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27th Annual National REP Conference, Grand Rapids, MI
Nicholas Dainiak, MD, FACP
Medical and Technical Director
Radiation Emergency Assistance Center/Training Site
(REAC/TS), Oak Ridge, TN 37831
Clinical Professor, Department of Therapeutic Radiology, Yale University School of Medicine
New Haven, CT 06510
Introduction and REAC/TS Overview
April 10, 2017
“Considerations for Supporting Medical Response to Radiological Incidents – REAC/TS Training for
Hospitals and Responders”
Brief History of Oak Ridge
• 1942: President Roosevelt appoints Colonel Leslie Groves to lead Manhattan
Project that let to Little Boy (U-235) and Fat Man (Pu-239).
• Within a few weeks: Groves selects “Secret City” (site “X”) as the perfect site with
valleys (safety), water supply (coolant), railroad (transport), electricity (TVA:
150,000 KW required) and workforce (Knoxville).
• Site “X” becomes Clinton Engineer Works with 4 plants to purify U-235 (by removal
of U-238) and demonstrate that plutonium can be extracted from U-235.
• Y-12: electromagnetic plant
• X-10: graphite reactor (Plutonium extraction) plant
• K-25: gaseous diffusion (became S50-thermal diffusion)
• K-27: gaseous diffusion plant
2
Brief History of Oak Ridge (cont.)
• 1945: Name changed from Clinton Engineer
Works to Oak Ridge National Laboratory
3
Location map for
Clinton Engineer
Works, Oak Ridge.
(1944), Ed Westcott
McGhee-Tyson
Workers Load Uranium Slugs
4
Workers using a push rod load the face of ORNL's graphite reactor
in the late 1940s. ORNL
Workers load uranium slugs into the X-10
Graphite Reactor, Photo by Ed Westcott
Ur was ionized, injected into a California University Cyclotron where it was accelerated by an electric field. U-238 was separated from U-235.
Nuclear Fission and Transmutation of Heavy Elements
• Postulated by Otto Hahn in 1938, and explained theoretically by Lise
Meitner in 1939.
• An exothermic reaction that releases energy as electromagnetic radiation
and kinetic energy. During fission, the nucleus transmutates, resulting in
fragments that are different elements.
5
Licensed under Public Domain
Hypothesis in 1939
?
Plutonium
Uranium
Workers Load Uranium Slugs (X-10 Site)
6
Workers using a push rod load the face of ORNL's graphite reactor
in the late 1940s. ORNL
Workers load uranium slugs into the X-10
Graphite Reactor, Photo by Ed Westcott
Pilot production of plutonium from uranium
REAC/TS is Established
1976 : Established to cadre of healthcare providers and health physicist with
expertise in radiation to provide advice and consultation for
management of radiation illnesses to the DOE and others.
2002: Homeland Security Act, Section 506, DOE Order 153.1, Departmental
Radiological Emergency Response Assets; REAC/TS is a member of the
Nuclear Incident Response Team (NIRT) as:
“a medical consulting and/or deployable tailored program that provides a
24-hour response center for medical advice, specialized training, and
unique on-site assistance in triage, diagnosis and treatment of all types of
radiation induced injuries.”
7
ORAU
DOE/NNSA
Functional Relationships of REAC/TS
8
ORISE
REAC/TS
DOE/NNSA’s Consequence Management
9
Capabilities
REAC/TS
Provides advice and consultation on diagnosis and management of ionizing radiation-related injuries
On-scene assistance can be provided by Emergency Response Teams with reachback to REAC/TS Home Team
Provides 24/7/365 advice
and medical consultation
world-wide
Provides state-of-the-science educational opportunities for the emergency preparedness and response community to expand the nation’s capacity to respond
Maintains a robust Radiation Accident Registry with details of ionizing radiation exposure/contamination incidents
Assistance worldwide to IAEA, foreign governments
Provides timely dose assessment/estimation for external and internal radiation exposures
Performs individual radiation bioassays using the Dicentric Chromosome Assay (DCA) as the “gold” standard of radiation biodosimetry in its Cytogenetics Biodosimetry Laboratory (CBL) 10
Radiation Medicine
Radiation Dose Assessment
Education and Expertise
REAC/TS Radiation Medicine
• On-scene assistance provided by two deployable emergency response teams (ERTs) within four hours – Physician, Health Physicist, Registered Nurse/Paramedic
– Advanced Cardiac Life Support (ACLS) capability
– Measurement of radiation dose and communication of health risk
• REAC/TS Home Team (HT) supports reach back capability for ERTs – Handles additional assistance calls; assists in travel
coordination and shipment of materials; covers daily operations; serves as “on call” team
11
REAC/TS Radiation Medicine
• After hours calls routed through DOE Oak Ridge Operations Center; (865) 576-1005
• Calls: – Assistance/Information – RSOs, HPs, poison control
centers, state and local health departments, industrial companies, DOE facilities, federal agencies, physicians, private citizens
– Exercise scenarios from states, hospitals, DOE sites
12
REAC/TS
Radiation Medicine
• Pan American Health Organization (PAHO)/ World Health Organization (WHO) Collaborating Center for Radiation Emergency Management
• Coordinates U.S. participation in WHO’s Radiation Emergency Medical Preparedness and Assistance Network (REMPAN)
• Member of International Atomic Energy Agency (IAEA) Radiation Assistance Network (RANET)
13
REAC/TS Education and Expertise
• Provide cutting edge educational courses for medical, public health, emergency planners, and health physics/radiation safety personnel – Radiation Emergency Medicine
– Advanced Radiation Medicine
– Health Physics
• Provide tailored courses for professional societies, governmental agencies, private entities off-site
14
REAC/TS Education and Expertise
• Conducts courses internationally through DOE NA-46 Basic I-Med courses and Advanced I-Med courses: – 3 - 4 countries per year, including IAEA
• IAEA Radiation Medicine Fellowship Program • Fulbright Scholar Host • Maintain Radiation Accident Registry lending
invaluable information for research • Maintain Diethylenetriaminepentaacetate (DTPA)
and Prussian Blue Registry
15
REAC/TS Radiation Dose Assessment
• Michael Bender: chromosome dicentric frequency and radiation dose (Radiat
Res 1962; 16: 44-53).
• Gayle Littlefield: developed REAC/TS CBL in 1970 that operated until 1988
when funding terminated.
• Gordon Livingston: reopened CBL in 2008. Member of IAEA’s Response
Assistance Network (RANET). Designated a WHO Collaborating Center in
REMPAN and participated in BioDoseNet. In 2009, became certified by the
Clinical Laboratory Improvement Amendments (CLIA). Recent WHO activities
include:
1. Attended REMPAN mtgs in Nagasaki (2011), Wuerzburg (2014).
2. Supported Conv Ex (3) in Mexico (2013).
3. Contributes to e-newsletters of BioDoseNet.
• Adayabalam Balajee: recruited from Columbia in 2015 to expand expertise and
automate processes in the CBL. 16
REAC/TS Radiation Dose Assessment
• Cytogenetic Biodosimetry Laboratory (CBL)
• Certified by Clinical Laboratory Improvement Amendment (CLIA) (both REAC/TS and Yale)
• Creation of ISO Standards for biodosimetry as a WHO Collaborating Center
• Provide guidance to regulatory agencies for monitoring quality of CBLs in the USA
• Developed SharePoint in 2010 as tool to share images of metaphases and teach others how to score dicentrics
17
Assessment of Absorbed Radiation Dose
3 Methods for Individual Dosimetry
Physical
Personal dosimeters
Biological Clinical
Cytogenetics, Proteomics
Transcriptomics,
Metabolomics
Nausea,
Vomiting,
Lymphopenia
Assessment of Absorbed Radiation Dose
3 Methods for Individual Dosimetry
Physical
Personal dosimeters
Biological Clinical
Cytogenetics, Proteomics
Transcriptomics,
Metabolomics
Nausea,
Vomiting,
Lymphopenia
Assessment of Absorbed Radiation Dose
3 Methods for Individual Dosimetry
Physical
Personal dosimeters
Biological Clinical
Cytogenetics, Proteomics
Transcriptomics,
Metabolomics
Nausea,
Vomiting,
Lymphopenia
Individual Biodosimetry
Absolute lymphocyte count (ALC)
Vomiting
Dicentric Chromosome Assay (DCA)
Goans, RE et al, Health Phys 2001; 81:446
Lymphocyte KineticsUS Radiation Accident RegistryREAC/TS
Rate Constant (day-1)
0 1 2 3
Dose (Gy)
0
2
4
6
8
10
12
Gamma Accidents
Liquid Criticality Accidents
Solid Criticality AccidentsTokaimura AccidentLymphocyte Kinetics Regr
Absolute Lymphocyte Count (ALC)
A decline in the ALC to an abnormal value has a good predictive value for dose. A CBC should be obtained every 6-8 hr to determine 2-4 ALCs in the first 24-48 hr.
Estimation of Dose by Vomiting and DCA
Time to Onset of Vomiting and Dose
The frequency dicentrics + rings is a linear-quadratic function of dose due to interactions of 2 separate breaks. EJ Hall, Radiology for the Radiobiologist, 5th Ed, 2000.
0
1
2
3
4
5
2 3 4 5 6 7 8 9 10
Dose (Gy)
Tim
e (H
ours
)
Nearly all vomit within 1 hour at a dose of 6 Gy. Vomiting occurs in only 35-50% of patients at a dose of 3 Gy (not shown).
DCA (the “Gold Standard”)
24
Gy/Sv is Convenient to Transmit Doses for ARS
Dose
[Gy]
Onset of
vomiting Lymphocyte count (x103/liter) by day
Lymphocyte
depletion rate
%
Time
[hr]
0.5
1
2
4
6
8
Rate constant
0 -- -- 2.45* 2.45 2.45 2.45 2.45 2.45 --
1 19 2.30 2.16 1.90 1.48 1.15 0.89 0.126
2 35 4.63 2.16 1.90 1.48 0.89 0.54 0.33 0.252
3 54 2.62 2.03 1.68 1.15 0.54 0.25 0.12 0.378
4 72 1.74 1.90 1.48 0.89 0.33 0.12 .044 0.504
5 86 1.27 1.79 1.31 0.69 0.20 0.06 .020 00.63
6 94 0.99 1.68 1.15 0.54 0.12 0.03 .006 0.756
7 98 0.79 1.58 1.01 0.42 .072 .012 .002 0.881
8 99 0.66 1.48 0.89 0.33 .044 .006 <.001 1.01
9 100 0.56 1.39 0.79 0.25 .030 .003 <.001 1.13
10 100 0.48 1.31 0.70 0.20 .020 .001 <.001 1.26
LD 50/60
0% deaths
100% deaths
Waselenko J et al, Ann Intern Med 2004; 140: 1037
25
Gy/Sv is Convenient to Transmit Doses for ARS
Dose
[Gy]
Onset of
vomiting Lymphocyte count (x103/liter) by day
Lymphocyte
depletion rate
%
Time
[hr]
0.5
1
2
4
6
8
Rate constant
0 -- -- 2.45* 2.45 2.45 2.45 2.45 2.45 --
1 19 2.30 2.16 1.90 1.48 1.15 0.89 0.126
2 35 4.63 2.16 1.90 1.48 0.89 0.54 0.33 0.252
3 54 2.62 2.03 1.68 1.15 0.54 0.25 0.12 0.378
4 72 1.74 1.90 1.48 0.89 0.33 0.12 .044 0.504
5 86 1.27 1.79 1.31 0.69 0.20 0.06 .020 00.63
6 94 0.99 1.68 1.15 0.54 0.12 0.03 .006 0.756
7 98 0.79 1.58 1.01 0.42 .072 .012 .002 0.881
8 99 0.66 1.48 0.89 0.33 .044 .006 <.001 1.01
9 100 0.56 1.39 0.79 0.25 .030 .003 <.001 1.13
10 100 0.48 1.31 0.70 0.20 .020 .001 <.001 1.26
LD 50/60
0% deaths
100% deaths
Waselenko J et al, Ann Intern Med 2004; 140: 1037
26
Gy/Sv is Convenient to Transmit Doses for ARS
Dose
[Gy]
Onset of
vomiting Lymphocyte count (x103/liter) by day
Lymphocyte
depletion rate
%
Time
[hr]
0.5
1
2
4
6
8
Rate constant
0 -- -- 2.45* 2.45 2.45 2.45 2.45 2.45 --
1 19 2.30 2.16 1.90 1.48 1.15 0.89 0.126
2 35 4.63 2.16 1.90 1.48 0.89 0.54 0.33 0.252
3 54 2.62 2.03 1.68 1.15 0.54 0.25 0.12 0.378
4 72 1.74 1.90 1.48 0.89 0.33 0.12 .044 0.504
5 86 1.27 1.79 1.31 0.69 0.20 0.06 .020 00.63
6 94 0.99 1.68 1.15 0.54 0.12 0.03 .006 0.756
7 98 0.79 1.58 1.01 0.42 .072 .012 .002 0.881
8 99 0.66 1.48 0.89 0.33 .044 .006 <.001 1.01
9 100 0.56 1.39 0.79 0.25 .030 .003 <.001 1.13
10 100 0.48 1.31 0.70 0.20 .020 .001 <.001 1.26
LD 50/60
0% deaths
100% deaths
27
Gy/Sv is Convenient to Transmit Doses for ARS
Dose
[Gy]
Onset of
vomiting Lymphocyte count (x103/liter) by day
Lymphocyte
depletion rate
%
Time
[hr]
0.5
1
2
4
6
8
Rate constant
0 -- -- 2.45* 2.45 2.45 2.45 2.45 2.45 --
1 19 2.30 2.16 1.90 1.48 1.15 0.89 0.126
2 35 4.63 2.16 1.90 1.48 0.89 0.54 0.33 0.252
3 54 2.62 2.03 1.68 1.15 0.54 0.25 0.12 0.378
4 72 1.74 1.90 1.48 0.89 0.33 0.12 .044 0.504
5 86 1.27 1.79 1.31 0.69 0.20 0.06 .020 00.63
6 94 0.99 1.68 1.15 0.54 0.12 0.03 .006 0.756
7 98 0.79 1.58 1.01 0.42 .072 .012 .002 0.881
8 99 0.66 1.48 0.89 0.33 .044 .006 <.001 1.01
9 100 0.56 1.39 0.79 0.25 .030 .003 <.001 1.13
10 100 0.48 1.31 0.70 0.20 .020 .001 <.001 1.26
LD 50/60
0% deaths
100% deaths
Measurement of Absorbed Radiation Dose
3 Methods for Individual Dosimetry
Most relevant for predicting
genetic effects
Physical
Personal dosimeters
Biological Clinical
Cytogenetics, Proteomics
Transcriptomics,
Metabolomics
Nausea,
Vomiting,
Lymphopenia
Cytogenetic Biodosimetry • Ionizing radiation induces chromosome aberrations
• Radiation causes the formation of dicentric chromosomes, rings,
fragments and translocations due to mis-rejoining of strand breaks
• The frequency of chromosomal aberrations formed is dependent on
absorbed radiation dose
Normal Aberrant Metaphase
Dicentric Chromosome Assay
Advantages – Low background rate
(1 per 1,000 cells)
– Independent of age
and gender
– Sensitivity range is
0.1-0.2 to 5.0-7.0 Gy
– Reproducible dose
response
– Proven in accidents
over four decades
Since its discovery (1962), DCA remains “gold standard”
Mechanism
Major Problems with DCA
1. It takes 4-5 days to obtain results due to long processing times and incubations.
2. Manual analysis is time consuming.
3. Specialized training in dicentric scoring is required.
Metafer Automated Imaging and Analysis Workstation
Slide feeder (80 slides)
Slides
CCD Camera
Monitor
Microscope
Two Metafer workstations available at REAC/TS’ CBL
Automated Detection of Dicentric Chromosomes
Centromere
Centromere
8.5 sec for dicentric analysis per metaphase
Number of People Requiring Medical Care in a R/N Mass Casualty Event
*Scenario: 10 kT bomb in an area with 2 million people Immediate care 282,300 (14%) Combined injury 24,000 (1.2%) Immediate fatalities 13,000 (0.65%) Expected to die 45,000 (2.25%) Intensive/Critical care 188,300 (9.41%) Normal care 70,000 (3.5%) Long term care 556,000 (28.3%) _______________________________________________________
*Based on atmospheric dispersion and prompt effects models. Buddemeier B, Lawrence Livermore National Laboratory, EPR BioDose, 2015, and Waselenko J et al., Ann Intern Med 2004; 140:1037.
How many people would like to know about exposure dose?
Criteria for metaphase selection: 46 chromosomes that are well spread with
moderate chromosome length and well separated sister chromatids.
Overlap
Scorer Amplification • Increase capacity to provide radiation dose estimates in a
R/N event • Includes both training and management of “student”
scorers
Development of Multiple High-Throughput Biodosimetry Assays
Dicentric Assay Micronucleus Assay
ϒ-H2AX Assay
D
R F
Translocations
PCC-FISH
Radhia M’kacher et al., Int. J. Rad.Oncol, 91, 2014,
Pseudo Pelger-Huët Anomaly
Multicolor FISH
Potential Molecular Approaches
Jacob NK et al, PLoS One 2013; 8:e57603
Arscott WT et al, Transl Oncol 2013; 6:638
mRNA and Protein Profiles
microRNA (miRNA) Profiles
Radiation Metabolomics
Albert J. Fornace Jr. Laboratory: a member of a consortium:
• Georgetown Univ • Columbia Univ • Lovelace Respiratory Inst • NYU School of Medicine • Translational Genomics
Research Inst • Univ of Bern
https://fornacelab.georgetown.edu/radiation%20metabolomics
REAC/TS –Future Directions
• Enhance integration with DOE assets, USG agencies and institutes/agencies in other countries to optimize medical response to radiological/nuclear incidents
• Expand education and training programs, including e-education, to meet needs of responding communities
• Work with others to refine national strategy for radiation response preparedness
• Provide estimates of biodose in exposed individuals and serve as validation tool for new and emerging biodosimetry applications
• Catalyze development of a network(s) of biodosimetry laboratories
• Develop new knowledge through basic and applied research in radiation dosimetry and molecular mechanisms of radiation-induced biological effects
39
Thank You
reac/tsreac/ts