BIOLOGICAL EFFECTS OFIONIZING RADIATION

H.L.ANIL RANJITHHEAD

DIVISION OF RADIATION PROTECTIONATOMIC ENERGY AUTHORITY

Module 1.1. Basic concepts

• 1895 X-rays discovered by Roentgen• 1896 First skin burns reported• 1896 First use of x-rays in the treatment of cancer• 1896 Becquerel: Discovery of radioactivity• 1897 First cases of skin damage reported• 1902 First report of x-ray induced cancer

• 1911 First report of leukaemia in humans and lung cancer from occupational exposure

• 1911 94 cases of tumour reported in Germany (50 being radiologists)

Early Observations of the Effects of Ionising Radiation

Information comes from: studies of humans (epidemiology) studies of animals and plants (experimental

radiobiology) fundamental studies of cells and their components

(cellular and molecular biology)The key to understanding the health effects of radiationis the interaction between these sources of information

Effects of Radiation Exposure

CELL• IS THE BASIC UNIT OF

LIFE• MAKES ORGANS AND TISSUES• HUMAN BODY CONSISTS

OF 1014 SUCH CELLS• BIOLOGICAL TISSUES

COMPRIZE OF 70% OF WATER

CELL MEMBRANE: CONTROL INTAKE & OUTPUT OF SOLUBLE SUBSTANCE

NUCLEAR MEMBRANE

NUCLEUSCONTAINS DNA, CHROMOSOME, GENES ETC.

CYTOPLASM

FLUID LIKE SUBSTANCE THAT CONTAINS MANY SEPARATE CONSTITUENTS

DIRECT ACTION ON CELLS

• IN DIRECT ACTION,THE SENSITIVE VOLUME OF THE CELL IS AFFECTED BY DIRECT TRANSFER

OF ENERGY FROM RADIATION TO THE

CELL AND SENSITIVE VOLUME CAN BE INACTIVATED

INDIRECT ACTION ON CELLS

• IN INDIRECT ACTION, THE SENSITIVE

VOLUME OF THE CELL IS INACTIVATED BY

TRANSFER OF ENERGY FROM ANOTHER

VOLUME THAT HAS ABSORBED ENERGY FROM RADIATION

Directeffects

Indirecteffects

Cell death

Primarydamage

Modifiedcell

Damageto organ

Somaticcells

Germcells

Hereditaryeffects

CancerLeukemia

Death oforganism

Repair

BIOLOGICAL EFFECTSBIOLOGICAL EFFECTS

Determinististiceffects

Stochasticeffects

    

 

                     

Biological Effects of Radiation

Deterministic Effects Stochastic Effects

Due to large doses of radiation exposure during short period of time

Due to large short term doses, or smaller doses received over a long period of time.

Deterministic effects(Short term biological effects)

Dose

Seve

rity

..threshold

• lots of cells killed in a given tissue or organ– high dose

• cell replacement (if able to happen) will tend to offset cell killing

Stochastic effectsLong Term Biological Effects (Chronic Radiation Effects)

  Cancer

            Hereditary Effects

Prob

abili

ty

of e

ffec

t

Dose

            

                 

 

All radiation induced cancers have a long latent period before they are detected.

                  The shortest latent period is about 5-10 year for Leukemia, and about 20 - 30 years for solid tumors.

SOMATIC EFFECTS

• ARISE FROM DAMAGE TO CELLS IN A PARTICLLAR TISSUE AND AFFECT ONLY TO THE IRRADIATED PERSON

• CAN BE EITHER STOCHASTIC EFFECT OR DETERMINISTIC EFFECT

HERIDITORY EFFECTS

• OCCUR IN CHILDREN OR FUTURE GENERATIONS OF IRRIDIATED PERSON DUE TO A ALTERED GERM CELL

• ARE STOCHASTIC EFFECTS

In direct Action on Cells

Indirect Actions

When water is irradiated with Ionizing radiation, the following reactions take place.

H2O H2O+ + e - 1.1

Positive ion dissolves immediately.

H2O+ H+ + OH 1.2

Electron is picket up by a neutral water molecule.

H2O + e- H2O- 1.3

This also dissolves immediately.

H2O- H + OH- 1.4

H and OH are free radicals and are highly reactive.

(The reactions 1.1 1.4 last only about 10-6 s)

The free radicals H & OH may recombine or react with other molecules.

If OH radicals are in close proximity, they can recombine to form H2O2

OH + OH H2O2

If irradiated water contains dissolved O2 the following reaction will take place.

H + O2 HO2

Since this hydroperoxyl radical has longer life time which allows.

H + HO2 H2O2

Since H2O2is a relatively stable oxydizing agent, H2O2 can affect molecules or cells .

Direct Action on Cells

Direct Actions

Direct ionization of molecules and atoms of a cell

Any part of the cell may be damaged

DNA damage is important

Biological Effects

• At low doses, damage to a cell is a random effect - either there is energy deposition or not.

Interaction of ionizing radiation with DNA

DIRECT ACTION INDIRECT ACTION

Damages to DNAThe critical Target of the cell

Damages to the DNAThree major types can be discussed.

• DNA Base Damage

- This is the most common damage to the DNA molecules.

- If the cell remain unprepared it can survive and reproduce as a altered

cell.

The critical target: DNA

Damage to DNA

Damages to StandsSingle strand break.

• Braking of a one strand

• Can be quickly repaired.

Double strand break

• Braking of both strands either by single event or two separate event.

Single event Two separate event

DAMAGE TO THE CELLS BY RADIATION CAN CAUSE:

• DELAY IN CELL REPRODUCTION• CHROMOSOME ABERATION • CELL DEATH• GENE MUTATION ETC.

Module 1.2. Deterministic effects

DETERMINISTIC EFFECTS

• OCCURS DUE TO CELL KILING AND THE PREVENTION OR DELAY OF CELL DIVISION

0 1 2 3 4 5 6 7 8 9 10

FREQUENCY

ABSORBED DOSE

SEVERITY

Diagnostic threshold

Threshold dose

Most radiosensitive individual

Most radioresistant individual

Deterministic effects

31

Deterministic effects• Due to cell killing• Have a dose

threshold • Specific to

particular tissues• Severity of harm is

dose dependentRadiation injury from an industrial source

Examples for deterministic effects

• Skin breakdown• Cataract of the lens of the eye• Sterility• Kidney failure• Acute radiation syndrome (whole body)

Skin reactions

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

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 ofeffect

threshold

Note on threshold values

• Depend on dose delivery mode:– single high dose most effective– fractionation increases threshold dose in most

cases significantly– decreasing the dose rate increases threshold in

most cases• Threshold may differ in different persons

Threshold doses for deterministic effects

Organ doses for adults typically > 50 Gy

Absorbed dose (Gy) Syndrome or Tissues involved

Symptoms

1 - 2 Bone marrow Mild leucopenia and thrombopenia

2 - 10 Bone marrow syndrome Leucopenia, thrombopenia, hemorrhage, infections

10 - 15 Intestinal syndrome Diarrhoea, fever, electrolytic imbalance

> 15 Neurological syndrome Cramps, tremor, ataxia, lethargy, impaired vision, coma

Absorbed dose (Gy)

Therapy Prognosis Lethality

1 – 2 Symptomatic Excellent 0-10 %

2 – 10 Transfusions of leucocytes and platelets. Bone marrow transplantation. Growth stimulating factors

Uncertain 0-90%

10-15 Palliative Very poor 90 - 100 %

> 15 Symptomatic Hopeless 100 %

Whole body exposureWhole body exposure

Radiation induced skin injuries

Effect

Typicalthresholddose (Gy)

Fluoroscopicon time

(minutes) toreach

threshold at adose rate of50 mGy per

min

Fluoroscopicon time

(minutes) toreach

threshold ata dose rateof 100 mGy

per min

Time toonset of the

effect

Early transient erythema 2 40 20 hoursTemporary epilation 3 60 30 ~3 weeksMain erythema 6 120 60 ~10 daysPermanent epilation 7 140 70 ~3 weeksDry desquamation 10 200 100 ~4 weeksInvasive fibrosis 10 200 100 ------------Dermal atrophy 11 220 110 >14 weeksTelangiectasia 12 240 120 >52 weeksMoist desquamation 15 300 150 ~4 weeksLate erythema 15 300 150 ~6-10 weeksDermal necrosis 18 360 180 >10 weeksSecondary ulceration 20 400 200 >6 weeks

RADIOSENSITIVITYHigh RS Medium RS Low RS

Bone MarrowSpleenThymusLymphatic nodesGonadsEye lensLymphocytes (exception to the RS laws)

SkinMesoderm organs (liver, heart, lungs…)

MuscleBonesNervous system

Module 1.3. Stochastic effects

STOCHASTIC EFFECTS

• MAY BE DUE TO EITHER A SINGLE LARGE OVER EXPOSURE OR CONTINUING LOW LEVEL OVER EXPOSURE

• RESULTS FROM : CHROMOSOME ABERATIONS AND, GENE MUTATIONS

Damage to DNA

Chromosome Aberration and Gene Mutation

If the stands broken are not repaired, the end of the breaks can attach to the broken or unbroken

chromosomes (healthy ones) and result chromosome aberrations, and gene mutations etc.

Stochastic effects

• Due to cell changes (DNA) and proliferation towards a malignant disease

• Severity (i.e. cancer) independent of the dose• No dose threshold (they are presumed to occur at

any dose however small)• Probability of effect increases with dose

Cancer

Over proliferation of viable cells which have received damages to their control systems in the form of gene mutations or chromosome aberrations.

… order of magnitudes• 1cm3 of tissue = 109 cells• 1 mGy --> 1 in 1000 or 106 cells hit• 999 of 1000 lesions are repaired - leaving 103 cells

damaged• 999 of 1000 damaged cells die (not a major

problem as millions of cells die every day in every person)

• 1 cell may live with damage (could be mutated)

RADIOSENSITIVITYHigh RS Medium RS Low RS

Bone MarrowSpleenThymusLymphatic nodesGonadsEye lensLymphocytes (exception to the RS laws)

SkinMesoderm organs (liver, heart, lungs…)

MuscleBonesNervous system

SENSITIVE ORGANS TO RADIATION INDUCED CANCERS

  

                    Female breast                  Lungs                  Bone                  Thyroid and                  Skin

      Current best estimate of the fatality risk from radiation induced cancer is 5 per 100 person – Sievert.

This means that, if 20000 people were each given 1.0 mSv, one of them may die 20 – 30 years later due to a cancer induced by that dose. However in that population of 20000 people, about 3200 of them would die from normal cancer in 20 – 30 years.

Module 1.4. Effects on embryo and fetus

Radiation effects on the embryo/foetus

• lethal effects• malformations/growth anomalies• mental retardation• cancer

– childhood, adulthood• hereditary effects

• For a dose of 10 mSv, probability of the above is less than 0.2%, compared with about 6% natural incidence of the same.

Effects of Antenatal Exposure• The effects on the embryo/fetus depend on the time of

exposure relative to conception.

• Lethal effects can be induced in experimental animal by relatively low doses (such as 100 mSv) before or immediately after implantation of the embryo into the uterine wall.

• They may also be induced after higher doses during all stages of intra-uterine development.

• Exposure of the embryo in the first three weeks following conception is not likely to result in deterministic or stochastic effects in the live-born child, despite the fact that the central nervous system and the heart are beginning to develop in the third week. It is thought that any cellular damage at this stage is much more likely to cause the death of the embryo/fetus than to result in stochastic effects expressed in the live-born.

PRE-IMPLANTATION

Pre-implant stage (up to 10 days) Only lethal effect, all or none Embryo contains only few cells which are not

specialized If too many cell are damaged-embryo is

resorbed If only few killed-remaining pluripotent cells

replace the cells loss within few cell divisions Atomic Bomb survivors - high incidence of

both - normal birth and spontaneous abortion

Effects of Antenatal ExposureMalformation• During the period of major organogenesis, conventionally

from the start of the third week after conception, malformations may be caused in the organ under development at time of exposure. These effects are deterministic in character with a threshold in man, estimated from animal experiments, to be about 0.1 Gy.

• Throughout the period from 3 weeks after conception until the end of pregnancy, it is likely that radiation exposure can cause stochastic effects resulting in an increased probability of cancer in the live-born. The available data are not consistent and considerable uncertainty exists. However, the ICRP assumes that the nominal fatality probability coefficient is, at most, a few times that for the population as a whole. Irradiated fetus seem to be susceptible to childhood leukemia and other childhood cancers which expressed approximately during the first decade of life.

Effects of Antenatal ExposureLoss of Intelligence• Values of intelligence quotient (IQ) lower than expected reported in some

children exposed in utero. • Mental retardation was not observed to be induced by radiation prior to 8

weeks from conception ,or after 25 weeeks. The period 8-15 weeks are more sensitive than the period 16-25 weeks. During the most sensitive period, the fraction of those exposed which became severely mentally retarded increased by approximately 0.4 per Sv. During weeks 16-25, it increased by about 0.1 per Sv.

• Observed a gneral downward shift in the distribution of IQ with increasing dose. the shift is proportional to dose. Small shifts cannot be clinically identified. A coefficient of about 30 IQ points per Sv relates exposure from 8 weeks to 15 weeks after conception. A similar, but smaller shift, is detectable exposure in the period from 16 weeks to 25 weeks.

At doses of the order of 0.1 Sv, no effect would be detectable in the general distribution of IQ, but at somewhat large doses the effect might be sufficient to show an increase in the number of children classified as severely retarded. All the observations on IQ and severe mental retardation relate to high dose.

Radiation-Induced Malformations

• Malformations have a threshold of 100-200 mGy or higher and are typically associated with central nervous system problems

• Fetal doses of 100 mGy are not reached even with 3 pelvic CT scans or 20 conventional diagnostic x-ray examinations

• These levels can be reached with fluoroscopically guided interventional procedures of the pelvis and with radiotherapy

Central Nervous System Effects

• During 8-25 weeks post-conception the CNS is particularly sensitive to radiation

• Fetal doses in excess of 100 mGy can result in some reduction of IQ (intelligence quotient)

• Fetal doses in the range of 1000 mGy can result in severe mental retardation particularly during 8-15 weeks and to a lesser extent at 16-25 weeks

Leukemia and Cancer

• Radiation has been shown to increase the risk for leukemia and many types of cancer in adults and children

• Throughout most of pregnancy, the embryo/fetus is assumed to be at about the same risk for carcinogenic effects as children

Leukemia and Cancer

• The relative risk may be as high as 1.4 (40% increase over normal incidence) due to a fetal dose of 10 mGy

• Individual risk, however, is small with the risk of cancer at ages 0-15 being about 1 excess cancer death per 1,700 children exposed “in utero” to 10 mGy

Module 1.5. Risk estimates

How do we know about radiation induced cancer?

• epidemiological studies– A bomb survivors (Life Span Study)– Medical exposures (eg Ankylosing Spondylitis Study)– Occupational exposures (eg. UK National Register for Radiation Workers)

• molecular biology studies

Epidemiological studies - features• Large population size

– Up to 100 000• Years of follow-up

– Often 30 or more years• Mix of ages, sex, ethnic groups• Setting

– War, medical, occupational• Organs irradiated

– All, through to specific organs• Dose range

– Mainly medium to high• Dose rate

– Mainly high

Cancer risk estimates• Estimated lifetime fatal cancer risk for the general

population with exposure to low LET radiation at high doses and dose rates– ICRP 60 risk estimate– 10% per Sv

• It is assumed there is NO threshold• Allowance is made for low doses/dose rates

– ICRP 60 used a factor of 2– 5% per Sv at low doses/dose rates– for workers the risk is assessed at 4% per Sv at low

doses/dose rates

Lifetime fatal cancer risks - low dose/rate• Risk per 100 person Sv

Organ ICRP 26 ICRP 60

Bone marrow 0.20 0.50

Bone surfaces 0.05 0.05

Lung 0.20 0.85

Thyroid 0.05 0.08

Breast 0.25 0.20

Colon 0.85

Oesophagus 0.30

Stomach 1.10

Liver 0.15

Urinary bladder 0.30

Skin 0.02

Ovaries 0.10

Remainder 0.50 0.50

TOTAL 1.25 5.00

Hereditary effects of radiation• effects associated with gene mutations and

chromosomal aberrations induced in parental germ cells and transmitted to progeny

• radiation does not produce new, unique mutations• information for humans is inconclusive - no direct

evidence• probability of hereditary effects is proportional to

the gonadal dose

Hereditary Effects of Radiation

• Ionising radiation is known to cause heritable mutations in many plants and animals

BUT

• intensive studies of 70,000 offspring of the atomic bomb survivors have failed to identify an increase in congenital anomalies, cancer, chromosome aberrations in circulating lymphocytes or mutational blood protein changes.

Neel et al. Am. J. Hum. Genet. 1990, 46:1053-1072Neel et al. Am. J. Hum. Genet. 1990, 46:1053-1072

Estimating risks of hereditary effects

• hereditary effects are stochastic in nature, with the amount of radiation exposure determining the probability of occurrence

• current risk estimates for hereditary effects over all generations– 2.4 x 10-2 per Sv - dose to gonads, reproductive pop– 1.0 x 10-2 per Sv - dose to gonads, general pop

• A derived figure to assess the risks of occupational exposures– 0.6 x 10-2 per Sv - dose to gonads, worker population

HIROSHIMA 1945 :Total Population : 330000

Deaths : 110000

Injured : 80000

NAGASAKI 1945 :Total Population : 210000

Deaths : 70000

Injured : 28000

HIROSHIMA 1945 :

70000 new born children 1946 – 1953 showed no genetic effects.

(Parents were survivors of Hiroshima or Nagasaki atomic bomb explosion)

HIROSHIMA 1945 :No. of monitored pregnancies 1945 / 46 : ca. 2800

No effect :

0 – 8 weeks

after 25 weeks

HIROSHIMA 1945 :Findings :

• Decrease of IQ

(foetus exposed)

• Delayed growth and development (exposed at young age)

• Leukemia

• Cancer

STOCHASTIC EFFECTS OF IONIZING RADIATION

Thyroid cancer diagnosed up to 1998 among children 0-17 years at the time of the Chernobyl

accident

0

50

100

150

200

250

300

1990 1991 1992 1993 1994 1995 1996 1997 1998

Year

Num

ber Belarus

Russian FederationUkraineTotal

Comparison of Radiation Worker Risks to Other Workers

Mean death rate 1989(10-6/y)

Trade 40Manufacture 60Service 40Government 90Transport/utilities 240Construction 320Agriculture 400Mines/quarries 430

Safe industries 2 mSv/y (100 mSv overa lifetime)

max permissible exposuremax permissible exposure(20 mSv/year or 1000 mSv(20 mSv/year or 1000 mSvover a lifetimeover a lifetime

The following activities are associated witha risk of death that is 1/1000000

•10 days work in a nuclear medicine department• smoking 1.4 cigarette• living 2 days in a polluted city• traveling 6 min in a canoe• 1.5 min mountaineering• traveling 480 km in a car• traveling 1600 km in an airplane• living 2 months together with a smoker• drinking 30 cans of diet soda

RISKS

In Perspective

• Loss of Life in Days– Unmarried Male – 3500 (~10 yr)

– Unmarried Female – 2250 (~5 yr)

– Smoking(1 pk/day) – 2250 (~ 7 yr)

– 25% Overweight – 777 (~ 2 yr)

– Alcohol Consumption – 465 (~ 1 yr)

– Driving a motor vehicle - 207– Radiation (1 mSv/yr for 70 years) - 10

Questions??