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

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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

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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

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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”)

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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

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Thank You

reac/tsreac/ts