l03 biological effects

IAEAInternational Atomic Energy Agency

RADIATION PROTECTION INDIAGNOSTIC AND

INTERVENTIONAL RADIOLOGY

L 3: Biological effects of ionizing radiation

IAEA Training Material on Radiation Protection in Diagnostic and Interventional Radiology

IAEA 3 : Biological effects of ionizing radiation 2

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



Radiation health effects

DETERMINISTICSomaticClinically attributable in the exposed individual

CELL DEATH

STOCHASTICsomatic & hereditaryepidemiologically attributable in large populations

ANTENATALsomatic and hereditary expressed in the foetus, in the live born or descendants

BOTH

TYPEOF

EFFECTS

CELL TRANSFORMATION


Biological effects of ionizing radiation

• Deterministic• e.g. Lens opacities, skin

injuries,

• infertility, epilation, etc

• Stochastic• Cancer, genetic 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

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 ofeffect

threshold

Threshold Doses for Deterministic Effects


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

DIRECT ACTIONDIRECT ACTION INDIRECT ACTIONINDIRECT ACTION


Outcomes after cell exposure

DAMAGEREPAIRED

CELL DEATH(APOPTOSIS)

TRANSFORMED CELL

DAMAGE TO DNA



DAMAGE REPAIRED

CELL NECROSIS

OR

APOPTOSIS

TRANSFORMEDCELL

DAMAGE TO DNA

How DNA is

repaired ?


Repair of DNA damage

• RADIOBIOLOGISTS ASSUME THAT THE REPAIR SYSTEM IS NOT 100% EFFECTIVE.



DAMAGE REPAIRED

CELL NECROSIS OR APOPTOSIS

TRANSFORMED CELL

DAMAGE TO DNA

Normal human

lymphocyte:

chromosomes

uniformly

distributed

Apoptotic cell:chromosomes

and nucleusfragmented

and collapsedinto apoptotic

bodies


Effects of cell death

Acute dose (in mSv)

Probability of cell death

5000

100%



DAMAGE REPAIRED

CELL NECROSIS OR

APOPTOSIS

TRANSFORMED CELL

DAMAGE TO DNA


Chromosomal deletions


Chromosomal translocations

CANCER INITIATION TUMOR PROMOTION

MALIGNANT PROGRESSION

METASTASISMALIGNANT TRANSFOMATION

STEAM CELL

DIVISION

MUTATION

NECROSIS ORAPOPTOSIS

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 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 DNAof a normal target cell

Failure to correctDNA repair

Appearance of specificneoplasia-initiating mutation

Promotional growthof pre-neoplasm

Conversion to overtlymalignant 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

100

109

106

103

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 processesDamage fixation

Cell killing

Promotion/completion

TeratogenesisCancer

Hereditary defects

Proliferation of "damaged" cells

Mutations/transformations/aberrations

TI M

E (

sec)

Timing of events leading to radiation effects.



Topic 2: Factors affecting the radiosensitivity



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 lensLymphocytes (exception to the RS laws)

Low RSMedium RSHigh RS


Factors affecting the radiosensitivity

G1

S

G2

M

G0

LET

LET% s

urv

ivo

r c

ell

s

MM

• 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)



Topic 3: Dose-effect response curve



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


InjuryThreshold Dose to

Skin (Sv)

Weeks to Onset

Early transient erythema 2 <<1Temporary epilation 3 3

Main erythema 6 1.5Permanent epilation 7 3Dry desquamation 10 4Invasive fibrosis 10Dermal atrophy 11 >14Telangiectasis 12 >52

Moist desquamation 15 4Late erythema 15 6-10

Dermal necrosis 18 >10Secondary ulceration 20 >6

Skin damagefrom prolongedfluoroscopicexposure

Skin reactions


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. > 0.155.0

Visual impairment (cataract)

> 0.10.5-2.0Detectable opacities

Sv/year for many years

Sv single brief exposure

Effect


Eye injuries



Topic 4: Whole body response: acute radiation syndrome



Whole body response: adult

Acute irradiation syndrome Chronic irradiation

syndrome

Sur

viva

l tim

e

Dose

Steps:

1. Prodromic (onset of disease)

2. Latency

3. Manifestation

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.



Topic 5: Effects of antenatal exposure and delayed effect



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

LethalityCongenital anomalies



• 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



• 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 week8-15 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



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

EF

FE

CT

IVE

D

OS

E

(mS

v)

510

-110010

010

110

110

210

210

410

410

310

310

610 710 810 910 1010 1110

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 0.1Esophagus 20.1 8.3 0.5 0.2 Stomach 95.5 40.1 5.2 2.2Colon 35.0 29.6 1.8 1.3Liver 46.7 11.5 0.7 0.3Lung+Bronchus 110.8 29.6 10.3 2.4Skin melanoma 33.1 29.8 0.2 0.2Breast female 103.7 14.6Cervix 53.5 3.0from UNSCEAR 2000


Data on irradiated populations

Population Approximate SizeAtomic bomb survivors Japan: 86 000Atomic tests:Semipalatinsk/Altai 30 000 Marshallese islanders 2 800Nuclear accidents: intervention teams Chernobyl (total) > 200 000

population Chernobyl (>185 kBq /m2 137Cs) 1 500 000population Chelyabinsk (total) 70 000

Medical procedures: low LET iodine treatment and therapy ~ 70 000

chest fluoroscopy 64 000children hemangioma treatment 14 000

high LET thorotrast angiography 4 200Ra-224 treatment 2 800

Prenatal exposure (fetal radiography, atomic bombs) 6 000Occupational exposure: workers nuclear industry (Japan, UK)115 000

uranium miners 21 000radium dial painters 2 500radiologists 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 amongAtomic-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

Est

imat

ed r

elat

ive

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 5000.3

1

0.5

0.6

2

0.4

Radon concentration Bq/m3

Rel

ativ

e ri

sk

miner studies (cohorts)indoor studies (case controls)log-linear fit to indoor studiesestimated from correlation

study in different regions

1.5


Breast Cancer in Women Exposed to Fluoroscopy

Ob

se

rve

d/e

xp

ect

ed

bre

as

t c

an

cers

0 1 2 3 40

1

2

3

4

Mean absorbed dose (Gy)


Thyroid Tumors in Irradiated Children

0 0.05 0.1 0.15 0.2 0.250

2

4

6

8

10

Mean dose (Gy)

Rel

ativ

e ri

sk

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 97 980

20

40

60

80

100

Ukraine

Russian Fed.

Belarus

No

of

Cas

es

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) 390Ukraine (1981-1985) 24 (1986-1995) 220Russia (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 SvAll cancer Leukemia

UK National RegistryRadiation Workers 0.47 (-0.12-1.20) 4.3 (0.4-13.6) 1,218,000 person years 34 mSv average doseUS Workers -1.0 (<0-0.83 <0 (<0-3.4) 705,000 person years 32 mSv average doseAtomic 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 tomographyAbdomen 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

An

nu

a l P

rob

ab

i lity

of

de

ath

/10

00 p

ers

on

s

Age Years55 60 65 70 75

15

5

25

35

45

Following exposure to 2 Gy at an age of 45 yearsSpontaneous 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 WorkersBladder 0.30 0.24Bone marrow 0.50 0.40Bone surface 0.05 0.04Breast 0.20 0.16Colon 0.85 0.68Liver 0.15 0.12Lung 0.85 0.68Esophagus 0.30 0.24Ovary 0.10 0.08Skin 0.02 0.02Stomach 1.10 0.88Thyroid 0.08 0.06Remainder 0.50 0.40Total all cancers 5.00 4.00Genetic effects weighted 1.00 0.50


Proportion of Fatal Cancers Attributable to Different Agents

Agent or Class Percentage of all Cancer Disease Best estimate RangeSmoking 31 29 - 33Alcoholic beverages 5 3 - 7Diet 35 20 - 60Natural hormones 15 10 - 20Infection 10 5 - 15Occupation 3 2 - 6Medicines, medical practices 1 0.5 - 2 Electromagnetic radiation 8 5 -10Ionizing (85% from natural radiation*) 4.5Ultraviolet 2.5Lower frequency <1Industrial products <1 <1 - 2Pollution 2 <1 - 4Other ? ?


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.

% E

ffe

ct

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.

% E

ffe

ct

Dose

dose

probability Risk factor

=

probability

dose


Indicators of relative organ tissue risk

0.05Remainder

0.01Bone surface

0.01Skin

0.05Thyroid

0.05Oesophagus

0.05Liver

0.05Breast

0.05Bladder

0.12Stomach

0.12Lung

0.12Colon

0.12Bone marrow (red)

0.20Gonads

wTTISSUE 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

Education

atlas de histologia

derive risk

atomic bomb

iaea training

mental retardation

breast cancer

populations

thyroid cancer