L03 Biological Effects

RADIATION PROTECTION IN DIAGNOSTIC AND INTERVENTIONAL RADIOLOGY L 3: Biological effects of ionizing radiation IAEA Training Material 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

Topics 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 Training Material on Radiation Protection in Diagnostic and Interventional Radiology

Radiation health effects DETERMINISTIC Somatic Clinically attributable in the exposed individual CELL DEATH STOCHASTIC somatic & hereditary epidemiologically attributable in large populations ANTENATAL somatic and hereditary expressed in the foetus, in the live born or descendants BOTH TYPE OF EFFECTS CELL TRANSFORMATION

Biological effects of ionizing radiation Deterministic e.g. Lens opacities, skin injuries, infertility, epilation, etc Stochastic Cancer, genetic effects.

Deterministic effects Deterministic(Threshold/non-stochastic) Existence of a dose threshold value (below this dose, the effect is not observable) Severity of the effect increases with dose A large number of cells are involved Radiation injury from an industrial source

Threshold Doses for Deterministic Effects Cataracts of the lens of the eye 2-10 Gy Permanent sterility males 3.5-6 Gy females 2.5-6 Gy Temporary sterility males 0.15 Gy females 0.6 Gy dose Severity of effect threshold

Stochastic Effects Stochastic(Non-Threshold) No threshold Probability of the effect increases with dose Generally occurs with a single cell e.g. Cancer, genetic effects

Outcomes after cell exposure DAMAGE REPAIRED CELL DEATH (APOPTOSIS) TRANSFORMED CELL DAMAGE TO DNA

Outcomes after cell exposure DAMAGE REPAIRED CELL NECROSIS OR APOPTOSIS TRANSFORMED CELL DAMAGE TO DNA

Repair of DNA damage RADIOBIOLOGISTS ASSUME THAT THE REPAIR SYSTEM IS NOT 100% EFFECTIVE.

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 cell death 5000 100%

CANCER INITIATION TUMOR PROMOTION MALIGNANT PROGRESSION METASTASIS MALIGNANT TRANSFOMATION STEAM CELL DIVISION MUTATION NECROSIS OR APOPTOSIS

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 lead to full tumor development.

MALIGNANT TUMOR The tumor breaks through 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 through 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 Damage to chromosomal DNA of a normal target cell Failure to correct DNA repair Appearance of specific neoplasia-initiating mutation Promotional growth of pre-neoplasm Conversion to overtly malignant phenotype Malignant progression and tumour spread

10 -6 10 -12 10 -9 10 -15 10 -3 1 second 1 hour 1 day 1 year 100 years 1 ms 10 0 10 9 10 6 10 3 Energy deposition Excitation/ionization Initial particle tracks Radical formation PHYSICAL INTERACTIONS PHYSICO-CHEMICAL INTERACTIONS BIOLOGICAL RESPONSE MEDICAL EFFECTS Diffusion, chemical reactions Initial DNA damage DNA breaks / base damage Repair processes Damage fixation Cell killing Promotion/completion Teratogenesis Cancer Hereditary defects Proliferation of "damaged" cells Mutations/transformations/aberrations T I M E ( s e c ) Timing of events leading to radiation effects.

Part 3: Biological effect of ionizing radiation Topic 2: Factors affecting the radiosensitivity IAEA Training Material on Radiation Protection in Diagnostic and Interventional Radiology

Radiosensitivity [RS] (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 M M

Part 3: Biological effect of ionizing radiation Topic 3: Dose-effect response curve IAEA Training Material 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 (*):alopecia: loss or absence of hair (**): ectasia: swelling of part of the body

Skin reactions Injury Threshold Dose to Skin (Sv) Weeks to Onset Early transient erythema 2 <<1 Temporary epilation 3 3 Main erythema 6 1.5 Permanent epilation 7 3 Dry desquamation 10 4 Invasive fibrosis 10 Dermal atrophy 11 >14 Telangiectasis 12 >52 Moist desquamation 15 4 Late erythema 15 6-10 Dermal necrosis 18 >10 Secondary ulceration 20 >6 Skin damage from prolonged fluoroscopic exposure

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

Part 3: Biological effect of ionizing radiation Topic 4: Whole body response: acute radiation syndrome IAEA Training Material 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 1 2 Steps: Prodromic (onset of disease) Latency Manifestation

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 Training Material 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 effects of ionizing radiation Topic 6: Epidemiology IAEA Training Material 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 )

Epidemiology II 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 III Most valid data come from high dose / high dose rate exposure to low LET radiation, including some radionuclides [iodine 131I], and from high LET internal exposure to a emitters in lung, bone and liver.

Epidemiology IV Information is scanty (not much,less than needed) 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 V 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 ?

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 2 3.3 9.5 0. 2 0. 1 Esophagus 2 0.1 8. 3 0.5 0. 2 Stomach 9 5.5 4 0.1 5. 2 2. 2 Colon 35.0 29.6 1.8 1.3 Liver 46.7 11.5 0. 7 0. 3 Lung+Bronchus 11 0.8 29.6 10.3 2 .4 Skin melanoma 33.1 29.8 0.2 0.2 Breast female 10 3 . 7 1 4 .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 3 0 000 Marshallese islanders 2 8 00 Nuclear accidents : intervention teams Chernobyl (total) > 200 000 population Chernobyl (>185 kBq /m 2 137 Cs) 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 2 00 Ra-224 treatment 2 8 00 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 5 00 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 (watch) 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           0 100 200 300 400 500 0.3 1 0.5 0.6 2 0.4 Radon concentration Bq/m 3 Relative risk miner studies (cohorts) indoor studies (case controls) log-linear fit to indoor studies estimated from correlation study in different regions 1.5

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 55 60 65 70 75

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 w T 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.

L03 Biological Effects

More Related Content

What's hot

Viewers also liked

Similar to L03 Biological Effects

More from lidgor

Recently uploaded

L03 Biological Effects

Editor's Notes