Natural

A B C92Mo 0.005 0.0060 0.09 14.8594Mo 0.005 0.0051 0.06 9.2595Mo 0.005 0.0076 0.10 15.9296Mo 0.005 0.0012 0.11 16.6897Mo 0.01 0.0016 0.08 9.5598Mo 2.58 0.41 0.55 24.13

100Mo 97.39 99.54 99.01 9.63

X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-1715 October 2013 46ANSL

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Impact of other Tc Radioisotopes on PatentAbsorbed Dose

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15 October 2013 ANSL 48

MIBI Effective Dose

  Tc-93 Tc-94 Tc-95 Tc-96 Tc-97m Tc-99mT1/2 2.75 h 293 min 20 h 4.28 days 90.1 days 6.01 h

0 h 0.04% 0.23% 0.07% 0.13% 0.09% 99.39%

2 h 0.03% 0.22% 0.08% 0.17% 0.12% 99.37%

8 h 0.01% 0.18% 0.13% 0.32% 0.23% 99.11%

24 h 0.00% 0.11% 0.45% 1.67% 1.36% 96.40%

The most significant contributions to the effective dose following injection of Tc labelled MIBI from Tc isotopes produced using 97% enriched 100Mo

X. Hou, A. Celler, J. Grimes, F. Bénard, T. Ruth, Phys. Med. Biol. 2012, 57, 1-17

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15 October 2013 49

Enrichment of 100Mo from different sources

49

Isotopes Enriched Natural

A B C92Mo 0.005 0.0060 0.09 14.8594Mo 0.005 0.0051 0.06 9.2595Mo 0.005 0.0076 0.10 15.9296Mo 0.005 0.0012 0.11 16.6897Mo 0.01 0.0016 0.08 9.5598Mo 2.58 0.41 0.55 24.13

100Mo 97.39 99.54 99.01 9.63

ANSL

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Separation Chemistry

15 October 2013 ANSL 50

Morley, et al. NMB 39 (2012)

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Target Transfer & Dissolution

15 October 2013 ANSL 51

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Chemical Purification System

15 October 2013 ANSL

•39 (2012): 551-9.

39 (2012): 551-9.

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15 October 2013 ANSL

Sample High Current Production Runs

• Dose calibrator reading, overestimated with 99.01% Mo-100 due to Tc94m

Date 2013/3/19 2013/4/9 2013/4/12 2013/4/16

Target 99.01% 100Mo

99.01% 100Mo 97.4% 100Mo 97.4% 100Mo

Duration91 min 85 min 6.6 h 6.2 h

Peak current100 μA 200 μA 200 μA 240 μA

Yield at EOB* 55.5 GBq (1.5 Ci)

96.2 GBq(2.6 Ci)

333 GBq(9 Ci)

348 GBq(9.4 Ci)

Saturated Yield* 4.05 GBq/μA 4.0 GBq/μA 3.3 GBq/μA 3.03 GBq/μA

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What does this mean in practice?

• Yields around 13-14 Ci (481-518 GBq) can be achieved at 250 µA for an overnight irradiation (9h run) at 18 MeV

• Batches of 16-17 Ci will likely be achieved at 300 µA• Higher yields possible with higher energy but careful

consideration of maximal threshold needed (20, 21, 22 MeV?) as it impacts:– Maximum irradiation time– Shelf life

• Beam current and target design are important

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• Neutral, cationic and anionic radiopharmaceutic kits have been prepared with yields as with generator Tc-99m (no evidence of any issues with quantity of Tc-99g or other Tc-isotopes)

• Note, we have not prepared kits at the end of shelf life but do not anticipate any issues.

Radiopharmaceutical kit labeling

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• Assumptions required to predict the capacity needed:– Lost due to chemical processing (isolation + decay time)– Lost due to decay during transport and time of day usage– Usage is typically in the 15-20 mCi doses

• 16.5 MeV, up to 130 mA for 3-6 hours - 50 and 160 GBq (1.4 and 4.5 Ci)

• 18 MeV, 300 mA for 3-6 hours – 255 and 480 GBq (7 and 13 Ci)

• Note: We have demonstrated dual beam operation on TR19 with 200 mA on 100Mo and 60 mA on 18O

Yield expectations

15 October 2013 ANSL 57

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15 October 2013 ANSL 58

TRL: Direct Production 100Mo(p,2n)99mTc

• Accelerator – Use of existing cyclotrons

• Targetry – High beam current demonstrated

• Processing – working at intermediate scale

• Production of Tc-99m Generators – not required

• Waste Management – minimal, track Tc-99g

• Regulatory Approval - – extensive testing required

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• IAEA has assisted with the installation of numerous cyclotrons around the world

• Direct production of Tc-99m is seen as an added value for these cyclotrons

• Commissioned a Coordinated Research Project (CRP)

IAEA

15 October 2013 ANSL 59

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• Impact of TC-99g on SA and labelling efficiency• Missing data for production across practical energy range

10-24 MeV• Enriched target production• Recovery and recycling of the enriched target material• Impact of recycling on the quality of Tc-99m produced.• QC metrics for assuring quality Tc-99m for clinical use• Participants: Armenia, Brazil, Canada, Hungary, India,

Italy, Japan, Kingdom of Saudi Arabia, Poland, Syria, USA

IAEA - CRP

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• Fission based Mo-99 (HEU/LEU):– > 5,000Ci/g, thus a 5 Ci generator will have 1 mg Mo

• ( ,g n) and (n,g) Mo-99:– 1-10 Ci/g dependent on flux, irradiation time, thus the generator

is dealing with grams(s) of Mo

Specific Activity – Mo 99

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15 October 2013 ANSL 62

graphic from http://www.covidien.com/

98Mo(n,g)99Mo

100Mo(p,2n)99mTc

100Mo(g,n)99Mo

ANSTOANSTO

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15 October 2013 ANSL

Conclusion

• 9.4 Ci produced in 6 hours and we have not yet reached maximum current on TR19 cyclotron

• Kits radiolabeled successfully and passed standard TLC QC (n = 3 each for anionic, neutral, cationic)

• Radiation dose to patients from cyclotron Tc99m not significantly different if target composition and irradiation energy/conditions are controlled

• Target dissolution and Tc99m purification methods optimized for large area targets

• Clear path for regulatory approval in Canada• Practical regional production of Tc99m is now possible for

large urban areas

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15 October 2013

Acknowledgements

64

ANSL

64

Paul Schaffer

, Nina Levi

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15 October 2013 ANSL

Acknowledgements

Gratefully acknowledge discussions anduse of slides:

Jim Harvey, NorthStarTim Meyer, TRIUMFAnna Celler, UBCFrancois Benard, BCCAPaul Schaffer, TRIUMFEd Bradley, IAEAKevin Crowley, NAS

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15 October 2013 ANSL

Thank you!Merci!

TRIUMF: Alberta | British Columbia | Calgary | Carleton | Guelph | Manitoba | McMaster | McGill | Montréal | Northern British Columbia | Queen’s | Regina | Saint Mary’s | Simon Fraser | Toronto | Victoria | Winnipeg | York

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