Radiation Protection

DETERMINANTS OF THE BIOLOGIC

EFFECTS OF RADIATION
Radiation-related factors:
- Absorbed dose (quantity)
- Dose rate
- Energy of the radiation (quality)
CLASSIFICATION OF BIOLOGIC
EFFECT
Classification of biologic effects:
- Stochastic
- Deterministic
CLASSIFICATION OF BIOLOGIC
EFFECT
Stochastic effect
- One in which the probability of the effect occurring
increases with dose
- Not focused on severity
- Does not have a dose threshold (one or more cell
damage can result to a production of the disease),
therefore minor injuries may also produce the same
result as major injuries
Example: Radiation-induced cancer, hereditary effects,
chronic injury to health workers
CLASSIFICATION OF BIOLOGIC
EFFECT
Stochastic effect
Risk increases with dose and there is no
threshold dose below which the magnitude of
the risk goes to zero
(As Low As Reasonably Achievable)
CLASSIFICATION OF BIOLOGIC
EFFECT
Deterministic effect
- Severity of injury increases with dose (rather than
probability)
- Requires much higher dose to have an observable
effect
- Exposure to below threshold does not have an
effect
Example: Skin erythema, fibrosis, and bone marrow
damage, severe radiation injury during radiotherapy
INTERACTION OF RADIATION WITH
TISSUE
Transfer of electrons in the environment
cause:
- Excitation
- Ionization
- Thermal heating
INTERACTION OF RADIATION WITH
TISSUE
Energy is deposited randomly and rapidly
(photoelectric absorption)
V
Secondary ionization (delta rays)
V
More low-energy ionization and excitation
(subexcitation electrons) along the path of
the initial energetic electron
LOW ENERGY ELECTRONS AND
COMPLEX DAMAGES
Caused by delta rays and other lower energy
electrons
Spurs - Low energy deposits tracts occurring
an average of three ionization events but is
the most abundant energy deposition events
Blobs - Longer and less frequent deposit
tracts with more ionization events (12)
LOW ENERGY ELECTRONS AND
COMPLEX DAMAGES
Spurs and blobs cause the formation of free
radicals
Locally multiply damaged sites
- Aka: clustered damage, complex damage,
multiply damaged sites (MDS)
- Damages produced in multiple locations in
the DNA in close proximity to one another
- More difficult to repair
LOW ENERGY ELECTRONS AND
COMPLEX DAMAGES
Hallmark of ionizing radiation
V
DNA DAMAGE
LOW ENERGY ELECTRONS AND
COMPLEX DAMAGES
Source of DNA oxidation events
- Endogenous = oxidative metabolism,
ionization
- Exogenous = chemotherapy
LOW ENERGY ELECTRONS AND
COMPLEX DAMAGES
Only a fraction of radiation cause ionization,
the rest causes heart deposition

1 degree Celsius = 4,000 Gy

FREE RADICAL FORMATION AND
INTERACTIONS
Radiation interaction with biologic materials:
- Direct = Direct action with DNA, RNA and
protein
- Indirect = Formation of ROS
FREE RADICAL FORMATION AND
INTERACTIONS
Most of the radiation-induced damages is
caused by radiation interaction with water
molecules
Electrons becomes hydrated causing:
- Hydroxyl radical
- Hydrogen radicals
FREE RADICAL FORMATION AND
INTERACTIONS
Most important of the reaction pathways in
creating radicals:
Radiation-induced excitation and
disassociation of water molecule
FREE RADICAL FORMATION AND
INTERACTIONS
Oxygen
- Enhances the damaging effect of free
radicals
Free radicals
- Acts as a strong reducing and oxidizing
agents by combining directly with
macromolecules
FREE RADICAL FORMATION AND
INTERACTIONS
Most of the total radiation-induced damage is
due to formation of free radicals
LET
- A parameter describing the average energy
deposition per unit path length of the
incident radiation
FREE RADICAL FORMATION AND
INTERACTIONS
Relative biological effectiveness (RBE)
- Dose of 250-kV x-ray (reference) over the
test radiation required to produce an effect
- Depends on total dose and dose rate
- Proportional to LET initially
- RBE decreases as LET increases, more
than 100 keV/um in tissue, because of
overkill
FREE RADICAL FORMATION AND
INTERACTIONS
Overkill / Wasted dose
- Refers to the deposition of radiation
energy in excess of that necessary to
produce the maximum biologic effect
- More than the set RBE that can cause an
End Point (cataract or lethality)
FREE RADICAL FORMATION AND
INTERACTIONS
FREE RADICAL FORMATION AND
INTERACTIONS
RBE
- A useful tool to help characterize the
potential damage from various type of
energies of ionizing radiation
- Used in establishing the radiation
weighting factor
SPECTRUM OF DNA DAMAGE
Structural changes of ionizing radiation:
- Hydrogen bond breakage
- Molecular degradation or breakage
- Intermolecular cross-linking
DNA Double Strand Breaks (DSB)
- Most genotoxic lesion that can result in
chromosome aberrations
SPECTRUM OF DNA DAMAGE
Chromosome breakage by radiation
- Occurs during anaphase and metaphase when
chromosome are condensed
- May transmit during mitosis and meiosis if not repaired
Chromosome aberration
- Damage that occur before DNA replication
Chromatid aberration
- Damage occurring after DNA synthesis
- Only one of the daughter cell will be affected if only one
of the chromatid pairs is damaged
CHROMOSOMAL ABERRATION
Chromosomal aberration
- May occur spontaneously
Use of reproductive integrity as a biologic effect
marker is limited and applicable only to
proliferating cell systems (eg, stem cells)
Differentiated cells that no longer have the
capacity for cell division (eg, muscle and nerves)
often lead to cell death defined as loss of specific
metabolic function or functional capacity
CELL SURVIVAL CURVE
Waiting until colonies are visible
- Most direct method of evaluating the ability
of a single cell to proliferate
- Calculated in a multitarget model
(extraplation number, quasithreshold dose,
and D0 dose)
-
CELL SURVIVAL CURVE
D0 dose
- Describes the radiosensitivity of the cell
population under study
- REciprocal of the slope of the linear
portion of the curve
- Dose of radiation that produces a 37%
reduction in the number of viable cells
- Higher D0 = Radioresistant cells
- Lower D0 = Less survival per dose
CELL SURVIVAL CURVE
Sublethal damage
- Concept based on when radiation dose is split into
two or more fractions, with sufficient time between
fractions, cell survival increases after low-LET
radiation
Presence of shoulder in the radiation curve
- More radiation is required to kill a cell
Reappearance of the shoulder when with a large dose
- Cells are capable of repairing sublethal damages
between fractions
FACTORS AFFECTING CELLULAR
RADIOSENSITIVITY
Conditional factor
- Those physical or chemical factors that
exist before and/or at the time of radiation
- Affects the dose-response relationship
including
- Dose rate
- LET
- Presence of oxygen
FACTORS AFFECTING CELLULAR
RADIOSENSITIVITY
Inherent factor
- Biological factors like mitotic rate, degree
of differentiation, and stage of the cell
cycle
CONDITIONAL FACTORS
Rate of which low-dose LET is equal to the
degree of biological damage (chromosomal
aberration, reproductive delay, and cell death)
Higher dose rate is more damaging than
lower dose rates.
Cells have a greater opportunity to repair
sublethal damage at low dose rates
CONDITIONAL FACTORS
Fractionation
- Reduction in radiation damage
- Used in radiotherapy
- Interval between doses allow the repair of
healthy tissues of sublethal damage
- Presence of a shoulder curve represents
repair of sublethal damage
- Presence of oxygen increases damage
caused by low-LET radiation
CONDITIONAL FACTORS
Oxygen enhancement ratio
- Relative effectiveness of radiation to
produce damage at various oxygen
tensions
- Radiation dose that produces a biologic
response in the absence of oxygen divided
by the dose of radiation that produces the
same response in the presence of oxygen
INHERENT FACTORS
Bergonie and Tribondeau fundamental of
radiosensitivity
- Greatest in cells with high mitotic rate
- Long mitotic future
- Undifferentiated

Exemption: lymphocytes
Example: stem cells, bone marrow
Radioresistant: nerves
INHERENT FACTORS
Stage of the cells in the reproductive cycle at
the time of irradiation greatly affects
radiosensitivity
Most RadioSENSITIVE:
- M phase (mitosis)
- Gap between S phase and mitosis G2
INHERENT FACTORS
Less RadioSENSITIVE:
- Preparatory period for DNA synthesis (G1)
Least RadioSENSITIVE:
- DNA synthesis (S phase)
ADAPTIVE RESPONSE
Adaptive response
- A priming dose or initial exposure reduces
the effectiveness of subsequent exposure
- Varies with dose and dose rates
BYSTANDER EFFECT
Bystander effect (abscopal/out-of-field)
- A phenomenon in which irradiated cells or
tissues can produce deleterious effect on
nonirradiated cells or tissues
GENOMIC INSTABILITY
Genomic instability
- Delayed lethality in cell cloning efficiency
- Mutation in the unirradiated progeny cells
- Example: errors in DNA repair enzymes
RADIATION-INDUCED RESPONSE
Radiation-induced response
- Genomic instability
- Adaptation
- Bystander effect
ORGAN SYSTEM RESPONSE
The higher the dose,
- the shorter the interval before the
physiologic manifestations of the damage
become apparent (latent period) and
- the shorter the period of expression during
which the full extent of the
radiation-induced damage is evident
ORGAN SYSTEM RESPONSE
In low threshold dose with no significant
changes, radiation induced pathology is
undistinguishable from naturally occurring
pathology
REGENERATION AND REPAIR
Healing of tissue damage by radiation occurs
by means of:
- Regeneration (repopulation)
- Repair
REGENERATION AND REPAIR
Regeneration
- Replacement of the damaged cells in the
organ by cells of the same type
- Replacing the lost of functional capacity
Repair
- Replacement of the damaged cells by
fibrotic scar tissue
- Functionality is compromised
REGENERATION AND REPAIR
Regeneration and repair depends on
- Dose
- Volume of tissue
- Relative radiosensitivity and regenerative
capacity
REGENERATION AND REPAIR
Fractionation allows reoxygenation of tumor
cells increasing effectiveness of radiation and
reassortment of cells into more radiosensitive
phase of the cell cycle
RADIOSENSITIVITY
Radiosensitivity of an organ depends on the
functional parenchyma
Supporting stroma only has intermediate
radiosensitivity
RADIOSENSITIVITY
Damage in radiosensitive cells is seen
initially with hypoplasia and concomitant
decrease in function within days or weeks
Damage in less radiosensitive cells is caused
by the changes in the supporting stroma with
decrease function and hypoplasia seen after
weeks or months
SPECIFIC ORGAN SYSTEM
RESPONSE
Focuses on skin, reproductive organ and
eyes

Acute radiation syndrome

- Includes effects in the hematopoietic,
gastrointestinal, and cardiovascular
system
SKIN
Radiation-induced skin injury
- Rare, but is still the most common
- Due to deterministic effect after high-dose
guided interventional procedures
- MC findings: erythema and acute radiation
dermatitis
- Cutaneous radiation syndrome - reaction
of the skin to the ionizing radiation
SKIN
Mechanism of skin injury
- Acute radiation-induced oxidative stress
- Reduction and impairment of functional
stem cells
- Endothelial cell changes
- Epidermal cell death
SKIN
Most radiosensitive structures in the skin
- Germinal epithelium
- Sebaceous glands
- Hair follicles

Deterministic effect threshold: 1 Gy

SKIN
Early transient erythema (1st)
- Initially, generalized erythema occurring within hours after
acute dose of 2 Gy and fades within a few hours
- Due to vasodilatation and histamine
Main erythema (2nd)
- Occurs 2 weeks after the initial injury with subsequent
irradiation (either high or low dose)
- Due to release of proteolytic enzyme from damaged basal
cells
Late erythema (3rd)
- Occurs after 8 to 52 weeks
- Represents dermal ischemia presenting as bluish or mauve
tinge skin discoloration
SKIN
Epilation (hair loss)
- Occurs after 3 weeks from 3 - 6 Gy dose
- Regrowth begins at 2 months
Desquamation
- Clear predictor of late delayed injury
- Reepithelialization occurs after 6 - 8 weeks
SKIN
Skin damage from radioactive contaminants
depends on:
- Quantity of radioactive material
- Characteristic of radionuclide
- Half-life and specific activity
- Region of the skin contaminated
- Length of time of contamination
SKIN
The higher the dose and dose rate (beyond
threshold for effects)
V
The shorter the latency and more severe the
effect
REPRODUCTIVE ORGANS
Gonads are radiosensitive

Testes cell population:

Most radiosensitive = Spermatogonia (Germ cells)
Intermediate radiosensitivity = primary and
secondary spermatocytes and spermatids
Most radioresistant = Mature Spermatozoa
REPRODUCTIVE ORGANS
Primary effect of radiation on the male
reproductive system:
- Reduced fertility
- Temporary sterility at 500 mGy
- Permanent sterility (azoospermia) at 6 Gy
REPRODUCTIVE ORGANS
Window of fertility
- Period before permanent sterility
- When there is enough mature sperm cells
REPRODUCTIVE ORGANS
Ova within the ovarian follicles (according to
size):
- Most radiosensitive = Intermediate follicles
- Most radioresistant = Large (mature) and
small follicles
Radiation dose = 1.5 Gy
Window period = due to relative
radioresistance of mature follicles
OCULAR EFFECTS
Lens
- Contains populations of radiosensitive
cells that can be damaged or destroyed
- Insofar, no removal system for these
damaged cells
OCULAR EFFECTS
Cataract formation
- Age-induced cataract = anterior pole of the
lens
- Radiation-induced cataract = posterior pole
of the lens
- Due to abnormal differentiation of
damaged epithelial cells and begins as a
small opacity of fibers in the anterior
subcapsular region that migrates
posteriorly
OCULAR EFFECTS
Deterministic effect threshold
(cataractogenic)
- Acute = 2 Gy
- Chronic = 5 Gy
SUMMARY
Acute dose of below 100 mGy will not result
to any functional impairment of tissues or
organs
ACUTE RADIATION SYNDROME
Radiation of the whole body and its response
ARS
- An organismal response quite distinct from
isolated local radiation injury
- Group of subsyndrome occurring in stages
over a period of hours to week after
exposure as the injury to various tissues
and organ system is expressed
ACUTE RADIATION SYNDROME
ARS occurs when high radiation dose is:
- Delivered acutely
- Involves exposure to the whole body or a
large portion
- External penetrating radiation (x-ray,
gamma ray, neutrons
SEQUENCE OF EVENTS
Clinical manifestation of EACH
SUNSYNDROME occurs in a predictable
sequence
- Prodromal
- Latent
- Manifest illness
- Fatality or Recovery
PRODROMAL
Prodromal
- Dose dependent
- Begins in minutes or hours
- Threshold of 0.5 to 1 Gy
- Non specific symptoms
- Subsides during the latent period
LATENT PERIOD
Latent period
- Shorter in duration when with high
radiation dose, and longer when with low
radiation dose
- Incubation period during which organ
damage is progressing
- Ends when clinical expression of organ
system damage, manifest illness stage
occurs, after 2 to 4 weeks from injury
MANIFEST ILLNESS PERIOD
Manifest illness period
- Most difficult to manage due to overlying
immunoincompetencies
- Higher risk for cancer and genetic
abnormalities in its progeny
HEMATOPOIETIC SYNDROME
All hematopoietic stem cells are very
radiosensitive, except for lymphocytes and
the mature counterparts
Posterior irradiation is more damaging due to
the location of the bone marrow maximizing
the damage
Deterministic effect threshold of 0.5 to 10 Gy
HEMATOPOIETIC SYNDROME
All hematopoietic stem cells are very
radiosensitive, except for lymphocytes and
the mature counterparts
Posterior irradiation is more damaging due to
the location of the bone marrow maximizing
the damage
Deterministic effect threshold of 0.5 to 10 Gy
HEMATOPOIETIC SYNDROME
Cause a transient increase in neutrophils due
to release from extravascular stores
Transient lymphopenia is due to
radiation-induced apoptosis
GASTROINTESTINAL SYNDROME
Becomes the dominant syndrome and source
of lethality in higher radiation doses (greater
than 12 Gy)
GASTROINTESTINAL SYNDROME
Radiation-induced intestinal mucositis
- Due to breakdown of the mucosal barrier
allowing entry of luminal contents (eg,
antigens, bacterial products, and digestive
enzyme)
- Poor regulation of electrolytes and
nutrients
- Entry of bacteria to the portal system
GASTROINTESTINAL SYNDROME
Most potentially serious effect
- Severe decrease in circulating white cells
at a time when bacteria are invading the
blood stream from the GI tract
Pancytopenia may not be seen because
patient may already die before significant
decrease in the bone marrow ensues
NEUROVASCULAR SYNDROME
Death occurs within 2 to 3 days after
supralethal dose of 50 Gy
Due to shock , edema, ICP and anoxia
Shortest time frame with most severe
symptoms
SUMMARY OF SUBSYNDROMES
RADIATION-INDUCED CARCINOGENESIS
RADIATION-INDUCED CARCINOGENESIS
RADIATION EFFECT IN UTERO
Response after exposure to ionizing radiation
depends on a number of factor:
- Total dose
- Dose rate
- Radiation quality
- Stage of development at the time of
exposure
RADIATION EFFECT IN UTERO
Gestational period stages:
- Preimplantation stage
- Major organogenesis
- Fetal growth stage
Each stage is different in response to
radiation due to relative radiosensitivity of the
tissues at the time of exposure
PREIMPLANTATION
Preimplantation stage
- Beings with the union of egg and sperm
and continues to D9
- Zygote embedded to the uterine wall
- Forms the morula and blastula
- Very sensitive to radiation (all-or-nothing
response)
- Dose less than 100 mGy - the risks are very
low
PREIMPLANTATION
Most sensitive times of exposure during
preimplantation:
- First 12 hours - fusion of two pronuclei
- At 30-60 hours - occurrence of 1st cell division

Most chromosomal loss at this early stage is

lethal
Dose of 350 mGy is required to induce prenatal
death
ORGANOGENESIS
Organogenesis
- At the 2nd to 8th week of gestation
- More frequent embryonic malformations
occurs
Critical period
- Greatest probability of a malformation in a
specific organ system when the radiation
exposure is received during the period of
peak differentiation
ORGANOGENESIS
CNS injury
- Only organ system showing an association
between malformations and low-LET
radiation doses less than 250 mGy
- Takes the longest time to develop hence
prone to radiation-induced damage
- Other organ malformation that is
radiation-induced is usually accompanied
by a CNS abnormality
FETAL GROWTH STAGE
Fetal growth stage
- Radiation-induced prenatal death and
congenital abnormalities are negligible
even in exceptional high doses but within
the therapeutic limits
- Anomalies in the CNS and sensory organs
are the primary radiation-induced
abnormalities observed in this period
FETAL GROWTH STAGE
Greatest sensitivity is seen in 8th and 15th
week of gestation
Risks included severe mental retardation
Classification of Biologic Effects
● Stochastic
● Deterministic
Stochastic Effect
● Example: Radiation Induced Cancer and Hereditary
Effects
● No difference in the severity of the disease
● Risk increases with dose and there is no threshold dose
below which the magnitude of the risk goes to zero
● The principal health risk from low-dose radiation
Deterministic Effect
● Requires a much higher dose to produce a clinically
observable effect
● Severity of the injury increases with dose
● Also known as tissue reactions
● Has a threshold dose below which the effect does not
occur or is subclinical
Deterministic Effect
● Includes: Skin Erythema, Fibrosis, Hematopoeitic
Damage
● Caused by severe radiation accident and observed in
healthy tissue that is unavoidable by severe radiation
during radiation therapy
Ubiquitous Background Exposure
● Natural occuring sources of r