chapter 20:radiation biology - human health campus · repairing radiation-induced dna damage...

IAEAInternational Atomic Energy Agency

Slide set of 97 slides based on the Chapter authored by

J. WONDERGEM

of the IAEA publication (ISBN 978-92-0-131010-1):

Diagnostic Radiology Physics:

A Handbook for Teachers and Students

Objective:

To familiarize students with the action of ionizing radiation

on living matter.

Chapter 20: Radiation Biology

Slide set prepared

by E.Okuno (S. Paulo, Brazil,

Institute of Physics of S. Paulo University)

IAEA

20.1. Introduction

20.2. Radiation Injury to DNA

20.3. DNA Repair

20.4. Radiation-Induced Chromosome Damage and Biological Dosimetry

20.5. The Cell Cycle

20.6. Survival Curve Theory

20.7. Concepts of Cell Death

20.8. Cellular Recovery Processes

20.9. Relative Biological Effectiveness

20.10. Carcinogenesis (Stochastic)

20.11. Radiation Injury to Tissues (Deterministic)

20.12. Radiation Pathology; Acute and Late Effects

20.13. Radiation Genetics: Radiation Effects on Fertility

20.14. Foetal Irradiation

Chapter 20. TABLE OF CONTENTS

Diagnostic Radiology Physics: a Handbook for Teachers and Students – chapter 20,2

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20.1. INTRODUCTION


• Radiation biology (radiobiology) is the study of the

action of ionizing radiations on living matter

• physical

• chemical

• biological

variables that affect

dose response at the

cellular

tissue

whole body

levels at dose and dose

rates relevant to

diagnostic radiology

An overview of the biological effects of ionizing radiation is

given, with attention paid to the:

IAEADiagnostic Radiology Physics: a Handbook for Teachers and Students – chapter 20,4

20.1. INTRODUCTION

20.1.1. Deterministic and stochastic responses

Biological effects of radiation in humans occur either in

irradiated individuals

(somatic effects)

descendants

(hereditary or genetic effects)

deterministic effect

(tissue reactions)

stochastic effects


• Result from cell loss or damage e.g. moist desquamation from

interventional cardiology

• Most organs or tissues of the body are unaffected by the loss of a few

cells, however, if the number of cells lost is sufficiently large, there is

observable harm and hence loss of tissue/organ function

• Above a threshold dose, the severity of the effect necessarily increases

with increasing dose. This threshold varies from one effect to another

• May occur a few hours or days after exposure (i.e. early skin reaction)

or may require months or years before expression (i.e. cataract of the

eye lens)

20.1. INTRODUCTION


Deterministic effects


20.1. INTRODUCTION


Stochastic effects

• Are probabilistic effects: the probability of the occurrence of an effect is

a function of dose

• The severity of an effect is not a function of dose

• The probability of the occurrence of an effect increases with dose

• Are assumed to exhibit no threshold dose below which they cannot

occur

• The major stochastic effects of concern at typical diagnostic radiology

levels are cancers and genetic effects. They are exclusively late effects

because they do not appear until years after radiation exposures


20.1. INTRODUCTION

20.1.2. Diagnostic radiology

There is a large range in

the amount of radiation

dose given by various

diagnostic procedures

0 2 4 6 8 10 12 14

1997–2007

1991–1996

1980–1990

1970–1979

Health care level I (UNSCEAR report 2008)

Average effective dose per examination (mSv)

Angiography

CT scan

Mammography

Abdomen X-ray

Chest radiography

In a small number of procedures, radiation damage to tissue

can occur in skin reactions from long interventional procedures


20.1. INTRODUCTION

20.1.2. Diagnostic radiology

• The amount of energy deposited in the tissue of patients as a

result of diagnostic radiology examinations or interventional

procedures is typically a number of orders of magnitude less than

delivered during radiation oncology

Consequently the detriment caused is largely confined to

stochastic effects

• The occupational dose, although orders of magnitude lower than

that of the patient during a single procedure, may become

considerable for a worker performing large numbers of procedures,

and especially if needed shielding precautions are not observed

Consequently there is an increasing incidence of injury to the lens

of the eye for some workers, for example, during interventional

procedures

patient

worker


20.1. INTRODUCTION

20.1.3. International Organisations on Radiation effects

BEIR (Biological Effects of

Ionizing Radiation)

UNSCEAR (United Nations

Scientific Committee on the

Effects of Atomic Radiation)

ICRP(International Commission

on Radiological Protection)

is involved in recommendation

and development of guidelines in

the field of radiation protection

Collect and analyze data from the

recent literature regarding

biological effects of ionizing

radiation

Report periodically on risk

estimates for radiation induced

cancer and hereditary effects


20.2. RADIATION INJURY TO DNA

20.2.1. Structure of DNA

Deoxyribonucleic acid (DNA) contains the genetic

information of the cell

Ref. Nature, vol 171, page 737, 1953

J. D. WATSON and F. H. C. CRICK

• The backbone of the DNA strand is made of

alternating sugar and phosphate groups

• A nucleotide is a subunit of DNA, and is

composed of a “base” linked to a sugar

(deoxyribose) and a phosphate group

• DNA is a large molecule and has a characteristic

double-helix structure consisting of

two strands, each made up of a sequence of

nucleotides



20.2.1. Structure of DNA

• The unique pairing of the nucleotide bases

provides DNA with its identity which is used in

replication

• One of the pair must be a purine and the other a

pyrimidine for bonding to occur

• The cell’s genetic information is carried in a

linear sequence of nucleotides that make up the

organism’s set of genes

The four bases of DNA can be classified in two groups:

purines pyrimidines

adenine (A)

guanine (G)

cytosine (C)

thymidine (T)

IAEA, Radiation Protection in

Nuclear Medicine



20.2.2. Radiation chemistry; direct and indirect effects

• When ionizing radiation energy is

deposited in a certain macromolecule,

associated with observable biological

effects, such as DNA, it is called a

direct effect of ionizing radiation

• The radicals formed, namely the hydrated electron (eaq-), the hydrogen

atom (H·) and the hydroxyl radical (OH·), are able to diffuse far enough to

reach and damage the critical targets

This is referred to as indirect action of ionising radiation

• Alternatively, photons may be absorbed in

the water of an organism causing

excitation and ionization in the water

molecules

Hall and Giaccia, 2006


The interactions of ionizing radiation with matter lead to loss of

radiation energy through ionization, and the formation of free

radicals



• react rapidly (10-10 s) with neighbouring molecules and produce

secondary DNA or lipid radicals

• are fragments of molecules having unpaired electrons, which have

high reactivity with cellular molecules and, therefore, have a short

life

• are generated in great number by ionizing radiation due to the

process of energy absorption and breakage of chemical bonds in

molecules

• are known to play a major role on biological tissues and organisms

Free Radicals:


• Water is the most predominant molecule in

living organisms (about 80 % of the mass of

a living cell)

• Therefore, a major proportion of the radiation

energy deposited will be absorbed in cellular

water

• About two thirds of the biological damage

caused by low LET radiations (sparsely

ionizing radiation) such as X rays or

electrons is due to indirect action



Hall and Giaccia, 2006

A complex series of chemical changes

occurs in water after exposure to ionizing

radiation; this process is called water

radiolysis

Indirect effects


DNA damage is the primary cause of cell

death induced by radiation

Radiation exposure produces a wide

range of lesions in DNA such as:• single strand breaks (SSBs)

• double strand breaks (DSBs)

• base damage

• protein-DNA cross links

• protein-protein cross links


20.2.3. DNA Damage

The numbers of lesions induced in the

DNA of a cell by a dose of 1-2 Gy are

approximately:

• base damages >1000

• single strand breaks ~1000

• double strand breaks ~40

Double

Strand

Break

Base Change

Dimer

Formation

Single

Strand

BreakInterstrand

Cross Link

Travis, 1989; courtesy of Dr Raymond E Meyn and Dr Ron

Humphrey, M D Anderson cancer Center


There are experimental data showing that:

• initially-produced DSBs correlate with radiosensitivity

and survival at lower dose

• unrepaired or mis-repaired DSBs also correlate with

survival after higher doses

• there is a causal link between the generation of DSBs

and the induction of chromosomal translocations with

carcinogenic potential


20.2.3. DNA Damage

Double

Strand

Break

Base Change

Dimer

Formation

Single

Strand

BreakInterstrand

Cross Link

Travis, 1989; courtesy of Dr Raymond E Meyn and Dr Ron

Humphrey, M D Anderson cancer Center

Double strand breaks (DSBs) play a critical

role in cell killing, carcinogenesis and

hereditary effects


20.3. DNA REPAIR

DNA repair mechanisms:

• base excision repair (BER)

• mismatch repair (MR)

• nucleotide excision repair (NER)

respond to damage such as base oxidation, alkylation, and strand

intercalation

There are multiple enzymatic mechanisms of detecting and

repairing radiation-induced DNA damage

Excision repair consists of cleavage of the damaged DNA strand by enzimes that

cleave the polynucleotide chain on either side of the damage and enzymes which

cleave the end of a polynucleotide chain allowing removal of a short segment

containing the damaged region

DNA polymerase can then fill in the resulting gap using the opposite undamaged

strand as a template


20.3. DNA REPAIR

For double strand breaks there are two primary repair pathways:

HR repair utilizes sequence homology

with an undamaged copy of the broken

region and hence can only operate in

late S- or G2- phases

Undamaged DNA from both strands is

used as templates to repair the

damage

The repair process of HR is error-free

NHEJ repair operates on blunt ended

DNA fragments

This process involves the repair

proteins recognizing lesion termini,

cleaning up the broken ends of the

DNA molecule, and the final ligation of

the broken ends

Repair by NHEJ operates throughout

the cell cycle but dominates in G1/S-

phases

The process is error-prone because it

does not rely on sequence homology

non-homologous end joining (NHEJ) and homologous recombination (HR)


20.3. DNA REPAIR

DNA repair mechanisms are important for the recovery of

cells from radiation and other damaging agents

Unrepaired or mis-repaired damage to DNA

will lead in the exposed cell to:

cell deathcancer or

hereditary effects

when severe often leads to:might lead to:

mutations and/or chromosome damage


20.4. RADIATION-INDUCED CHROMOSOME DAMAGE AND

BIOLOGICAL DOSIMETRY

When the repair of DNA-double strand breaks is incomplete there may

be serious implications for a cell, namely it may lead to chromosomal

damage (aberrations)

Aberrant (damaged) chromosomes:

• rings generated when broken ends rejoin with other broken ends

• dicentrics (chromosomes having two centromeres)

• translocations

• other chromosome aberrations

Chromosomes:

• can be found in the nucleus of the cell in the living cell

• consist of DNA and proteins forming a threadlike structure

containing genetic information arranged in a linear sequence

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• Dicentrics and rings are

“unstable” aberrations and are

lethal to the cell and as a

consequence they are not

passed on to progeny

• Symmetric translocations and

small deletions are in general

non lethal

• When translocations occur in

germ cells they may lead to an

increase in hereditary effects in

the offspring Inversion

Symmetrical

(Stable)Breaks

Intrachange

Asymmetrical

(Unstable)

Centric

Ring

Interchange

Translocation DicentricAdapted from IAEA - Biodosimetry: available methods and role in dose assessment and prognosis




• Structural chromosome aberrations can be used as an indicator of

radiation exposure

• Chromosome analysis in mitotic spreads (karyotyping), micronucleus

formation and fluorescent in situ hybridisation (FISH) can detect

unrepaired DNA damage in chromatids by radiation and a variety of

DNA damaging agents

• These cytological techniques are used in biodosimetry (assays to

estimate the radiation dose based on the type and/or frequency of

chromosomal aberrations in the exposed cells/tissues)

• Biodosimetry has provided an important tool for assessing doses in

known or suspected cases of acute (unwanted) radiation exposure


20.5. THE CELL CYCLE

The cell cycle has two well defined time

periods:

• Mitosis (M), where division takes place

• the period of DNA-synthesis (S)

The S and M portions of the cell cycle are

separated by two periods (gaps) G1 and G2

• Cells in a growing population (e.g. skin, gut, bone marrow), but

not resting fully differentiated G0 phase cells, participate in the cell

cycle and thus are more sensitive to radiation

• Replication of the genome occurs in the S-phase and mitotic

propagation to daughter generations occurs in the G2/M phases



Typical cell generation times are 10 – 40 hours with

the:

• G1 phase taking about 30 %

• S- phase 50 %,

• G2 phase 15 %

• M- phase 5 % of the cell cycle time

There are checkpoints at the G1/S

and G2/M boundaries that ensure the

fidelity of genomic processing



Radiosensitivity differs throughout the cell

cycle with, in general:

• late S-phase being most radio resistant

• G2/M being most radiosensitive

• G1 phase taking an intermediate position

• The greater proportion of repair by HR than by NHEJ in late S phase

may explain the resistance of late S phase cells

• Chromatin compaction and poor repair competence (reduced enzyme

access) could explain the high radiosensitivity in G2/M phase

• Resting cells, not involved in the cell cycle, are even more resistant to

radiation when compared to late S-phase cells


20.6. SURVIVAL CURVE THEORY

20.6.1. Survival curves

• The generally accepted standard for measuring the

radiosensitivity of a cell population is

“the retention of reproductive integrity”

i.e. the ability of a cell to undergo more than

5-6 cell divisions and produce a viable colony

containing at least 50 cells

• This is referred to as cell survival


Typical survival curves for cells irradiated by densely ionizing

radiation (high LET) and sparsely ionizing radiation (low LET)


20.6.1. Survival curves

For high LET radiation, the survival curve may be exponential,

i.e. linear on a semi-logarithmic plot

Model

linear quadratic

Model

multi target single hit



20.6.2. Linear-quadratic (LQ) model

• This model assumes that there are two

components to cell killing by radiation,

commonly represented by two

constants, α and β

• In this model, cell survival fraction S is

described as a function of dose D by the

following equation:

• The most common model used today is

the linear-quadratic model, where cell

death as a function of dose is described

by a second-order polynomial

)( 2DDeS βα +−=

)( 2DDeS βα +−=

S



20.6.2. Linear-quadratic (LQ) model

A plausible explanation of the linear

component is that the majority of DNA-

interactions are single-radiation track events

• Under these circumstances, DNA damage can be

effectively repaired before possible interaction

with another single track when enough time is

available and doses are relatively low

• As the dose or dose rate increases, multi-track

events, reflecting the quadratic component, will

predominate resulting in an increased probability

of mis-repair and cell death

)( 2DDeS βα +−=

S



20.6.3. Target theory

The target theory is based upon the idea that there

are n targets in a cell, all of which must be “hit” to kill

the cell

An alternative older model is the single-hit

single-target model described by:

D0 is effectively the reciprocal of α (of LQ model)

and represents the dose which reduces survival to

e -1 or 37 %

0/ DDeS−

=

0/ DDeS−

=

S



20.6.3. Target theory

• This is reliable at high dose but not at low dose,

because it does not describe accurately the

‘shoulder’ region at low doses, even if another

single-hit term is added

• The log-linear relationship is consistent with data

from some bacteria but it does not apply in

eukaryotic cells (except at high LET), which show

shouldered survival curves that can be

accommodated by a single-hit multi-target model

described by:

nDDeS )1(1 0/−

−−=

n is the number of targets

0/ DDeS−

=

S


20.7. CONCEPTS OF CELL DEATH

• Radiation doses in the order of several sieverts may lead

to cell loss

• Cells are generally regarded as having been “killed” by

radiation if they have lost reproductive integrity, even if

they physically survived

Loss of reproductive integrity can occur by:

• apoptosis

• necrosis

• mitotic catastrophe

• induced senescence

although all but the last of these

mechanisms ultimately results in

physical loss of the cell, this may

take a significant time to occur



Necrosis

• is a form of cell death associated with loss of cellular membrane

activity

• cellular necrosis generally occurs after high radiation doses

Apoptosis or programmed cell death:

• can occur naturally or result from insult to the cell environment

• occurs after low doses of irradiation in particular cell types:

lymphocytes

serous salivary gland cells

certain cells in the stem cell zone in testis and intestinal crypts



Reproductive cell death

• is a result of mitotic catastrophe (cells attempt to divide

without proper repair of DNA damage) which can occur in

the first few cell divisions after irradiation

• it occurs with increasing frequency after increasing doses

Senescent cells

• are metabolically active but have lost the ability to divide


20.8. CELLULAR RECOVERY PROCESSES

At higher doses and dose rates (i.e.

multiple radiation exposures during

interventional cardiology), cellular

recovery may play an important role in

the fixation of the radiation damage

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Due to cellular recovery an increase in cell

survival can be expected when the same

dose is given as:

• 2 fractions separated by 2 or more

hours compared to the

• single fraction

This greater survival is attributed to:

sub-lethal damage repair (SLDR)

between dose fractions



20.8.1. Sub-lethal and potentially lethal damage repair




• T½ is the half time of repair, defined as the time it takes for

half the repair to take place

T½ ≈ ½ to 1 h for cells in culture, but can be longer for tissues

Thus full repair may take 6 - 8 hours and can be longer in tissues

In central nervous system (CNS) it may be greater than 24 hours

• The recovery ratio is a measure of sub-lethal damage repair

(SLDR) and is given by :

dose single a as dose total the receiving cells of survival

dose split a receiving cells of survivalSLDR =




• Potentially lethal damage repair (PLDR) is determined

by delayed plating experiments

• In such experiments contact inhibited (i.e. confluent cell cultures)

cells are:

- irradiated

- incubated for various periods

- subsequently reseeded

• Analysis of cell survival by colony assay then gives a measure of

this type of repair



20.8.2. Fractionation effect

• The ‘shoulder’ or the curvature of a survival curve is

usually considered to be a reflection of the repair capacity

of a cell population

• In terms of the target theory this can be thought of as

arising from the concept that sub-lethal DNA damaging

events must be accumulated to allow sub-lesion

interactions for cell killing to occur



20.8.3. Dose rate effects

• The successive increase of cell survival with declining dose rate

is consistent with the role of time in repair

• The dominance of repair at low dose rate eliminates the

shoulder/curvature of the survival curve and results in a straight

but shallower line on a semi-logarithmic plot, with good separation

of survival between cell lines with different repair capacity. This is

due to the cells having different radiosensitivities

• Repair during irradiation is:

- negligible at dose rates of 1- 5 Gy/min

- significant at dose rates <100 mGy/min


20.9. RELATIVE BIOLOGICAL EFFECTIVENESS

Equal doses of different types of radiation produce unequal

biological effects

• Comparison of effects of different types of radiation is

expressed as Relative Biological Effectiveness (RBE), defined

as:

• Historically the reference used was 250 kV X rays but more recently

Co-60 radiation has become the standard

effect biological same the produce to radiation test from Dose

effect biological given a produce to radiation standard from Dose=RBE


20.9. RELATIVE BIOLOGICAL EFFECTIVENESS

RBE - Relative Biological Effectiveness

• varies with cell system endpoint

• varies with dose

• is higher at lower doses and low dose rates

• is lower for high doses with a single fraction than for multiple

small fractions

For radiation protection purposes (at low doses and low dose

rates), the ICRP has described the effectiveness of radiations of

differing qualities by a series of Radiation Weighting Factors (wR)


20.10. CARCINOGENESIS (STOCHASTIC)

20.10.1. Mechanism of multistage carcinogenesis

The development of cancer in

tissues is assumed to be a

multi-stage process that can be

sub-divided into four phases:

This subdivision is an over- simplification yet it provides a suitable

frame work for the identification of specific molecular and cellular

changes involved

neoplastic initiation

promotion

conversion

progression




Neoplastic initiation leads to the irreversible potential of normal

cells for neoplastic development by creating unlimited proliferative

capacity

• Further neoplastic development of initiated cells depends on promotional

events which involves intercellular communication, e.g. by growth factors,

hormones or environmental agents

This results in the proliferation of the initiated pre-neoplastic cells in a

semi-autonomous manner

• There is good evidence that this event results from one or more

mutations in a single cell which is the basis of the clonal evolution of the

cancer




During the process of conversion of the

pre-neoplastic cells into fully malignant cells:

• additional mutations in other genes are accumulated,

probably facilitated by increasing loss of genomic stability

• The subsequent progression into an invasive cancer

depends on still more mutations in the unstable genome




There is strong evidence from animal studies and

some human studies that the risk of radiation-induced

cancer may be influenced by various genes, such as

mutations of the:

• Rb gene (predisposing for retinoblastoma and osteosarcoma)

• BRCA1 gene (predisposing for early breast cancer and ovarian

cancer)

or the presence of polymorphisms (SNPs: single nucleotide

polymorphisms) in the gene

However, at the present state of knowledge the role of genetic

susceptibility on individual risks of radiation-induced cancer cannot

be resolved definitively, although there is general agreement that it

will be important



20.10.2. Mechanism of mutation induction

Mutations e.g. by the translocation of

a promoter, may result in an

increased rate of proliferation

Proto-oncogene mutations to

oncogenes are thus classified as

“gain-of-function” mutations

Two classes of cancer-associated

genes have been identified:

tumour suppressor genproto-oncogenes

Normal genes involved in growth

regulation

Genes involved in growth regulation of

normal cells and that prevent excessive cell

proliferation

The critical mutation in these genes are

“loss-of-function” mutations which may be

the result of partial or complete loss of the

gene structure, e.g. by deletions. Since

radiation-induced DNA damage preferentially

causes deletions, it is generally assumed

that the inactivating mutation of tumour

suppressor genes is the most probable

mechanism for the induction of cancer by

radiation



20.10.2. Mechanism of mutation induction

• There is good evidence that many, if not most cancers, are the clonal

descendants of a single neoplastic cell and, furthermore, that a

single double strand break may, although with an extremely low

probability, cause a deletion in a specific DNA sequence, e.g. of a

tumour suppressor gene

• It has hence been argued that, in principle, a single mutational event

in a critical gene in a single target cell in vivo can create the potential

for neoplastic development

• Thus, a single radiation track traversing the nucleus of an

appropriate target cell has a finite probability, albeit very small, of

generating the specific damage of DNA that results in the initiating

mutation

• This argument would strengthen the hypothesis that the risk of

radiation induced cancer increases progressively with increasing

dose, and there is no lower threshold



20.10.3. Risk models

In order to evaluate the health effects of radiation on exposed

populations or workers, the incidence or frequency of a certain

effect is studied in both the exposed and non exposed control

group

Risk estimates derived from these studies are

generally presented as

• RR (relative risk)

• ERR (excess relative risk)

• EAR (excess absolute risk)

per unit of radiation dose




Excess Relative Risk (ERR)

1−= RRERR

Excess Absolute Risk (EAR)

0RREAR r −=

Relative Risk (RR)

group exposed-non the in effect same the offrequency

group exposed the in cases) cancer of number (i.e. effect certain a offrequency =RR

0R

RRR r=




For assessing the risk of radiation-induced cancer in humans

two conceptually different models are used:

• This model assumes that the effect is to

increase the natural incidence at all ages

subsequent to exposure by a given factor

• Because the natural or spontaneous

cancer incidence rises significantly in old

age, this model predicts a larger number

of radiation-induced cancers in old age

• This model is favoured by the BEIR

committee estimating risks after radiation

exposure

relative-riskabsolute-risk

• This model assumes that

radiation induces a “crop” of

cancers over and above the

natural incidence and

unrelated to it

• After the latency period has

passed, the cancer risk

returns to “spontaneous”

levels



20.10.4. Time course and latency period

Epidemiological information derived from:

• the life span study (LSS) of the A-bomb survivors in Japan

• data from other studies

has provided the main source of risk estimates currently used in

radiation protection

is the time interval between exposure to

irradiation and the appearance of cancer

• Leukaemia has a minimum latency of about 2 years after exposure; the

pattern of risk over time peaks after ten years (most cases occur in the

first 15 years) and decreases thereafter

• Solid tumours show a longer latency than leukaemia, by anything from

10 to 60 years or even more

Latency period



20.10.5. Dose response relationship for cancer

• The linear non-threshold (LNT) hypothesis was introduced by

the ICRP as the best practical approach to managing risk from

radiation exposures to low dose/low dose rates

• The LNT model postulates that there is a linear relationship

between radiation dose and health risk without a threshold at low

doses

It means that there is no level of radiation exposure that can be

assumed to have no associated health risk

• The slope of the linear dose-response curve provides the risk

coefficient (cancer risk per unit radiation dose received)

appropriate for low level exposures



20.10.6. Dose and dose-rate effectiveness factor (DDREF)

Both BEIR and UNSCEAR committees considered that there is a

dose-rate effect for low energy transfer radiation, with fewer

malignancies induced if a given dose is spread out over a period of

time at low dose rate than if it is delivered in an acute exposure

Comparison of the:

• Japanese data of A-bomb survivors with those of other

• epidemiological studies including multiple medical and

chronic exposures

have demonstrated that the risk calculated in proportion of the

dose differs



20.10.6. Dose and dose-rate effectiveness factor (DDREF)

• The DDREF is defined as the factor by which radiation

cancer risks observed from large acute doses should

be reduced when the radiation is delivered at low dose

rate or in a series of small dose fractions

• For general purposes in radiological protection,

the ICRP recommends a

for doses below 200 mSv at any dose rate and

for higher doses if the dose rate is < 100 mSv/hDDREF = 2



20.10.7. Cancer risk

The ICRP recommendations for radiation protection purposes are

based on the Japanese and other epidemiological studies

The risk coefficients for cancer lethalithy

non radiation workers

• 5x10-2 per Sv

• 10x10-2 per Sv for high doses and

dose rates

high doses: higher than 200 mSv

high dose rates: higher than 100 mSv/h

These estimates show mean values

for the whole population

workers

• 4x10-2 per Sv

• 8x10-2 per Sv for high doses and

dose rates



20.10.7. Cancer risk

• There is ample evidence that cancer risk is

not only dependent on the dose but also on

the age at exposure and to a lesser extend

also on gender

• In most cases, those exposed at an early

age are more susceptible than those

exposed at later times and females are

slightly more susceptible than males

Since not all radiation exposures concern

the whole body but only a region or just a

part of the body, tissue weighing factors (wT )

should be taken into account

Hall and Giaccia, 2006, adapted from ICRP:

Recommendations. Annals of the ICRP Publication 60,

Oxford, England, Pergamon Press, 1990

From a single small dose of irradiation

Relatice risk model with DDREF=2

(

)

(y)


males age of exposure (y)

5 15 30 50 70

Stomach 65 46 28 25 14

Colon 285 204 125 113 65

Liver 50 36 22 19 8

Lung 261 180 105 101 65

Prostate 80 57 35 33 14

Bladder 177 127 79 76 47

Other 672 394 198 140 57

Thyroid 76 33 9 1 0.1

All solid 1667 1076 602 507 270

Leukemia 149 105 84 84 73

All cancers 1816 1182 686 591 343


20.10.7. Lifetime attributable risk of cancer incidence from BEIR VII, (2006)

Number of cases per 100,000 persons exposed to a single dose of 0.1 Gy

These estimates are obtained as combined estimates based on relative and absolute risk transport and have been

adjusted by a DDREF of 1.5, except for leukemia, which is based on a linear-quadratic model

Stomach 85 61 36 32 19

Colon 187 134 82 73 45

Liver 23 16 10 9 5

Lung 608 417 242 230 147

Breast 914 553 253 70 12

Uterus 42 30 18 13 5

Ovary 87 60 34 25 11

Bladder 180 129 79 74 47

Other 719 409 207 148 68

Thyroid 419 178 41 4 0.3

All solid 3265 1988 1002 678 358

Leukemia 112 76 63 62 51

All cancers 3377 2064 1065 740 409

Stomach 85 61 36 32 19

Colon 187 134 82 73 45

Liver 23 16 10 9 5

Lung 608 417 242 230 147

Breast 914 553 253 70 12

Uterus 42 30 18 13 5

Ovary 87 60 34 25 11

Bladder 180 129 79 74 47

Other 719 409 207 148 68

Thyroid 419 178 41 4 0.3

All solid 3265 1988 1002 678 358

Leukemia 112 76 63 62 51

All cancers 3377 2064 1065 740 409

females age of exposure (y)5 15 30 50 70



20.10.7. Lifetime attributable risk of cancer mortality from BEIR VII, (2006)

Number of cases per 100,000 persons exposed to a single dose of 0.1 Gy

males age of exposure (y)

5 15 30 50 70

Stomach 34 25 16 13 8

Colon 139 99 61 57 36

Liver 37 27 16 14 8

Lung 264 182 107 104 71

Prostate 15 10 7 7 7

Bladder 38 27 17 17 15

Other 255 162 94 77 36

All solid 781 533 317 289 181

Leukemia 71 70 64 71 69

All cancers 852 603 381 360 250

These estimates are obtained as combined estimates based on relative and absolute risk transport and have been

adjusted by a DDREF of 1.5, except for leukemia, which is based on a linear-quadratic model

females age of exposure (y)5 15 30 50 70

Stomach 48 34 21 19 13

Colon 86 62 38 35 25

Liver 20 14 9 8 5

Lung 534 367 213 204 140

Breast 214 130 61 19 5

Uterus 10 7 4 3 2

Ovary 47 34 20 18 10

Bladder 51 36 23 22 19

Other 287 179 103 86 47

All solid 1295 862 491 415 265

Leukemia 52 52 51 54 52

All cancers 1347 914 542 469 317

Stomach 48 34 21 19 13

Colon 86 62 38 35 25

Liver 20 14 9 8 5

Lung 534 367 213 204 140

Breast 214 130 61 19 5

Uterus 10 7 4 3 2

Ovary 47 34 20 18 10

Bladder 51 36 23 22 19

Other 287 179 103 86 47

All solid 1295 862 491 415 265

Leukemia 52 52 51 54 52

All cancers 1347 914 542 469 317


20.11. RADIATION INJURY TO TISSUES (DETERMINISTIC)

20.11.1. Tissue and organ anatomy

• Tissues and organs in the human body are composed of

many different cells

• The majority of cells in tissues and organs are differentiated

and have developed a specific morphology and function

• In many tissues and organs, but not all, the rate of death of

differentiated cells is balanced by renewal from a “pool” of

tissue stem cells in order to maintain a healthy state and

function

IAEA




• Since radiation may lead to sterilization of dividing

cells, in particular tissue stem cells, terminally

differentiated (mature) cells can no longer be

replaced

• Lack of replacement can eventually result in a loss

of sufficient numbers of functioning cells and as a

consequence a loss of tissue and/or organ integrity

and function




• Tissue and organ reactions are generally

classified under deterministic effects

• Above a certain threshold (sufficient number of cells

sterilized by radiation), the severity of the effect will

increase steeply with increasing radiation dose



20.11.2. Expression and measurements of damage

The radiosensitivity of the cells of a number of normal tissues

can be determined directly using in situ assays in the

laboratory

Considerable variability in sensitivity is apparent within and

between the different tissues and organs

Detailed knowledge about radiation-induced

normal tissue effects comes primarily from

experience with:

• radiotherapy patients

• radiation accidents

• laboratory studies, mainly with rodents




For the study of the response of individual organs, one widely used

approach is to define a level of functional deficit and to determine the

percentage of irradiated individuals (or animals in laboratory studies)

that express at least this level of damage following different radiation

dosesThis approach results in

sigmoidal dose response curves

ICRP publication 103, 2007

In any exposed population, there is

individual variation in radiosensitivity

which is influenced by several factors

including:

• hormonal status

• age

• state of health of the individuals




Upper panel: expected sigmoidal

increase in frequency in a population

of individuals with varying

sensitivities

ICRP publication 103, 2007

Relationships between dose and the:

• frequency

• severity of tissue reactions (deterministic effects)

Lower panel: expected dose-severity

relationships for three individuals with

different sensitivities


20.12. RADIATION PATHOLOGY; ACUTE AND LATE EFFECTS

20.12.1. Acute and late responding normal tissues

• Radiation-induced cell death in normal tissues generally occurs

when the cells attempt to divide (mitosis)

• Tissue tends to respond on a time scale similar to that of the normal

rate of loss of functional cells in the tissue

Traditionally the effects of radiation on normal tissues, based largely

on functional and histopathological endpoints, has been classified,

according to the time of clinical symptoms after the exposure to

manifest, into:

within a few weeks

early (or acute) responses

many months or years

late responses



20.12.2. Pathogenesis of acute and late effects

• Acute responses occur primarily in tissues with rapid cell renewal,

where cell division is required to maintain the function of the organ

Because many cells express radiation damage during mitosis, there is

early death and loss of cells by radiation

Examples of early responding tissues are:

• bone marrow

• gastrointestinal tract

• skin

In these tissues the acute radiation responses

have been related to death of critical cell

populations such as the stem cells in the cripts of

the: • bone marrow

• small intestine

• basal layer of the skin




In lymphoid and myeloid tissue, death by apoptosis plays an important

role in the temporal response of these tissues to irradiation

In the crypts of the small bowel there is a fraction of stem cells that die

by apoptosis, while other cells die by a mitosis-linked death

Radiation-induced apoptosis has

also been detected in many cells

and tissues, such as:

• lymphoid

• thymic

• hematopoietic

• spermatogonia

• salivary gland

• intestinal crypts

Acute responses




Late responses tend to occur under normal conditions in organs

whose parenchymal cells divide:

infrequently rarely

liver or kidney central nervous system

or muscle

Depletion of the parenchymal cell population due to entry of

cells into mitosis, with the resulting expression of radiation

damage and cell death, will thus be slow




• Late responses also occur in tissues that manifest early

reactions, such as skin/subcutaneous tissue and intestine,

but the nature of these reactions (subcutaneous fibrosis,

intestinal stenosis) is quite different from the early reactions

• One common late reaction is the slow development of tissue

fibrosis and vascular damage that occurs in many tissues and

is often seen in cancer patients a number of years after

radiation treatment



20.12.3. Radiation-induced skin reaction

The skin consists of a :

relatively thin epidermis

• renews rapidly (15-30 days)

much thicker underlying dermis

• is highly vascularised

connective tissue

hair follicles

sweat glands

sebaceous glands

nerve endings

• contains


• The early erythema is believed to be related to the release of

5-hydroxy-tryptamine by mast cells, increasing vascular permeability

• Similar mechanisms may lead to the early nausea and vomiting observed

following irradiation of the intestine



• A second and more severe erythema develops after a latent period of

8-10 days, mainly due to an inflammatory reaction of the skin

It is bright red in colour, limited to the radiation field, and accompanied

by a sensation of heat and itching

• early transient erythema similar to sunburn

• occurs within a few hours after irradiation

• reaches a peak value within 24 hours

A wide-variety of expressions of radiation-induced skin effects

have been described




SKIN EFFECTS AFTER A SINGLE EXPOSURE (Wagner et al., 1994)

Effect Acute exposure threshold (Gy) Onset Peak

Temporary epilation 3 ~3 weeks

Permanent epilation 7 ~3 weeks

Early transient 2 ~ hours ~24 hours

Erythema

Main erythema 6 ~10 days ~2 weeks

Dry desquamation 10 ~4 weeks ~5 weeks

Moist desquamation 15 ~4 weeks ~5 weeks

Secondary ulceration 20 >6 weeks

Late erythema 15 ~6–10 weeks

Dermal necrosis 18 >10 weeks

Telangiectasia 12 > 52 weeks




• Expression of moist desquamation and ulceration depends on

the relative rates of cell loss and cell proliferation of the basal

cells

• They occur more rapidly in murine (7 to 10 days) than in

human skin (2 to 4 weeks)

• The extent of these reactions and the length of time for

recovery depend on the dose received and the volume (area)

of skin irradiated, because early recovery depends on the

number of surviving basal cells that are needed to repopulate

the tissue




Demarcated erythema above

right elbow at 3 weeks after

radiofrequency cardiac

catheter ablation

Koenig et al 2001

• Transient erythema in human skin occurs

after single doses greater than 2 Gy

• Main erythema occurs at doses greater than

about 7 Gy

• Moist desquamation and ulceration occur

after single doses of 15 to 20 Gy

After the desquamation reaches a peak value,

recovery and regeneration of the epidermis

will start from islands of surviving cells in the

basal layer



20.12.4. Radiation-induced cataract formation

• The lens of the eye contains transparent lens fibres and a

small number of dividing cells limited to the pre-equatorial

region of the epithelium within the lens capsule

• During life, the progeny of these mitotic cells differentiate into

lens fibres and accrete at the equator

• It has been known for many years that the lens of the eye is

very sensitive to radiation. Radiation even may lead to total

blindness

• If dividing epithelium is injured by radiation, opacity (spots or

cloudiness) of the lens (cataract) will develop because there is

no mechanism for removal of injured cells and abnormal fibres



20.12.4. Radiation-induced cataract formation

Moderate doses of radiation can produce cataracts in a few

individuals, with the incidence increasing to 100 % in individuals

exposed to a single dose of 2 Gy or higher

• The frequency of cataracts varies with exposure to:

chronic doses – lower frequency

acute doses – higher frequency

• The time period between exposure and the appearance of cataract

might vary between about 6 months and 30 years. The radiation dose

greatly influences the latent period

• In general it can be stated that, the higher the dose the shorter the latent

period


20.13. RADIATION GENETICS: RADIATION EFFECTS ON FERTILITY

20.13.1. Target cells for infertility

Radiation exposure to the gonads may lead to temporary or

permanent sterility or to hereditary effects in the offspring of the

exposed individuals, depending on the dose

The reproductive organs (gonads) of the human species are

in which the gametes are developed

• spermatozoa (in males)

• the ovum (in females)

• the testis (in males)

• the ovaries (in females)




Effect of irradiation on Spermatogenesis:

• The process in which male spermatogonia develop into mature

spermatozoa is called spermatogenesis and starts with puberty

• The initial development starts with the spermatogonial stem cells,

which first proliferate to spermatogonia (type A and B), and then

differentiate into spermatocytes, (primary and secondary)

• The spermatocytes undergo meiosis to become haploid spermatids

Without further cell divisions, the spermatids differentiate into

spermatozoa

• The whole process will takes approximately 74 days in humans




• The sensitivity of germ cells to a given dose of radiation is strongly

related to the stage they are in at the time they are irradiated

• Recovery of spermatogenesis will occur from the stem cell compartment

when the exposure is below the sterilisation dose Depending on the

dose, recovery to pre-irradiation levels of sperm might take 2 to 3

months up to several years

Effect of irradiation on Spermatogenesis:

The primary effect of radiation on the male reproductive system is:

• damage

• depopulation of the spermatogonia

eventually resulting in depletion of mature sperm in the testis




Effect of irradiation on oogenesis:

• The process in which primary oocytes develop into the ovum (egg

cell) is called oogenesis and starts with puberty and ends with

menopause

• In contrast to spermatogenesis where new sperms are produced

all the time, the female can only produce a limited number of egg

cells since, after the foetal stage, oocytes no longer divide

• At birth a fixed number of oocytes are present and their number

diminishes steadily with age




Effect of irradiation on oogenesis:

• During development from the primary oocyte to ovum, the

developing oocytes are very sensitive to radiation while the

primary oocytes and the ovum are less sensitive

• Maturation from primary oocyte to mature egg cells lasts several

months. Every month one mature egg cell (occasionally two or

three) is released during the menstrual cycle

• In the case of radiation exposure of one or both of the ovaries it is

recommended to delay a wanted pregnancy by at least 6 months

because in this period the developing and more radiosensitive

oocytes have been ovulated



20.13.2. Doses necessary for temporary and permanent infertility

• 1.0 Gy leads to a temporary reduction in the number of

spermatozoa

• 1.5 Gy leads to temporary sterility

• 2.0 Gy results in temporary sterility (for several years)

• 5.0 to 6.0 Gy (acute) can produce permanent sterility

In males, a dose of

• of 0.65 to 1.50 Gy will lead to a reduced fertility

• greater than 6.0 Gy produces sterility

The “sterility” dose is smaller for older women who have

fewer primary oocytes

In females, a dose



20.13.3. Genetic effects

At low doses, radiation may cause damage to the germinal cells

in the gonads which:

• do not lead to cell death

• but may lead to DNA-damage gene mutations

an increase in hereditary disease in the

offspring of exposed parents




• Mendelian (mutation in a single gene)

• chromosomal

• multifactorial diseases

• Although animal studies clearly show the hereditary effects of

radiation, no hereditary effects have been observed in human

populations exposed to radiation

• For example no significant increase in heritable diseases was found

in a study on 70,000 children of Japanese A-bomb survivors whose

parent had received a conjoint radiation dose to their gonads of

0.15 Gy on average

Hereditary diseases are classified into three major categories:




Based on mouse data:

the doubling dose is estimated to be 1 Gy, for

low dose-rate exposures

Doubling dose is the dose necessary to double the spontaneous

mutation frequency

There is no good reason to assume that in humans, the

doubling dose may differ significantly from that in mice

The mutation doubling dose does not give any useful

information on the risk of heritable disease. Therefore, the

mouse doubling dose is combined with information derived

from human population genetics to estimate the risk of

heritable disease in the progeny of irradiated people




The fact that the risk factor for workers is lower than the risk

factor for the whole population is due to the fact that the age

structure of both groups differs

For protection purposes, ICRP recommend a

risk factor for hereditary disease of:

• 0.2 % per Sv for members of the public

• 0.1 % per Sv for workers


20.14. FOETAL RADIATION

20.14.1. Foetal radiation effects vs. gestational date

• the radiation dose

• the stage of development at the time of exposure

Radiation-induced lethality and specific gross

abnormalities in the embryo and foetus are

dependent on two factors:

• pre-implantation (day 1 to 10)

• organogenesis (day 11 to 42)

• growth stage (day 43 to birth)

Between conception and birth, the foetus passes

through three basic stages of development:




• foetal or neonatal death

• malformations

• growth retardation

• congenital defects

• cancer induction

The principal effects of radiation on a foetus are:

• death of the conceptus

• early spontaneous abortion

Those embryos, however, which survive this

stage, develop normally

Embryos in the pre-implantation stage are very

radiosensitive and radiation damage inevitably will lead to:




• However, in most cases the damage to the foetus is too severe for

survival, ultimately resulting in neonatal death

• During this period the developing brain is very sensitive to radiation

• Irradiation during the foetal period (after week 6) results in a much

lower incidence of gross organ malformation abnormalities and mental

retardation

In the human early foetus, radiation exposure during the period of

major organogenesis will lead to the development of abnormalities,

mostly related to the:

• central nervous system (brain defects

and/or mental retardation)

• skeleton

• organ systems



20.14.2. What to do when the foetus has been exposed to radiation?

• Systematic studies of the effect of radiation on the developing

embryo have been conducted in laboratory animals, particularly

mice and rats

• In experimental studies, no damage to the intrauterine

development of animals has been found for doses < 100 mGy

• In the studies of the Hiroshima children there is evidence for a threshold

dose of >100 mGy

• The risk of severe mental retardation increases rapidly to a value of 40 %

at 1 Gy

• In the later stages of pregnancy, the threshold dose may be higher

• At foetal doses >500 mGy, there can be significant foetal damage, the

magnitude and type of which is a function of dose and stage of pregnancy




• The findings of a probable threshold of 100 mGy will influence

the advice to be given to pregnant women after a diagnostic

radiology procedure

• After abdominal CT investigations, careful analysis of the

radiation dose to the uterus as well as medical anamnestic

exploration has to be performed

• According to the ICRP- publication 84, termination of

pregnancy at foetal doses of less than 100 mGy is not justified

based upon radiation risk

• At foetal doses between 100 and 500 mGy, the decision

should be based upon the individual circumstances




The issue of pregnancy termination is undoubtedly

managed differently around the world

It is complicated by individual:

• ethical

• moral

• religious beliefs

• laws or regulations at a local or national level

This complicated issue involves much more than radiation protection

considerations and require the provision of counselling for the patient

and her partner




• Regarding the radiation induced risk of cancer, the ICRP-

publication 103 considers the life-time cancer risk following in-

utero exposure will be similar to that following radiation in early

childhood, i.e., at most, about three times of that of the

population as a whole (>15 % per Sv)

• So far no effect of gestational date on the cancer risk has been found

There is always a certain risk in a pregnant population not

exposed to radiation of:

spontaneous abortion (larger than 15 %)

intrauterine growth retardation (about 4 %)

genetic abnormalities (between 4-10 %)

major malformation (between 2-4 %)

IAEA

• HALL, E., GIACCIA, A.J., Radiobiology for the Radiologist, 6th edn,

Lippincott Wilkins & Williams, Philadelphia, USA (2006)

• INTERNATIONAL ATOMIC ENERGY AGENCY, Radiation Oncology

Physics: A Handbook for Teachers and Students, IAEA, Vienna (2005).

http://www-naweb.iaea.org/nahu/dmrp/publication.asp

• INTERNATIONAL ATOMIC ENERGY AGENCY, Radiation Biology: A

Handbook for Teachers and Students, Training Course Series, 42,

IAEA, Vienna (2010). http://www-

pub.iaea.org/MTCD/publications/PDF/TCS-42_web.pdf

• INTERNATIONAL ATOMIC ENERGY AGENCY, Radiobiology modules

in the “Applied Sciences of Oncology” distance learning course.

Available on CD Contact: [email protected], or downloadable

for free from the IAEA website:

http://www.iaea.org/NewsCenter/News/2010/aso.html

BIBLIOGRAPHY


IAEA

BIBLIOGRAPHY


• INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION,

Pregnancy and Medical Radiation ICRP Publication 84, Pergamon Press,

Oxford and New York (2000)

• INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION,

Recommendations of the ICRP, ICRP Publication 103, Annals of the ICRP

Volume 37/2-4, Elsevier (2008). via www.sciencedirect.com

• JOINER, M.C., VAN DER KOGEL, A.J., (Eds), Basic Clinical Radiobiology,

4th edn., Hodder Arnold, London, UK, (2009)

• KOENIG, T.R., WOLFF, D., METTLER, F.A., WAGNER, L.K., Skin injuries

from fluoroscopically guided procedures: part 1, characteristics of

radiation injury, AJR Am J Roentgenol 177 1 (2001) 3-11


• NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES,

Health risks from exposure to low levels of ionizing radiation; BEIR VII

phase 2, Committee to Assess Health Risks from Exposure to Low

Levels of Ionizing Radiation, National Academies Press, Washington,

DC (2006). http://www.nap.edu/openbook.php?isbn=030909156X

• TANNOCK, HILL, BRISTOW, HARRINGTON, (Eds), The Basic

Science of Oncology, Chapters 14 & 15, 4th edn., McGraw Hill,

Philadelphia, (2005)

• WAGNER, L.K., EIFEL, P.J., GEISE, R.A., Potential biological effects

following high X-ray dose interventional procedures, J Vasc Interv

Radiol 5 1 (1994)

BIBLIOGRAPHY

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