Bridging the Gaps: Public Health and Radiation Emergency Preparedness Management of Internal Contamination

1
Bridging the Gaps Public Health and Radiation
Emergency PreparednessManagement of Internal
Contamination

• Ronald E Goans, PhD, MD, MPH
• Senior Medical/Scientific Advisor
• Radiation Emergency Assistance Center and
  Training Site
• Oak Ridge Institute for Science and Education

2
Objectives

• Help public health professionals recognize the
  issues associated with internal contamination and
  prepare to provide an appropriate emergency
  response.
• Identify materials for future reference (slides
  at end)

3
Definition of Internal Contamination

• Radioactive material deposited inside the body.
• Not deposited on skin
• Not local injury
• But can sometimes have internal contamination
  from wound or transdermal absorption

4
Potential Exposure Situations

• Stages of the nuclear fuel cycle
• Accidental intake with radioactive sources
• Medical maladministration
• Industrial
• Other personal or environmental uptake associated
  with accidental or intentional releases of
  radioactivity (e.g. reactor accident, terrorist
  act, criminal assault)

5
Important Factors

• Route of entry
• Physical properties e.g., particle size, phase
  (liquid, solid, etc.)
• Chemical properties e.g., solubility, pH,
  biological half-life
• Radiological properties radiological half-life

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Toxicological Terms

• Intake movement past the 3D confines of the
  body
• Uptake transportation inside the body
• Incorporation inclusion in the metabolism of a
  critical tissue
• Decorporation removal from the body or from the
  metabolism of a critical tissue

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The Industrial Three

• Ir-192
• Cs-137
• Co-60

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The University Seven

• H-3
• C-14
• P-32
• Co-60
• I-125
• I-131
• Cf-252

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The Military Three

• U-235
• Pu-239
• Am-241

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Common Routes of Entry

• Inhalation
• Ingestion
• Absorption through wounds or skin
• Injection

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Immediate Diagnosis

• History!
• Nasal swabs
• Nasal blows
• Facial surveys
• Sputum
• Spot check urine

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Methods for Assessing Intakes

• Whole Body Counting
• Feasible for nuclides that emit penetrating x-ray
  or gamma rays
• Useful also for nuclides emitting energetic beta
  particles
• Bioassay
• Urine - most widely used
• Feces
• Excised material from wounds

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Inhalation Pathway

• Size of the particle determines where particle is
  deposited
• Insoluble particles remain in the lung for long
  periods of time
• A small fraction will be transported to the
  tracheo-bronchial lymph nodes by pulmonary
  macrophages
• Some cleared through airways, swallowed, and
  excreted in feces

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Particle Size and Distribution in the
Respiratory Tract
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Clearance Time Nasopharynx
Time to Swallowing
Anterior Nares 60 min.
Nasopharnyx 10 min. 10 mm/min.
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Clearance Time Respiratory Tract
Time
Trachea 0.1 hours
Bronchi 1 hours
Bronchioles 4 hours
Terminal Bronchioles 10 hours
Alveoli 100 Days
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Clearance Time GI Tract
Occupancy Time hours
Stomach 6
Small Intestine 14
Upper Large Intestine 18
Lower Large Intestine 22
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Clearance Time GI Tract

• Average stay time in the GI tract 48 hours (1-5
  days).
• To manage ingested radioactive materials,
• Remove the contaminant or
• Speed up transit time to decrease irradiation of
  surrounding tissues

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General Principles

• Insoluble substances tend to be excreted via the
  GI tract
• Soluble substances tend to be excreted via the
  renal system
• Route of internalization dictates methods for
  removal

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Major Treatment Methods

• Reduce and / or inhibit absorption from the
  gastrointestinal (GI) tract
• Block uptake to the organ of interest
• Isotopic dilution
• Alter chemistry
• Displace from receptors
• Chelation
• Excision of radionuclide from wound
• Consider broncho-alveolar lavage (BAL) for
  insoluble inhaled materials.

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Management Issues

• In the absence of personal dosimetry, the delay
  in presentation of clinical findings will cause
  some difficulties for decision-making
• Alpha-emitting radionuclides present
  difficulties for detection, identification and
  quantification

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Management Issues

• Instrumentation for identification of
  radionuclides may not be immediately available
• Laboratories for bioassay analysis or body
  counting may not be immediately available

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Medical Management of Specific Nuclides
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Tritium - 3HDilute

• Follows pathway of water in the body.
• Penetrates skin, lungs, and GI tract, either as
  tritiated water (HTO) or in the gaseous form.
• Single exposures are treated by forcing fluids.
• This has the dual value of diluting the tritium
  and increasing excretion.
• Biological half-life - 10 days.
• Forcing fluids to tolerance (3-4 L/d) will reduce
  the biological half-life to 1/3 to 1/2 of the
  normal value.

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Use of Ethanol - NOT FDA APPROVED
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NCRP 65 (1980) Rule of Thumb

• 1 µCi/L of urine equates to 10 mrem whole body
  dose (conservative)
• Five teens steal a H-3 exit sign and open it in
  an enclosed basement bedroom.
• Highest urine activity is approximately 5.8
  µCi/L.
• Maximum estimate of CEDE is 58 mrem.
• This is a conservative estimate.

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Iodine Block Uptake

• The dominant initial internal contaminant after a
  reactor accident, nuclear weapons test, or any
  incident involving fresh fission products is
  likely to be 131I.
• Thyroid is generally blocked by dilution 130 mg
  KI tablet stat and one tablet daily x 7-14 days.
• 5 or 6 drops of SSKI, Saturated Solution of
  Potassium Iodide (1 g/ml) is another convenient
  way to administer stable iodide.
• Potassium perchlorate (200 mg) may be used in
  patients with iodine sensitivity.

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US FDA Recommendations for Potassium Iodide
Group Daily Dose mg
Infants lt1 month 16
Children 1 month 3 years 32
Children and teenagers 3 18 years 65
Adults (including pregnant and lactating women and adolescents over 150 pounds) 130
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US FDA Recommendations for Potassium Iodide

• Daily dosing should continue until the risk of
  exposure has passed and/or until other measures
  (evacuation, sheltering, control of the food and
  milk supply) have been successfully implemented

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Childhood Thyroid Cancer Cases

• In Gomel region of Belarus, north of Chernobyl,
  children were screened for thyroid cancer by
  physical examination, ultrasound imaging of the
  thyroid, and by thyroid function tests.
• Prior to the accident, thyroid cancer rate
  0.5/million. In the period 1991-1994, rate
  96.4/million. This represents almost a 200-fold
  increase.
• Reference BMJ, vol 310, p 801, March 25, 1995.

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Childhood thyroid cancer around Chernobyl in
1986-1998 (children lt15 years old at diagnosis)

• UNSCEAR Exposures and Effects of the Chernobyl
  Accident, Annex J, New York, 2000

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Clinical and Epidemiological Features of
Childhood Thyroid Carcinomas

• In Belarus, childhood thyroid carcinomas were
  less influenced by gender
• Female/male ratio 1.41.0 (spontaneous ratio
  2.5/1)
• Mean age
• At time of first diagnosis 9.42.8 years
• At time of the accident 3.8 2.4 years
• More than 90 of the patients were less than 6
  years old and 3 were still in utero at time of
  accident.

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Potential Alternatives to KI Tablets (Not
FDA-Approved)

• 5 or 6 drops of Saturated Solution of Potassium
  Iodide or SSKI (1 g/ml)
• Potassium perchlorate (200 mg) may be used in
  patients with iodine sensitivity
• Povidone-iodine (Betadine) topically
• Anti-thyroid propylthiouracil (PTU) or
  methimazole (MMI) interferes with oxidation of
  iodide ion may be effective if given lt8 hrs
  toxicity issues

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Clinical Case Hyperthyroidism in a Young Woman

• 32 yo WF with hyperthyroidism pulse 150
  anxious Thyroid hormone level 18 µg/dL (normal
  5-12.5)
• Given 9.2 mCi 131I.
• Patient found to be approximately 16 weeks
  pregnant.
• Fetal self dose 2.4 rad.
• Fetal thyroid dose 8800 rad.
• At birth, infant is in 6th percentile for growth.
• Legal action?

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CesiumReduce Absorption, Promote Excretion

• 137Cs (physical half-life, 30 years biological
  half-life 109 days) is dominant radioisotope in
  aged fission products.
• Distributes in body fluids similarly to
  potassium.
• Most effective means for removing radioactive
  cesium is the oral administration of ferric
  ferrocyanate, commonly called Prussian Blue.
• Current recommendation 3 grams orally three
  times daily x 3 weeks (total 9 grams/day)
• Reduces the biological half-life to about 1/3 of
  the normal value.
• For higher intake, titrate upward.

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Prussian Blue
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Prussian Blue Capsules (500 mg each)
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AFRRI Package Insert Data
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Goiania Data
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Strontium and RadiumAlter the Chemistry

• Strontium-90 (Sr-90) is a by-product of the
  nuclear fission process
• Medical countermeasures include aluminum
  phosphate, aluminum hydroxide, barium sulfate, IV
  calcium gluconate, sodium alginate.
• Radium (Ra-226) is also an element of concern and
  is treated like Sr.

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Medical Therapy for Strontium

• Aluminum hydroxide PO 60-100 mL once
• Aluminum phosphate gel PO 100 mL immediately
  after exposure once
• Ammonium chloride PO 1-2 g QID for 6 d.
  Generous doses at least 1.5 - 2 g daily PO.
• Calcium IV 5 ampules (500 mg calcium each) in
  500 mL D5W over 4 h continue x 6
• Calcium gluconate PO 10 gram powder in a 30 cc
  vial, add water and drink
• Sodium Alginate PO 5 gram twice daily with
  water
• Barium Sulfate 100-300 g in 250 cc of water x 1.

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UraniumAlter the Chemistry

• In acidic urine, uranyl ion complex with tubule
  surface proteins.
• Some of the bound UO22 is retained in the
  kidney.
• Kidney is the first organ to show chemical damage
  in the form of nephritis and proteinuria.
• Oral doses or infusions of sodium bicarbonate are
  the treatment of choice and should be dosed to
  keep the urine alkaline by frequent pH
  measurements.

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Recent Clinical Research I - Uranium

• Henge-Napoli have evaluated the efficacy of
  ethane-1-hydroxy-1,1 bisphosphonate (EHBP,
  Etidronate, Didronel) in experiments to obtain
  compounds that will reduce the fixation of
  uranium in its main target organs of bone and
  kidney.
• One injection of EHBP (50-100 micromol/kg), given
  acutely after uranium inhalation in animals,
  reduced uranium deposition in the renal system by
  a factor of five, and still a factor of two when
  given 30 minutes post-exposure.

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Recent Clinical Research II - Uranium

• In another series of animal experiments,
  Destombes, et al, compared the carbonic
  anhydrase inhibitor, acetazolamide (Diamox?),
  with bicarbonate in the treatment of internal
  contamination with uranium.
• Acetazolamide is three times more effective than
  bicarbonate in reducing the renal content of
  uranium, but has no effect on skeletal content..

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Actinides

• Plutonium, Americium, Curium, and Californium.
• All have long biological half-lives.
• Inhalation is approximately 75 of industrial
  exposures.
• If the compound is soluble (nitrate, citrate,
  fluoride), compound is ultimately translocated
  from the lungs to ultimate disposition sites
  (bone and liver).
• Ca-DTPA and Zn-DTPA chelation therapy is the
  treatment of choice.

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Uptake of Actinides is Remarkably Rapid
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DTPA

• Trisodium calcium diethylenetriaminepentaacetate
  (Ca-DTPA).
• Chelating agent for transuranic elements.
• Ca-DTPA is approximately 10 times more effective
  than Zn-DTPA for initial chelation of
  transuranics. It is the treatment of choice for
  initial patient management. Must be given as
  soon as possible after accident.
• After 24 hours, Ca-DTPA and Zn-DTPA are
  essentially equally effective.
• Repeated dosing of Ca-DTPA can deplete the body
  of zinc and manganese.

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Ca-DTPA
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Zn-DTPA
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DPTA Ampules ( 1 gm per vial)
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Clinical Pharmacology of DTPA

• DTPA belongs to the group of synthetic polyamino
  polycarboxylic acids which form stable complexes
  (metal chelates) with a large number of metal
  ions.
• DTPA
• Exchanges calcium (zinc) for another metal of
  greater binding power.
• New chemical complex then excreted by the
  kidneys.
• Plasma half-life of DTPA is 20-60 minutes.
• DTPA undergoes only a minimal amount of metabolic
  change.

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Clinical Pharmacology of DTPA

• DTPA
• No accumulation of DTPA in specific organs has
  been observed.
• promptly cleared from the body by glomerular
  filtration.
• Ca-DTPA can deplete the body of zinc and, to a
  lesser extent, manganese with repeated dosing.
• Ca-DTPA is approximately 10 times more effective
  than Zn-DTPA for initial chelation of
  transuranics.

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DTPA Dosing Schedules

• Dosage of Ca-DTPA and Zn-DTPA is 1 gm IV or
  inhalation in a nebulizer (11 dilution with
  water or saline).
• Very safe drug with no significant adverse
  reactions noted during 25 years of usage.
• Initially 1 gm Ca-DTPA repeat 1 gm Zn-DTPA
  daily up to five days if bioassay results
  indicate need for additional chelation.
• Ca-DTPA - Pregnancy category D Zn-DTPA -
  Pregnancy category C.
• DTPA DFOA may be a better combination.

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DTPA - Relative Contraindications

• Pregnancy Ca teratogenic in rats no human
  data, but Zn less effective.
• Get pregnancy text for female patient!
• If pregnant, consider first dose as Zn-DTPA
  instead of Ca-DTPA, especially in first trimester.

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DTPA - Relative Contraindications

• Diabetic on insulin Insulin and zinc interact
• Use Zn-DTPA and monitor glucose levels.
• Depressed myelopoietic function
• Use clinical judgment.
• Impaired renal function
• Use clinical judgment.
• Children - no data available.

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Clinical Case Industrial Accident

• 21 year old male involved in industrial explosion
  in LA (industrial radiography source)
• Significant inhalation of material later
  identified to be Ir-192.
• Sent to ORNL for evaluation and whole-body count.

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Clinical Case Whole Body Counting Results

• Lung Count 11.71 0.01 µCi Ir-192
• Whole-body Activity 15.79 0.95 µCi Ir-192
• ALI 200 µCi Ir-192 Class Y (ICRP 30)
• CEDE 0.079 ALI
• No medical issues
• Significant regulatory issues

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Quiz How do we treat?

• Tritium (H-3)
• Iodine (I-131)
• Cesium (Cs-137)
• Uranium (U-235, U233, U238)
• Actinides (plutonium, Americium, Curium, etc)
• Strontium (Sr-90, Sr-89, etc)

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Reference Materials
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Summary of Treatment Modes

• Americium (Am)
• Californium (Cf)
• Calcium (Ca)
• Cesium (Cs)
• Cobalt (Co)
• Curium (Cm)
• Fluorine
• Gold (Au)

• DTPA
• DTPA
• Strontium therapy
• Prussian Blue
• DTPA and EDTA
• DTPA
• Aluminum Hydroxide
• BAL

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Summary of Treatment Modes

• Iodine (I)
• Iron
• Phosphorus (P)
• Plutonium (Pu)
• Radium (Ra)
• Strontium (Sr)
• Tritium (H-3)
• Uranium (U)

• KI
• DFOA
• Dibasic Phosphorus
• DTPA
• Strontium therapy
• Strontium therapy
• water diuresis
• Bicarbonate

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Summary of Treatment Modes

• Tritium therapy

• Water diuresis PO gt3-4 L per day

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Summary of Treatment Modes

• Dimercaprol (BAL)
• DTPA (Ca or Zn)

• IM 300 mg/vial for deep IM use, 2.5 mg/kg (or
  less) q4h x 2 days,then bid for 1 day, then qd
  for days 5-10
• IV1 gram in 250 mL NS or 5 glucose, given in
  1-2 h, or IV push over 3-4 min Inhalation 1g
  in 11 dilution with water or NS over 15-20 min
  (not FDA approved)Pediatrics less than 12 years
  old 14 mg/kg as above, not to exceed 1.0 gram

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Summary of Treatment Modes

• D-Penicillamine (Cuprimine)
• Deferoxamine

• PO 250 mg, QD between meals at bedtime. May
  increase to 4 or 5 g QD in divided doses.
• Deferoxamine mesylate injectable (DFOA) IM is
  preferred. 1 g IM or IV (2 ampules) slowly (15
  mg/kg/h) Repeat as indicated as 500 mg IM or IV
  q 4 h x 2 doses then 500 mg IV q 12 h for 3
  days.

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Summary of Treatment Modes

• PHOSPHORUS THERAPY
• Potassium phosphate, dibasic

• PO 250 mg phosphorus per tablet.Adult 1-2 tabs
  p.o. qid, with full glass of water each time,
  with meals and at bedtime.Children over 4y 1
  tab qid.

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Summary of Treatment Modes

• POAdults gt40 years of agewith thyroid exposure
  gt 500 cGy130 mg/d Adults 18-40 years of
  agewith thyroid exposure gt 50 cGy130 mg/d
  Pregnant or lactating women130 mg/d
  Children and adolescents 3-18with thyroid
  exposure gt 5 cGy65 mg/d Infants 1 month to 3
  years32.5 mg/d Neonates from birth to 1
  month16 mg/d

• Potassium Iodide (KI)

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Summary of Treatment Modes

• Prussian Blue

• PO Begin with 1 gram TID PO with 100-200 mL
  water may titrate up to 4 gram QID for thallium
  or high Cs intake.
• Pediatrics, 2-12 years old 1 gram PO TID
• FDA approved

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Summary of Treatment Modes

• Sodium Bicarbonate

• IV 2 ampules sodium bicarbonate (44.3 meq each,
  7.5) in 1000 mL NS, 125 mL/L, or 1 ampule of
  sodium bicarbonate (44.3 meq, 7.5) in 500 mL NS,
  500 mL/h

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Summary of Treatment Modes

• STRONTIUM THERAPY
• Aluminum hydroxide
• Aluminum phosphate gel
• Ammonium chloride
• Calcium
• Calcium gluconate
• Sodium Alginate

• PO 60-100 mL. once
• PO 100 mL immediately x1
• PO 1-2 g QID for 6 d
• Generous doses at least 1.5 - 2 g daily PO.
• IV 5 ampules (500 mg calcium each) in 500 mL D5W
  over 4 h continue x 6 d
• PO 10 gram powder in a 30 cc vial, add water and
  drink

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Further References

• NCRP 65 Management of Persons Accidentally
  Contaminated with Radionuclides (April, 1980)
• IAEA EPR Medical 2005 Generic Procedures for
  Medical Response during a Nuclear or Radiological
  Emergency. ICRP 60x-70x.
• NCRP Report 161, vols 1 and 2. 2008. Management
  of persons Contaminated with Radionuclides

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NCRP Report No. 156

• NCRP Report No. 156, Development of a Biokinetic
  Model for Radionuclide-Contaminated Wounds and
  Procedures for Their Assessment, Dosimetry and
  Treatment

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IAEA Recommendations

• http//www-pub.iaea.org/MTCD/publications/PDF/EPR-
  MEDICAL-2005_web.pdf

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NCRP 161