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    Người gửi: Lại Hoàng Hiệp
    Ngày gửi: 18h:55' 13-12-2007
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    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
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