Radiation Syndromes

1
Radiation Syndromes
2
Symptoms of Acute Radiation Sickness

• Three categories (E. Hall, 1994)
• Hemopoietic 3-8 Gy LD50/60
• radiation damages precursors to red/white blood
  cells platelets
• prodromal may occur immediately
• symptoms septicemia,
• survival mixed
• examples include Chernobyl personnel (203
  exhibited symptoms, 13 died)

3
Symptoms, continued

• Gastrointestinal gt10 Gy
• radiation depopulates GI epithelium (crypt cells)
• abdominal pain/fever, diarrhea, dehydration
• death 3 to 10 days (no record of human survivors
  above 10 Gy)
• examples include Chernobyl firefighters
• Cerebrovascular gt 100 Gy
• death in minutes to hours
• examples include criticality accidents

4
Delayed Effects

• Some biological effects, either from acute or
  chronic exposure may take a long time to develop
  become evident in exposed individual.
• Called delayed or late, somatic effects
• Cancer
• Leukemia
• Bone Cancer
• Lung Cancer
• Life Shortening
• Cataracts

5
Other Effects

• Mental Retardation
• Genetic Effects

6
Sources of Human Data

• Considerable body of data exists
• Atomic-bomb survivors
• RERF
• 93,000 survivors
• 27,000 nonexposed comparators

7
Sources of Human Data

• Medical patients
• Therapeutic
• Thymus treatments - increase in thyroid tumors
• Tinea capitis (ringworm of the scalp)- 10,000
  children- 6 fold increase in malignant tumors of
  thyroid
• Ankylosing spondylitis (inflammatory arthritis
  that affects the spinal joints) - 14,000 patients
  - increase in leukemia
• Diagnostic

8
Sources of Human Data, contd

• Body of data, contd
• Radium dial painters - several hundred, bone
  cancer
• Uranium miners - thousands - lung cancer
• Accidents
• Critical assemblies
• Particle accelerators
• Radiation devices
• Weapons fallout
• Chornobyl

9
Examples of Dose-Response Relationships

• Two effects of radiation exposure
• deterministic (threshold)
• stochastic cancer
• Radiation Standards
• set below threshold
• set to limit stochastic risk
• Controversy on Risk
• possibility of threshold
• low-dose data limited

10
Non-Stochastic (Deterministic) Effects

• Occurs above threshold dose
• Severity increases with dose
• Alopecia (hair loss)
• Cataracts
• Erythema (skin reddening)
• Radiation Sickness
• Temporary Sterility

11
Stochastic (Probabilistic) Effects

• Occurs by chance
• Probability increases with dose

• Carcinogenesis
• Mutagenesis
• Teratogenesis

12
Linear non-threshold hypothesis

• Fits data
• Single hit effect
• Accepted by most regulatory bodies
• Conservative
• Basis of current regulations

13
Biological Effects Summary

• What We Know and What We Dont Know About
  Radiation Health Effects
• Borrowed from a talk by G. Roessler An
  Educational Briefing By The HEALTH PHYSICS
  SOCIETY Specialists In Radiation Safety March 28,
  2001

14
Health Effects of Ionizing Radiation

• More known about radiation effects than effects
  from any other potentially toxic substance --
  more than chemicals

15
Sources of Information

• Molecules and Cells
• Animals
• Humans (Epidemiological Studies)
• Medical
• Occupational
• Hiroshima and Nagasaki

16
Time Frame of Effects

• Physical -- less than seconds
• Chemical -- seconds
• Biological -- seconds to many years
• Reactions with molecules, cells
• Tissue changes
• Cancer, leukemia

17
Effects

• The radiation may enter the body but miss
  important targets
• The radiation may not cause any damage to a
  target
• The damage may be repaired
• A damaged cell may die
• A damaged cell may be changed (mutated)

18
Effects

• High Doses
• May Lead to Early Effects or Death
• Low Doses
• Cancer and Leukemia
• Inherited Effects
• Embryo and Fetus

19
What We Know

• Radiation is a weak carcinogen
• The probability of getting cancer is a function
  of the dose
• No evidence of any cancer effects below about 10
  rem

20
What We Dont Know

• If there are
• any bad effects below about 10 rem
• beneficial effects below about 10 rem
• any effects other than cancer and leukemia
• any inherited effects at any dose

21
Important Points

• High normal incidence of cancer (about 30)
• Cant prove relationship on an individual basis -
  only an increased relative risk on a large group
  basis
• Long latent period
• Leukemia - 2 to 7 years from exposure
• Cancer - 10 to 40 or 50 years from exposure
• Dose to tissue
• Cancer wont occur in an organ of the body unless
  that organ has received a dose

22
Another Important Point

• Some cancers are not associated with
  low-to-moderate doses of ionizing radiation
• Hodgkin's Disease
• Non-Hodgkin's Disease
• Chronic Lymphocytic Leukemia
• Cutaneous Malignant Melanoma
• Uterus
• Prostate

23
Current Issues in Radiobiological Research
24
Current Issues in Radiobiological Research

• There are several areas which are challenging our
  fundamental understanding of radiation damage at
  the cellular level (where DNA has historically
  been viewed as the principal target of concern).
  
• Three of these areas are now presented

25
Genomic Instability

• Also known as genetic and chromosomal instability
• Refers to genetic change occurring serially and
  spontaneously in cell-populations as they
  replicate.
• Radiation can induce a genome-wide process of
  instability in cells.
• Transmitted over many generations leads to
  enhanced frequency of genetic changes among
  progeny of the original irradiated cell.
• Observed with
• Cell systems in vivo and in vitro and
• Low as well as high-LET radiation.
• Adjacent, un-irradiated cells.
• Generally accepted
• Unanswered questions
• mechanisms,
• how it is initiated and how it is maintained

26
Bystander effects

• Conventional model of radiation-induced damage
  requires damage of DNA either from direct
  interactions of radiation or from free radicals
  created nearby.
• Recent studies have demonstrated damage (such as
  altered gene expression) occurring in cells not
  directly exposed to radiation.
• Evidence that damage may be a consequence of
  intercellular signaling, production of cytokines,
  or free-radical generation.
• Thought that these effects are related to
  inflammatory-type responses.
• Significance of the bystander effect as it
  relates to consequences of radiation exposure is
  not yet known.

27
Adaptive Response

• Increasing number of studies show
• adaptive protection responses occur in living
  cells
• after single or protracted exposures to X- or
  ?-radiation at low doses.
• Observed both in vivo and in vitro
• Documented across a wide range of organisms from
  bacteria, and viruses to plants and animals.
• Two types of protection are identified
• Prevention and repair of DNA damage.
• Removal of damaged cells.
• Mechanism is not immediate, but develops,
  presumably in response to physiologic stress.
• Manifests within hours and may persist weeks to
  months.
• No strong data supporting adaptive response
  following exposures to high LET radiation.

28
RHP 483/583Radiation Biology

• Prof. Higley
• 737-0675, E-122
• higley_at_ne.orst.edu
• Radiation Biology and Radiation Risk
• the study of the biological effects of ionizing
  radiation on tissues, cells, and molecules
• considering both acute and chronic radiation
  effects
• emphasis on vertebrates

29

• Radiation Interactions
• Hall, Chapter 1

30
Interactions with Matter

• Types of radiation
• Electromagnetic
• gamma, X ray
• Particles
• alpha, beta, neutron, etc.
• Interaction mechanisms
• ionization, excitation
• photoelectric, Compton scatter, pair production

31
Mechanisms

• Absorption of energy in biological material
  causes excitation or ionization
• excitation raises electron to higher energy
  state
• ionization liberates electron from the atom
• radiation may be emitted as a result of these
  processes (characteristic x-rays or Auger
  electrons)

32
Electromagnetic Radiation

• Photons - energy packets traveling in the form of
  a wave (with wave and particle characteristics)
• X rays
• produced by
• transitions in electron orbitals
• deceleration of electrons (bremsstrahlung)
• g rays
• produced from within the nucleus
• from transition or rearrangement of nucleons
• With the exception of origin, g and x rays are
  indistinguishable

33
Wave/Particle Properties

• l c/n
• l wavelength (m)
• c speed of light (3x108 m/s)
• n frequency (s-1)
• Wavelengths of common EM radiations
• radio waves - 300 m
• visible light - 5x10-7 m
• X and g rays - 10-11 m ( tenths of Angstroms)

34
Wave/Energy Relationships

• E hn hc/l
• E energy, keV (Joules, ergs, etc.)
• h Plancks constant, 4.136 x 10-18 keV-sec
• Wavelength inversely related to energy freq.
• Ionizing electromagnetic radiation
• 10 eV
• 3 EHz
• 100 nm

35
(No Transcript)
36
Electromagnetic Spectrum
Wavelength
Frequency
Gamma Rays
Energy
X Rays
Ultraviolet Light
Visible Light
Infrared (heat) radiation
Radio Waves
37
Photon Interactions

• Photoelectric photon strikes inner-shell
  electron and transfers all energy
• Compton Scatter photon strikes a free or
  loosely-bound orbital electron (outer shell) and
  transfers portion of kinetic energy
• Pair Production high-energy photon produces
  positron/electron pair

38
Photoelectric Effect

• More likely for low-energy photons (10s of keV)
• Photon absorption proportional to Z3
• bone shows up as unexposed areas on X-ray
• Inner-shell electron is ejected
• Thus, characteristic X rays also emitted
• 0.5 keV of little biological impact
• localized dose - relevant in microdosimetry
• Photoelectric hn hn - EB

39
Compton Scatter

• More likely at intermediate photon energies
• Interaction results in scattered photon (lower
  energy) and scattered electron
• a wide range of energies are possible for both
• Photon absorption is independent of Z of
  absorber, thus energy absorption by this
  mechanism is similar for soft tissue, muscle and
  bone

40
Pair Production

• Photon energy gt 1.02 MeV
• KE 1/2(hn - 1.02)
• Ultimately, the positron annihilates and produces
  two 0.511 MeV photons
• Exact mechanism unknown

e- (or ?-)
b
41
Important to Remember

• Regardless of the absorption process
  (photoelectric, Compton scatter, or pair
  production), a portion of the photon energy is
  always given to an electron as kinetic energy
• Thus, fast electrons deposit photon energy

42
Energy Absorption

• LD50/60 4 Gy (4 J/kg)
• If a 70 kg person receives a dose of 4 Gy,
  theyve absorbed an equivalent of 280 J.
• What is the caloric equivalent of 280 J?
• 4.186 J 1 cal, thus 280/4.186 67 calories
• What would be the temperature rise in the body
  from this energy deposition?
• Would we expect this to be fatal?

43
Energy Rise from Radiation Event

• What does 67 calories get you in the real world?
  Hall says ...
• 1 sip of coffee (rise in body temperature)
• lifting 70 kg 16 inches
• smelling a Big Mac and fries
• Then, why is this a lethal dose?

Because its not about heat!
44
Absorption Mechanisms

• Radiation can be classified as directly or
  indirectly ionizing
• Direct absorption - by primary radiation
• charged particles
• Indirect absorption - by secondary radiation
• photons, neutrons

45
Charged-Particles

• More densely ionizing than photons
• More efficient at ionizing tissue
• Larger mass than electrons
• for a given kinetic energy, it is deposited over
  a shorter path length
• thus, greater ionization density
• Linear Energy Transfer (LET)
• energy imparted per unit path length
• particles have a greater LET than photons

46
Neutrons vs. Photons

• X and g-rays
• indirectly ionizing
• produce fast-moving, secondary electrons
• Neutrons
• indirectly ionizing
• produce recoil protons and heavier atoms

47
n and g Secondary Particles

• Secondary electrons
• small, 1/1800 mass of proton
• single negative charge
• sparsely ionizing (low LET)
• Recoil protons and heavy fragments
• massive, similar size to absorption media
• positively charged
• densely ionizing (high LET)

48
Neutrons

• Similar to a proton in mass
• No electrical charge, thus, neutrons interact
  with the nucleus of absorber atoms
• Classified as
• thermal (lt 1 eV)
• epithermal (1 eV - 10 keV)
• fast (gt 10 keV)
• Important to us because they are by-products of
  nuclear fission, and can cause activation

49
Absorption of Neutron Energy

• Uncharged, thus highly penetrating
• Interactions with atomic nuclei
• Generate fast (high energy) recoil protons,
  alphas, and heavy fragments
• In biological systems - neutron interaction with
  hydrogen (protons) is the dominant process
• Energy absorbed by inelastic or elastic scatter

50
Fast Neutron Interactions
e
n

p

n
n

p


p
n
n

e
p

n
With high energy neutrons, the collision is
inelastic (nucleus absorbs energy) and heavy
fragments result (fission or spallation
products).
51
Epithermal Neutron Interactions
n
e


p
p

n
n
n

p


p
n
e
n
With intermediate energy neutrons, the
collision is elastic, part of the energy is
transferred to nucleus and part is retained by
the incident neutron.
52
Thermal Neutron Interactions
e
n
n

p


p
n
n
n
e


p
p

n
With low energy neutrons, the neutron is
absorbed by the nucleus, a prompt photon is
emitted, and the atom is activated.
53
Direct and Indirect Action

• Biological effects of radiation result
  principally from damage to the DNA
• DNA is the critical target
• Target can receive direct damaged by physical
  interaction with radiation, or
• indirect damaged by free radicals formed when
  radiation interacts with water molecules in the
  cell

54
Direct Action

• Physical interaction that directly ionizes the
  DNA molecule
• DNA damage results from the physical breakage of
  chemical bonds within the DNA backbone
• Nucleotide bonds, phosphate bonds or strand
  breaks may result from radiation damage
• This damage may or may not be repairable

55
Indirect Action

• H2O hn --gt H2O e- --gt H OH
• Chemical interactions
• H2O is an ion (charged)
• electron ejected from the water molecule
• OH is the hydroxy radical
• a free radical has an unpaired electron from a
  broken covalent bond and is very reactive
• must be in close proximity to DNA to do its
  damage by chemical reaction

56
Direct and Indirect ActionNeutrons
57
Direct and Indirect ActionPhotons
Indirect Action Dominant for Low LET Radiation
58
Energy Absorption in Radiobiology

• Energy is absorbed, but damage is done by
  breaking chemical bonds
• Energy deposited in cells and tissues
• unevenly in discrete packets
• average absorption per ionizing event 34 eV
• typical CC binding energy 4.9 eV
• remainder goes into other ionization, excitation,
  and biological damage

59
Time Scale of Events

• Initial ionization 10-15 sec
• Free-ion lifetime 10-10 sec
• Free-radical lifetime 10-5 sec
• Breakage of bonds and expression of biological
  effects
• cell death hours to days
• oncogenesis years
• germ cell mutation generations

60
Classic Paradigm of Radiation Injury
Early (Acute) Effects (Radiation sickness)
Chemical Repair (ions recombine)
Enzymatic DNA Repair
Cell Death
Late effects
Ionizations (free radical formation, etc)
DNA Damage
Developmental effects (fetal)
Heritable Effects
Ionizing Radiation
DNA Mutation
Heat
Cancer
Excitations
? 1 s ?
? min - hrs ?
? days ?
? weeks ?
? months ?
? years ?
? generations ?
61
Summary

• Biological effect is due to direct and indirect
  action on the DNA
• Photons are indirectly ionizing, and act on the
  DNA primarily by the indirect action
• photons produce fast electrons
• Neutrons are indirectly ionizing, but generally
  their products act on the DNA by direct action
• neutrons produce protons, a-particles, hcp

62
More Generally .

• Low-LET radiations
• 2/3 of bioeffect is by indirect action
• indirect effect can be chemically modified
• High-LET radiations
• produce most biological damage by direct action
• direct effect cannot be chemically modified