Hoang Hiep

RADIATION PROTECTION IN DIAGNOSTIC RADIOLOGY
Part 3 : Biological effects of ionizing radiation
IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Introduction
Subject matter : radiobiology
The mechanisms of different types of biological effects following exposure to ionizing radiation
Types of models used to derive risk coefficients for estimating the detriment
Contents
Classification of radiation health effects
Factors affecting radio sensitivity
Dose-effect response curve
Whole body response: acute radiation
syndrome
Effects of antenatal exposure and delayed effects of radiation
Epidemiology

Overview
To become familiar with the mechanisms of different types of biological effects following exposure to ionizing radiation. To be aware of the models used to derive risk coefficients for estimating the detriment.
Part 3 : Biological effect of ionizing radiation

Topic 1 : Classification of radiation health effects

IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Radiation health effects
Effects of ionizing radiation
Deterministic
Existence of a dose threshold value (below this dose, the effect is not observable)
Effect severity increases with dose
Stochastic
No threshold
Probability of the effect increases with dose
Severity is weighted by a factor G.
For fatal cancer and extreme genetic effects G = 1. For non fatal cancers G < 1.
Biological effects of ionizing radiation
Deterministic
e.g. Lens opacities, skin injuries,
infertility, epilation, etc
Stochastic
Cancer, genetic effects.
radiation hit cell nucleus!
No change
DNA mutation
DIRECT ACTION
INDIRECT ACTION
DNA Mutation
Cell survives but mutated
Cancer ?
Cell death
Mutation repaired
Unviable Cell
Viable Cell
Outcomes after cell exposure
Outcomes after cell exposure
How DNA is repaired ?
Altered base
Enzyme Glycosylases recognizes
lesion and releases damaged base
AP-endunuclease makes incision
and releases remaining sugar
DNA-polymerase fills resulting gap but nick remains
DNA ligase seals the nick Repair completed
DNA has been repaired with no
loss of genetic information
Repair of DNA damage
RADIOBIOLOGISTS ASSUME THAT THE REPAIR SYSTEM IS NOT 100% EFFECTIVE.
Conditioning dose
Conditioning dose
Challenging dose
Challenging dose
Response
Response
Response
ADAPTIVE
RESPONSE
Outcomes after cell exposure
Normal human
lymphocyte:
chromosomes
uniformly
distributed
Apoptotic cell:
chromosomes
and nucleus
fragmented
and collapsed
into apoptotic
bodies
Effects of cell death
Acute dose (in mSv)
Probability of death
5000
100%
Outcomes after cell exposure
Chromosomal deletions
Chromosomal translocations
CANCER INITIATION
TUMOR PROMOTION
MALIGNANT PROGRESSION
METASTASIS
MALIGNANT TRANSFOMATION
STEAM CELL
DIVISION
MUTATION
NECROSIS OR
APOPTOSIS
NORMAL TISSUE

CELL INITIATION

An initiating event
Creates a mutation in
One of the basal cells
DYSPLASIA

More mutations occurred.
The initiated cell has
gained proliferative
advantages.
Rapidly dividing cells
begin to accumulate
within the epithelium.

BENIGN TUMOR

More changes within
the proliferative cell line leads to full tumor development.
MALIGNANT TUMOR

The tumor breaks trough
the basal lamina.
The cells are irregularly
Shaped and the cell line is immortal. They have an increased mobility and invasiveness.
METASTASIS

Cancer cells break trough
the wall of a lymphatic
vessel or blood capillary.
They can now migrate
throughout the body and
potentially seed
new tumors
A simple generalized scheme for multistage oncogenesis
Timing of events leading to radiation effects.
Part 3 : Biological effect of ionizing radiation
Topic 2 : Factors affecting the radiosensitivity

IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Radiosensitivity (1)
RS = Probability of a cell, tissue or organ of suffering an effect per unit of dose.
Bergonie and Tribondeau (1906): “RS LAWS”: RS will be greater if the cell:
Is highly mitotic.
Is undifferentiated.
Has a high cariocinetic future.
Radiosensitivity (2)
Muscle
Bones
Nervous system
Skin
Mesoderm organs (liver, heart, lungs…)
Bone Marrow
Spleen
Thymus
Lymphatic nodes
Gonads
Eye lens
Lymphocytes (exception to the RS laws)
Low RS
Medium RS
High RS
Factors affecting the radiosensitivity
Physical
LET (linear energy transfer):  RS
Dose rate:  RS
Chemical
Increase RS: OXYGEN, cytotoxic drugs.
Decrease RS: SULFURE (cys, cysteamine…)
Biological
Cycle status:
 RS: G2, M
 RS: S
Repair of damage (sub-lethal damage may be repaired e.g. fractionated dose)
G1
S
G2
M
G0
 LET
 LET
% survivor cells
Part 3 : Biological effect of ionizing radiation
Topic 3 : Dose-effect response curve

IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Systemic effects
Effects may be morphological and/or functional
Factors:
Which Organ
How much Dose
Effects
Immediate (usually reversible): < 6 months e.g.: inflammation, bleeding.
Delayed (usually irreversible): > 6 months e.g.: atrophy, sclerosis, fibrosis.
Categorization of dose
< 1 Gy: LOW DOSE
1-10 Gy: MODERATE DOSE
> 10 Gy: HIGH DOSE
Regeneration means replacement by the original tissue while Repair means replacement by connective tissue.
Skin effects
Following the RS laws (Bergonie and Tribondeau), the most RS cells are those from the basal stratum of the epidermis.
Effects are:
Erythema: 1 to 24 hours after irradiation of about 3-5 Gy
Alopecia: 5 Gy is reversible; 20 Gy is irreversible.
Pigmentation: Reversible, appears 8 days after irradiation.
Dry or moist desquamation: traduces epidermal hypoplasia (dose  20 Gy).
Delayed effects: teleangiectasia, fibrosis.
Histologic view of the skin
Basal stratum cells, highly mitotic, some of them with melanin, responsible of pigmentation.
From “Atlas de Histologia...”. J. Boya
Skin injuries
Skin injuries
Effects in eye
Eye lens is highly RS.
Coagulation of proteins occur with doses greater than 2 Gy.
There are 2 basic effects:
From “Atlas de Histologia...”. J. Boya
Histologic view of eye:
Eye lens is highly RS, moreover, it is surrounded by highly RS cuboid cells.

> 0.15

5.0
Visual impairment (cataract)
> 0.1
0.5-2.0
Detectable opacities
Sv/year for many years
Sv single brief exposure
Effect
Eye injuries
Part 3 : Biological effect of ionizing radiation
Topic 4 : Whole body response: acute radiation syndrome

IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Whole body response : adult
Acute irradiation syndrome
Chronic irradiation syndrome
Survival time
Dose
Lethal dose 50 / 30
BONE MARROW
GASTRO
INTESTINAL
CNS
(central nervous system)
1-10 Gy
10 - 50 Gy
> 50 Gy
Whole body clinic of a partial-body irradiation
Mechanism: Neurovegetative disorder
Similar to a sick feeling
Quite frequent in fractionated radiotherapy
Lethal dose 50 / 30
“Dose which would cause death to 50% of the population in 30 days”.
Its value is about 2-3 Gy for humans for whole body irradiation.
Part 3 : Biological effect of ionizing radiation
Topic 5 : Effects of antenatal exposure and delayed effect
IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Effects of antenatal exposure (1)
As post-conception time increases RS decreases
It is not easy to establish a cause-effect relation because there are a lot of teratogenic agents, effects are unspecific and not unique to radiation.
There are 3 kinds of effects: lethality, congenital anomalies and large delay effects (cancer and hereditary effects).
Time
%
Pre-implantation
Organogenesis
Foetus
Lethality
Congenital anomalies
Effects of antenatal exposure (2)
Lethal effects can be induced by relatively small doses (such as 0.1 Gy) before or immediately after implantation of the embryo into the uterine wall. They may also be induced after higher doses during all the stages during intra-uterine development.
Time
%
Pre-implantation
Organogenesis
Foetus
Lethality
0.1 Gy
Effects of antenatal exposure (3)
Mental retardation:
ICRP establishes that mental retardation can be induced by radiation (Intelligence Quotient score < 100).
It occurs during the most RS period: 8-25 week of pregnancy.
Risks of antenatal exposure related to mental retardation are:

Severe mental retardation with a Risk factor of 0.1/Sv

Severe mental retardation with a Risk factor of 0.4/Sv
15-25 week
8-15 week
Delayed effects of radiation
Classification:
SOMATIC: they affect the health of the irradiated person. They are mainly different kinds of cancer (leukemia is the most common, with a delay period of 2-5 years, but also colon, lung, stomach cancer…)
GENETIC: they affect the health of the offspring of the irradiated person. They are mutations that cause malformation of any kind (such as mongolism)
Part 3 : Biological effect of ionizing radiation
Topic 6 : Epidemiology
IAEA Standard syllabus course on Radiation Protection in diagnostic and interventional radiology
Epidemiology I
Irradiated populations can be studied by
following cohorts of exposed and non-exposed people
back-tracing patients suffering from the disease with regard to possible exposure (case controls)

Irradiated populations are
people exposed from the atomic bomb explosions
people exposed during nuclear and other radiation accidents
patients exposed for medical reasons
people exposed to natural radiation
workers in radiation industries
Epidemiology II

Most valid data come from high dose / high dose rate exposure to low LET radiation, including some radionuclides [131I], and from high LET internal exposure to a emitters in lung, bone and liver.
Epidemiology III
Information is scanty on:
Consequences of low doses delivered at low dose rates
To detect an increase from a 20% spontaneous cancer incidence to 25% (corresponding to an exposure to ~1 Sv) > 1300 persons must be studied
Consequences of external high LET radiation
(neutrons) and several radionuclides
Presence and influence of confounding factors
especially if different populations are to be compared
Epidemiology IV
Modifying influence of cancer background incidence
does radiation-induced cancer increase at a fixed level or in proportion to existing cancer additive vs. multiplicative risk model ?
Is, for example, the risk greater in:
European women which have a higher background breast tumor rate than Japanese women ?
Smokers exposed to radon in homes or mines than in non-smokers ?
Epidemiology V
Detectability limits in Radioepidemiology
Number of people in study and control groups
E
F
F
E
C
T
I
V
E

D
O
S
E

(
m
S
v
)
5
10
-1
10
0
10
0
10
1
10
1
10
2
10
2
10
4
10
4
10
3
10
3
10
6
10
7
10
8
10
9
10
10
10
11
10
CHERNOBYL DOSES
REGION OF DETECTABILITY
REGION OF UNDETECTABILITY
Theoretical limit of detectability due to statistical causes (90% confidence interval)
High and Low Spontaneous Cancer Rates Incidence/105
Tissue High Low
Male / Female Male /Female
Nasopharynx 23.3 9.5 0.2 0.1
Esophagus 20.1 8.3 0.5 0.2
Stomach 95.5 40.1 5.2 2.2
Colon 35.0 29.6 1.8 1.3
Liver 46.7 11.5 0.7 0.3
Lung+Bronchus 110.8 29.6 10.3 2.4
Skin melanoma 33.1 29.8 0.2 0.2
Breast female 103.7 14.6
Cervix 53.5 3.0
from UNSCEAR 2000
Data on irradiated Populations
Population Approximate Size
Atomic bomb survivors Japan: 86 000
Atomic tests::Semipalatinsk/Altai 30 000
Marshallese islanders 2 800
Nuclear accidents: intervention teams Chernobyl (total) > 200 000
population Chernobyl (>185 kBq /m2 137Cs) 1 500 000
population Chelyabinsk (total) 70 000
Medical procedures:
low LET iodine treatment and therapy ~ 70 000
chest fluoroscopy 64 000
children hemangioma treatment 14 000
high LET thorotrast angiography 4 200
Ra-224 treatment 2 800
Prenatal exposure (fetal radiography, atomic bombs) 6 000
Occupational exposure: workers nuclear industry (Japan, UK) 115 000
uranium miners 21 000
radium dial painters 2 500
radiologists 10 000
Natural exposure (Chinese, EC and US studies) several 100 000
Populations Studied for Specific Cancers (I)
Leukemia: atomic bomb survivors, radiotherapy for ankylosing spondylitis and cervix cancer, radiologists, people at the Majak plant, Chelyabinsk and the Techa river, prenatal radio-diagnostics (Oxford survey)
Lung Cancer: atomic bomb survivors, U and other miners in CSSR, Canada, USA, Germany, Sweden
Populations Studied for Specific Cancers (II)
Breast Cancer : atomic bomb survivors, fluoroscopy TB patients, radiotherapy mastitis
Thyroid Cancer : radiotherapy thymus enlargement, tinea capitis skin hemangioma, fallout at Marshall islands, children near the Chernobyl accident
Liver Cancer : Thorotrast angiography;
Osteosarcoma : 224Ra (226Ra) treatment, 226Ra dial painters.
Excess Solid-Tumor Deaths among Atomic-Bomb Survivors
Relative Mortality Risks at Different Times After Exposure
0.5
5
1950-
1954
1963-
1966
1959-
1962
1955-
1958
1971-
1974
1967-
1970
1975-
1978
1979-
1982
1
10
20
2
Interval of follow-up Atomic bomb survivors
Estimated relative risk at 1 Gy
All cancers except
leukaemia (+ 4.8%/y)
Leukaemia ( ~10.7%/y)
Relative Risks of Radon from Indoor Exposure and from Mining
Breast Cancer in Women Exposed to Fluoroscopy
Observed/expected breast cancers
,
,
,
,
,
0
1
2
3
4
0
1
2
3
4
Mean absorbed dose (Gy)
Thyroid Tumors in Irradiated Children
,
,
,
,
,
,
,
,
0
0.05
0.1
0.15
0.2
0.25
0
2
4
6
8
10
Mean dose (Gy)
Relative risk
Thyroid Cancer
Thyroid benign
tumors
Thyroid Cancer Cases in Children after the Chernobyl Accident
&
&
&
&
&
&
&
&
&
&
&
&
$
$
$
$
$
$
$
$
$
$
$
$
$
"
"
"
"
"
"
"
"
"
"
"
"
"
86
87
88
89
90
91
92
93
94
95
96
97
98
0
20
40
60
80
100
Ukraine
Russian Fed.
Belarus
No of Cases
Children under 15 years of age at diagnosis
Thyroid Cancer in Children in the Chernobyl Region
Region No of Cases
before the accident after the accident
Belarus (1977-1985) 7 (1986-1994) 390
Ukraine (1981-1985) 24 (1986-1995) 220
Russia (Bryansk and Kaluga region only) (1986-1995) 62

The data represent incidences (not mortality) and are preliminary results.
Most excess cancers occurred since 1993.
Thyroid cancer has a high rate of cure >90%, but many of the cancers found are of the aggressive papillary type.
Risk Estimates from Occupational Exposure
Study Excess relative risk per Sv
All cancer Leukemia
UK National Registry
Radiation Workers 0.47 (-0.12-1.20) 4.3 (0.4-13.6)
1,218,000 person years
34 mSv average dose
US Workers -1.0 (<0-0.83 <0 (<0-3.4)
705,000 person years
32 mSv average dose
Atomic Bomb Survivors 0.33 (0.11-0.6) 6.2 (2.7-13.8)
2,185,000 person years
251 mSv average dose
Doses and Risks for in Utero Radiodiagnostics
Exposure Mean foetal dose Hered. Disease Fatal cancer
(mGy) to age 14 y
X-ray
Abdomen 2.6 6.2 10-5 7.7 10-5
Barium enema 16 3.9 10-4 4.8 10-4
Barium meal 2.8 6.7 10-5 8.4 10-5
IV urography 3.2 7.7 10-5 9.6 10-5
Lumbar spine 3.2 7.6 10-5 9.5 10-5
Pelvis 1.7 4.0 10-5 5.1 10-5
Computed tomography
Abdomen 8.0 1.9 10-4 2.4 10-4
Lumbar spine 2.4 5.7 10-5 7.1 10-5
Pelvis 25 6.1 10-4 7.7 10-4
Nuclear medicine
Tc bone scan 3.3 7.9 10-4 1.0 10-4
Tc brain scan 4.3 1.0 10-5 1.3 10-4
Extrapolation by Additive and Multiplicative Risks Models
Annual Probability of death /1000 persons
Age Years
15
5
25
35
45

Following exposure to 2 Gy at an age of 45 years
Spontaneous risks : increase with age:
Radiation risks become apparent after a lag period
(5) -10 years
Additive risk models: imply constant risk
independent of background.
Multiplicative risk models: imply an increase
proportional to background risk
Risk Probability Coefficients (ICRP)
Tissue Probability of fatal Cancer (10-2/Sv)
Population Workers
Bladder 0.30 0.24
Bone marrow 0.50 0.40
Bone surface 0.05 0.04
Breast 0.20 0.16
Colon 0.85 0.68
Liver 0.15 0.12
Lung 0.85 0.68
Esophagus 0.30 0.24
Ovary 0.10 0.08
Skin 0.02 0.02
Stomach 1.10 0.88
Thyroid 0.08 0.06
Remainder 0.50 0.40
Total all cancers 5.00 4.00
Genetic effects weighted 1.00 0.50
Proportion of Fatal Cancers Attributable to Different Agents
Agent or Class Percentage of all Cancer Disease
Best estimate Range
Smoking 31 29 - 33
Alcoholic beverages 5 3 - 7
Diet 35 20 - 60
Natural hormones 15 10 - 20
Infection 10 5 - 15
Occupation 3 2 - 6
Medicines, medical practices 1 0.5 - 2
Electromagnetic radiation 8 5 -10
Ionizing (85% from natural radiation*) 4.5
Ultraviolet 2.5
Lower frequency <1
Industrial products <1 <1 - 2
Pollution 2 <1 - 4
Other ? ?
Tissue risk factor (1)
RISK FACTOR: The quotient of increase in probability of a stochastic effect and the received dose. It is measured in Sv-1 or mSv-1.
% Effect
Dose
 dose
 probability
Risk factor
=
 probability
 dose
Tissue risk factor (2)
EXAMPLE: A risk factor of 0.005 Sv-1 for bone marrow (lifetime mortality in a population of all ages from specific fatal cancer after exposure to low doses) means that if 1,000 people would receive 1 Sv to the bone marrow, 5 will die from a cancer induced by radiation.
% Effect
Dose
 dose
 probability
Risk factor
=
 probability
 dose
Indicators of relative organ tissue risk
0.05
Remainder
0.01
Bone surface
0.01
Skin
0.05
Thyroid
0.05
Oesophagus
0.05
Liver
0.05
Breast
0.05
Bladder
0.12
Stomach
0.12
Lung
0.12
Colon
0.12
Bone marrow (red)
0.20
Gonads
wT
TISSUE OR ORGAN
Summary
Effects of ionizing radiation may be deterministic and stochastic, immediate or delayed, somatic or genetic
Some tissues are highly radiosensitive
Each tissue has its own risk factor
Risk from exposure may be assessed through such factors
Where to Get More Information (1)
1990 Recommendations of the ICRP. ICRP Publication 60. Pergamon Press 1991
Radiological protection of the worker in medicine and dentistry. ICRP Publication 57. Pergamon Press 1989
Sources and Effects of Ionizing Radiation. United Nations Scientific Committee on the Effects of Atomic Radiation UNSCEAR 2000 Report to the General Assembly, with Scientific Annexes. New York, United Nations 2000.
Where to Get More Information (2)
Avoidance of radiation injuries from medical interventional procedures. ICRP Publication 85. Ann ICRP 2000;30 (2). Pergamon
Manual of clinical oncology 6th edition. UICC. Springer-Verlag. 1994
Atlas de Histologia y organografia microscopica. J. Boya. Panamericana. 1998
Tubiana M. et al. Introduction to Radiobiology. London: Taylor & Francis, 1990. 371 pp. ISBN 0-85066-763-1