Radiotherapy, Cancer, Radiation Protection , FRCR, Oncology

1. BIOLOGICAL EFFECTS OF
IONIZING RADIATION
H.L.ANIL RANJITH
HEAD
DIVISION OF RADIATION PROTECTION
ATOMIC ENERGY AUTHORITY

2. Module 1.1. Basic concepts

3. • 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

4. 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 radiation
is the interaction between these sources of information
Effects of Radiation Exposure

5. 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
NUCLEUS
CONTAINS DNA,
CHROMOSOME,
GENES ETC.
CYTOPLASM
FLUID LIKE SUBSTANCE THAT
CONTAINS MANY SEPARATE
CONSTITUENTS

6. 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

7. Direct
effects
Indirect
effects
Cell death
Primary
damage
Modified
cell
Damage
to organ
Somatic
cells
Germ
cells
Hereditary
effects
Cancer
Leukemia
Death of
organism
Repair
BIOLOGICAL EFFECTSBIOLOGICAL EFFECTS
Determinististic
effects
Stochastic
effects

8. 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.

9. Deterministic effects
(Short term biological effects)
Dose
Severity
..
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

10. Stochastic effects
Long Term Biological Effects (Chronic Radiation Effects)
Cancer
Hereditary Effects
Probability
ofeffect
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.

11. 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

12. HERIDITORY EFFECTS
• OCCUR IN CHILDREN OR FUTURE
GENERATIONS OF IRRIDIATED
PERSON DUE TO A ALTERED GERM
CELL
• ARE STOCHASTIC EFFECTS

13. In direct Action on Cells

14. 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

15. 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)

16. 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

17. 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 .

18. Direct Action on Cells

19. Direct Actions
Direct ionization of molecules and
atoms of a cell
Any part of the cell may be damaged
DNA damage is important

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

21. Interaction of ionizing radiation
with DNA
DIRECT ACTIONDIRECT ACTION INDIRECT ACTIONINDIRECT ACTION

22. Damages to DNA
The critical Target of the cell

23. Damages to the DNA
Three 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.

24. The critical target: DNA

25. Damage to DNA

26. Damages to Stands
Single 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

27. DAMAGE TO THE CELLS BY
RADIATION CAN CAUSE:
• DELAY IN CELL REPRODUCTION
• CHROMOSOME ABERATION
• CELL DEATH
• GENE MUTATION ETC.

28. Module 1.2. Deterministic effects

29. DETERMINISTIC EFFECTS
• OCCURS DUE TO CELL KILING AND
THE PREVENTION OR DELAY OF
CELL DIVISION

30. 0
1
2
3
4
5
6
7
8
9
10
FREQUENCY
ABSORBED DOSE
SEVERITY
Diagnostic
threshold
Threshold
dose
Mostradiosensitive
individual
Mostradioresistant
individual
Deterministic effects

31. 31
Deterministic effects
• Due to cell killing
• Have a dose
threshold
• Specific to
particular tissues
• Severity of harm is
dose dependent
Radiation injury from an industrial source

32. Examples for deterministic
effects
• Skin breakdown
• Cataract of the lens of the eye
• Sterility
• Kidney failure
• Acute radiation syndrome (whole body)

33. 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

34. 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

35. 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

36. Threshold doses for deterministic
effects
Organ doses for adults
typically > 50 Gy

37. 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

38. Radiation induced skin injuries
Effect
Typical
threshold
dose (Gy)
Fluoroscopic
on time
(minutes) to
reach
threshold at a
dose rate of
50 mGy per
min
Fluoroscopic
on time
(minutes) to
reach
threshold at
a dose rate
of 100 mGy
per min
Time to
onset of the
effect
Early transient erythema 2 40 20 hours
Temporary epilation 3 60 30 ~3 weeks
Main erythema 6 120 60 ~10 days
Permanent epilation 7 140 70 ~3 weeks
Dry desquamation 10 200 100 ~4 weeks
Invasive fibrosis 10 200 100 ------------
Dermal atrophy 11 220 110 >14 weeks
Telangiectasia 12 240 120 >52 weeks
Moist desquamation 15 300 150 ~4 weeks
Late erythema 15 300 150 ~6-10 weeks
Dermal necrosis 18 360 180 >10 weeks
Secondary ulceration 20 400 200 >6 weeks

39. RADIOSENSITIVITY
High RS Medium RS Low RS
Bone Marrow
Spleen
Thymus
Lymphatic nodes
Gonads
Eye lens
Lymphocytes
(exception to the
RS laws)
Skin
Mesoderm organs
(liver, heart,
lungs…)
Muscle
Bones
Nervous system

40. Module 1.3. Stochastic effects

41. 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

42. Damage to DNA

43. 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.

45. 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

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

47. … 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)

48. RADIOSENSITIVITY
High RS Medium RS Low RS
Bone Marrow
Spleen
Thymus
Lymphatic nodes
Gonads
Eye lens
Lymphocytes
(exception to the
RS laws)
Skin
Mesoderm organs
(liver, heart,
lungs…)
Muscle
Bones
Nervous system

49. 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.

50. Module 1.4. Effects on embryo and fetus

51. 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.

52. 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.

53. PRE-IMPLANTATION

54. 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

56. Effects of Antenatal Exposure
Malformation
• 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.

57. Effects of Antenatal Exposure
Loss 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.

58. 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

59. 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

60. 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

61. 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

62. Module 1.5. Risk estimates

63. 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

64. 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

65. 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

66. 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

67. 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

68. 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

69. 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

70. HIROSHIMA 1945 :
Total Population : 330000
Deaths : 110000
Injured : 80000
NAGASAKI 1945 :
Total Population : 210000
Deaths : 70000
Injured : 28000

71. HIROSHIMA 1945 :
70000 new born children 1946 – 1953
showed no genetic effects.
(Parents were survivors of Hiroshima
or Nagasaki atomic bomb explosion)

72. HIROSHIMA 1945 :
No. of monitored pregnancies
1945 / 46 : ca. 2800
No effect :
0 – 8 weeks
after 25 weeks

73. HIROSHIMA 1945 :
Findings :
• Decrease of IQ
(foetus exposed)
• Delayed growth and development
(exposed at young
age)
• Leukemia

74. 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
Number
Belarus
Russian Federation
Ukraine
Total

75. Comparison of Radiation Worker Risks
to Other Workers
Mean death rate 1989
(10-6
/y)
Trade 40
Manufacture 60
Service 40
Government 90
Transport/utilities 240
Construction 320
Agriculture 400
Mines/quarries 430
Safe industries
≡ 2 mSv/y (100 mSv over
a lifetime)
≡ max permissible exposuremax permissible exposure
(20 mSv/year or 1000 mSv(20 mSv/year or 1000 mSv
over a lifetimeover a lifetime

76. The following activities are associated with
a 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

77. 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

78. Questions??