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Efek Biologi Radiasi

Tuti Amalia,M.Si
Fisika Medis RSCM
Mengetahui

Konsep dasar dan efek radiasi pada sel,


Efek Deterministik
Efek Stochastik
Efek radiasi terhadap embrio dan janin
Resiko radiasi
Observasi awal terhadap efek radiasi
1895 Roentgen menemukan sinar-X
1896 Laporan terjadinya efek kulit terbakar untuk pertama kali
1896 Sinar-X pertama kali digunakan untuk pengobatan kanker
1896 Becquerel: Penemuan radioaktivitas
1897 Pertama kali dilaporkan terjadinya kerusakan pada kulit
1902 Laporan pertama kali bahwa sinar- X dapat menyebabkan
penyakit kanker
1911 Laporan pertama kali terjadinya leukaemia pada manusia dan
kanker paru yang disebabkan oleh paparan pekerja
1911 94 kasus tumor terjadi di Jerman
Efek Paparan Radiasi
Informasi diperoleh dari:
epidemiology
percobaan secara radiobiology
cellular and molecular biology
Efek Radiasi terhadap sel

Chromosom
es
Target kritis : DNA

DIRECT ACTION INDIRECT ACTION


Kerusakan pada DNA

Slide IAEA
Exposure of the cell

No change

radiation hit
DNA mutation
cell nucleus!

Slide IAEA
Outcomes after cell exposure

Mutation Viable Cell


repaired

Unviable Cell
Cell death

DNA Mutation Cancer?


Cell survives but
mutated

Slide IAEA
Repair

Tubuh manusia terdiri dari 1014 sel.


Dosis serap sebesar 1 mGy/tahun (radiasi
alam) akan menyebabkan terjadinya ionisasi
1016, ini sama artinya dengan 100 per sel
dalam tubuh.
Jika kita asumsikan bahwa massa DNA adalah
1% dari massa sel, diperoleh hasil bahwa satu
ionisasi dalam molekul DNA disetiap sel tubuh
setiap tahun.
Radiosensitiviti Sel (RS)

RS = Probabilitas kerusakan sel, jaringan atau organ


per unit dosis.
Bergonie and Tribondeau (1906): RS LAWS:
RS akan tinggi jika:
Mitotik sel tinggi
Sel tidak terdifferensiasi
RADIOSENSITIVITY
High RS Medium RS Low RS
Bone Marrow Skin Muscle
Spleen Mesoderm Bones
Thymus organs (liver, Nervous system
Lymphatic heart, lungs)
nodes
Gonads
Eye lens
Lymphocytes
(exception to the RS
laws)

Slide IAEA
Efek Biologi pada tingkat sel

Cellular effects of ionizing radiation are


Mekanisme kematian sel :
studied by cell survival curves
Kematian secara fisik
n = targets Kematian secara
% survival cells (semi logarithmic)

fungsional :
Kematian selama interfase
100%
Penundaan pada fase
Dq mitotik
(threshold) Kegagalan reproduksi
D0
(radiosensitivity)

Dose
Slide IAEA
Faktor yang mempengaruhi
radiosensitivitas sel
Fisika
LET (linear energy transfer): RS

% survivor cells
Laju dosis : RS LET
Suhu : RS
Kimia LET
Peningkatan RS: OXYGEN, cytotoxic drugs.
Pengurangan RS: SULFURE (cys,
cysteamine)
G0
Biologi M
Cycle status:
G2 G1
RS: G2, M
RS: S
Repair of damage (sub-lethal damage may
be repaired e.g. fractionated dose)

Silde IAEA
CELL SURVIVAL
Radiation quality
lowLET
Lg LET
Surviving fraction ..
.........
...
.........

low LET
Hg
highLET
LET
high LET

Absorbed dose

LET (linear energy transfer) is the amount of energy (MeV) a particle will loose in traversing
a certain distance (m) of a material.

Slide IAEA
IONIZATION PATTERN

Adapted from Marco Zaider (2000)


BIOLOGICAL EFFECTS
Direct Indirect
effects effects

Repair
Primary
damage

Modified
Cell death
cell

Damage Somatic Germ


to organ cells cells

Death of Cancer Hereditary


organism Leukemia effects

Deterministic Stochastic
effects effects

Silde IAEA
Timing of events leading to radiation effects
10-15 Energy deposition
Excitation/ionization PHYSICAL INTERACTIONS
10-12 Initial particle tracks

Radical formation
10-9
Diffusion, chemical reactions PHYSICO-CHEMICAL INTERACTIONS
Initial DNA damage
10-6
TIME (sec)

10-3 1 ms DNA breaks / base damage

100 1 second
Repair processes
Damage fixation
103 Cell killing
BIOLOGICAL RESPONSE
1 hour
1 day Mutations/transformations/aberrations
106 Proliferation of "damaged" cells
1 year Promotion/completion

10 9 Teratogenesis MEDICAL EFFECTS


Cancer
100 years Hereditary defects

Side IAEA
EFFECTS OF CELL DEATH
Probability of death

100%

Dose
(mSv)

Side IAEA
Deterministic effects
SEVERITY
Most radiosensitive Most radioresistant
individual individual

Diagnostic
threshold

FREQUENCY
0

10
Threshold ABSORBED DOSE
dose

Side iAEA
Dosis Ambang untuk Efek Deterministik

Katarak : 2-10 Gy
Severity of
Sterilisasi Permanent effect

Laki laki 3.5-6 Gy


Perempuan 2.5-6 Gy
Sterilisasi Sementara
Laki laki 0.15 Gy dose
Perempuan 0.6 Gy threshold
Nilai untuk dosis ambang
Tergantung mode dose delivery :
Single high dose
Fraksinasi
Laju dosis , dosis ambang
Dosis ambang akan berbeda untuk setiap
orang.
Efek Sistemik
Efek morphologi atau fungsional
Faktor :
Organ
Dosis
Efek :
Langsung (reversible): < 6 bulan , e.g.: inflamasi, perdarahan.
Tunda ( irreversible): > 6 bulan, e.g.: atrophy, sclerosis, fibrosis.
Kriteria dosis :
< 1 Gy: LOW DOSE
1-10 Gy: MODERATE DOSE
> 10 Gy: HIGH DOSE
Regeneration : replacement oleh jaringan asal
Repair : replacement oleh jaringan penghubung.
Efek pada kulit
Histologic view of the skin
Menurut RS laws (Bergonie and
Tribondeau) :
RS sel kulit berasal dari basal stratum of
EPIDERMIS the epidermis.
Efek dapat berupa :
Erythema: 1-24 jam sesudah radiasi 3-5 Gy.
DERMIS
Alopecia: 5 Gy bersifat reversible; 20 Gy
bersifat irreversible.
From Atlas de Histologia.... J. Boya
Pigmentasi : Reversible, terlihat setelah 8 hari
radiasi.
Basal stratum cells, highly
mitotic, some of them with
Kering/ desquamasi : dosis mencapai 20 Gy.
melanin, responsible of Efek Tunda : teleangiectasia, fibrosis.
pigmentation.
Skin effects
Threshold
Weeks to
Injury Dose to
Onset
Skin (Sv)
Early transient erythema 2 <<1
Temporary epilation 3 3
Main erythema 6 1.5
Permanent epilation 7 3
Dry desquamation 10 4
Skin damage
Invasive fibrosis 10 from prolonged
Dermal atrophy 11 >14 fluoroscopic
Telangiectasis 12 >52 exposure
Moist desquamation 15 4
Late erythema 15 6-10
Dermal necrosis 18 >10
Secondary ulceration 20 >6

Side IAEA
Eye injuries

Side IAEA
Whole body response : adult

Chronic irradiation
syndrome
Acute irradiation syndrome
1-10 Gy Whole body clinic of
Steps:
10-50 Gy a partial-body
1. Prodromic irradiation
> 50 Gy 2. Latency Mechanism:
3. Manifestation Neurovegetative
disorder
BMS
(bone GIS
Similar to a sick
marrow) (gastro Lethal dose 50 / 30
feeling
intestinal) CNS
(central nervous
system) Quite frequent in
fractionated
Dose radiotherapy

Side IAEA
Lethal dose 50 / 30

Menyatakan persentase kematian dosis


sebagai fungsi waktu.
Artinya : Dosis yang dapat menyebabkan
kematian sebesar 50% dari populasi dalam
jangka waktu 30 hari
Besar dosis : 2-3 Gy untuk radiasi seluruh
tubuh manusia.
Whole body exposure
Absorbed dose Syndrome or Symptoms
(Gy) tissue involved

1-10 Bone marrow Leucopenia,


syndrome thrombopenia,
hemorrhage,
infections
10-50 Gastrointestinal Diarrhoea,
fever,
electrolytic
imbalance
>50 Central nervous Cramps,
syndrome tremor, ataxia,
lethargy,
impaired
vision, coma

Silde IAEA
Whole body exposure
Absorbed Therapy Prognosis Lethality
dose (Gy)

1-10 Symptomatic Excellent to 0-90%


Transfusions of uncertain
leucocytes and
platelets. Bone
marrow
transplantation
Growth stimu-
lating factors
10-50 Palliative Very poor 90-100%
>50 Symptomatic Hopeless 100%

Side IAEA
STOCHASTIC EFFECTS OF IONIZING
RADIATION

Chernobyl accident

Side IAEA
STOCHASTIC EFFECTS OF IONIZING
RADIATION
Thyroid cancer diagnosed up to 1998 among
children 0-17 years at the time of the Chernobyl
accident

300

250

200 Belarus
Number

Russian Federation
150
Ukraine
100 Total

50

0
1990 1991 1992 1993 1994 1995 1996 1997 1998
Year

Side IAEA
Genetic Effects
Ionising radiation is known to
cause heritable mutations in many
Frequency (%)
plants and animals
10
BUT

intensive studies of 70,000


offspring of the atomic bomb 5
survivors have failed to identify an
increase in congenital anomalies,
cancer, chromosome aberrations
in circulating lymphocytes or 0 10 20 30 4
mutational blood protein changes. Absorbed dose (Gy)

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


Sensitivity of the early conceptus
Till early 1980s, early conceptus was considered to
be very sensitive to radiation - although no one knew
how sensitive?
Realization that:
organogenesis starts 3-5 weeks after conception
In the period before organogenesis high radiation
exposure may lead to failure to implant. Low dose may not
have any observable effect.

Side IAEA
Incidence of
Prenatal & Neonatal
Death and
Abnormalities

Hall, Radiobiology for the


Radiologist pg 365

Side IAEA
PRE-IMPLANTATION

Side IAEA
Tahap Pre-implant (sampai dengan 10 hari )
Efek Lethal
Embrio hanya mengandung beberapa sel non
spesifik
Jika terlalu banyak sel yang rusak ...embrio akan
mati
Bom Atom akan berefek terjadinya insiden yang
tinggi pada kelahiran normal dan abortus secara
spontan.
Rfek Radiasi pada Janin
Resiko bahaya radiasi selama proses kehamilan,
berhubungan dengan tahapan kehamilan dan
besarnya dosis serap.
Resiko akibat bahaya radiasi akan tinggi selama
proses organogenesis pada tahap awal
kehamilan, dan resikonya akan berkurang pada
trisemester kedua dan ketiga.

Most
risk Less Least
Radiasi memicu terjadinya Malformasi
Malformasi mempunyai dosis ambang 100-200
mGy atau lebih umumnya terkait dengan masalah
pada central nervous system (CNS).
Dosis janin 100 mGy dapat dicapai dengan
prosedur IR dilengkapi dengan fluoroskopi pada
daerah pelvis dan radioterapi.

Heterotopic gray matter (arrows) near the


ventricles in a mentally retarded individual
occurring as a result of high dose in-utero
radiation exposure
Efek Radiasi
pada Masa Kehamilan
Selama periode kehamilan 8-25 minggu
post-konsepsi ,sistem syaraf pusat sensitif
terhadap radiasi.
Dosis janin :
> 100 mGy penurunan IQ
1000 mGy (1 Gy) retardasi mental
Effects on embryo and fetus

Slide IAEA
Effects on embryo and fetus
Age Threshold for Threshold for
lethal effects malformations
(mGy) (mGy)
1 day 100 No effect

14 days 250 -

18 days 500 250

20 days >500 250

50 days >1000 500

50 days to >1000 >500


birth

Side IAEA
EPIDEMIOLOGICAL DATA FROM:

Hiroshima-Nagasaki
Patients with
ancylosing spondylitis
cervical cancer
tuberculosis
mastitis
tinea capitis
thymus enlargement
thyrotoxicosis
hemangiomas

and more may come

Chernobyl
Techa river
Semiplatinsk
Nevada
..

Side IAEA
Populations used in the UNSCEAR Reports
Characteristic Atomic Bomb Spondylitis Cervical Cancer
Survivors Series Series

Number 86,500 14,000 83,000

Age at irradiation 0 -> 90 > 15 < 30 -> 70

Average 28.8 y 23.0 y 7.6 y


follow-up
Mean dose 0.24 Gy 1.9 Gy Inhomogeneous

Range of doses 0.01 6.0 Gy 0 8.06 Gy

Type of Instantaneous / Fractionated / Chronic /


irradiation whole-body partial-body partial-body

Side IAEA
Variation of Cancer
Incidence with time
following the
Atomic Bombs

Side IAEA
Risk (%/ Sv) for Cancer induction
by Age at exposure and Sex

20

Male
15
Female

10

0
0 10 20 30 40 50 60 70 80
(age at exposure)
Side IAEA
Radiation risks - embryo and fetus

Threshold dose
deterministic effects 50-100 mSv

Mental retardation 40% / Sv

Cancer and leukemia


before 10 y of age 2% / Sv
lifetime 15% / Sv

Hereditary effects 1% / Sv

Slide IAEA
TYPES OF EFFECTS FOLLOWING IRRADIATION IN UTERO

Time after Effect Normal incidence


conception in live-born

First three weeks No deterministic or stochastic -


effects in live-born child
3rd through 8th Potential for malformation of 0.06
weeks organsa (1 in 17)
8th through 25th Potential for severe mental 5 x 10-3
weeks retardationb (1 in 200)
4th week throughout Cancer in childhood or in adult 1 x 10-3
pregnancy lifec (1 in 1000)

a Deterministic effect. Threshold ~ 0.1 Gy


b 30 IQ units shift: 8-15th week; <30 IQ units shift: 16 - 25th week
c Risk in utero ~ risk < 10 years of age
Slide IAEA
Fetus/Embrio terhadap
Radiasi Pengion
Fetus/embrio lebih sensitive terhadap radiasi pengion
dibandingkan manusia dewasa.
Terjadi peningkatan aborsi spontan pada embrio setelah
beberapa hari konsepsi.
Peningkatan dosis dapat menyebabkan :
Mental retardasi
Microcephaly (small head size) setelah 8-15 minggu konsepsi
Malformations: skeletal, stunted growth, genital
Peningkatan resiko kanker (esp. leukemia)
Scale of Radiation Exposures
10000
Cancer deaths /year/1M people

1000
Typical
Bone scan Radiotherapy
100 CT scan Fraction

Annual natural cancer


mortality
10 Background
additional cancer
deaths due to radiation

1
0.1 1 10 100 1000 10000
Dose (mGy)

Slide IAEA
Comparison of Radiation Worker Risks to Other
Workers

Mean death rate 1989


(10-6/y)
Trade 40
Safe industries
Manufacture 60 2 mSv/y (100 mSv over
Service 40 a lifetime)

Government 90
Transport/utilities 240
max permissible exposure
Construction 320 (20 mSv/year or 1000 mSv
Agriculture 400 over a lifetime

Mines/quarries 430
Slide IAEA
Where to Get More Information

Other sessions
Part 2 Radiation Physics
Further readings
WHO/IAEA. Manual on Radiation Protection in Hospital and
General Practice. Volume 1. Basic requirements (draft
manuscript)
ICRP publications (41, 60, 84)
UNSCEAR reports
ALPEN E.L Radiation Biophysics. Academic Press, 1998
RUSSEL, J.G.B., Diagnostic radiation, pregnancy and
termination, Br. J. Radiol. 62 733 (1989) 92-3.

Part 1. Biological effects of


52
ionizing radiation

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