Principles of Radiobiology

Antnio Sebastio Rodrigues, Gentica, FCM,UNL

LIP, Braga, Janeiro 2010
Ionizing radiation
We live in a naturally radioactive environment:
We are exposed to: - Cosmic Radiation
- Earth Radiation
- Radon
Internal radioactivity:
-Radioactive Poloniumand radiumpresent in bones
- Radioactive Carbon and Potassiumpresent in muscles - Radioactive Carbon and Potassiumpresent in muscles
- Radioactive Gases present in lungs
Human activity:
-X ray medicine
-Nuclear Medicine
-Consumer products (water, food, tobacco)
-Occupational exposure
-Nuclear Accidents
-Nuclear fuel cycle
Hiroshima
Litvinenko
Kosovo
Samut Prakarn
Goiania, Brasil
Cochabamba, Bolvia
Lilo, Georgia
Main Sources of exposure to Ionizing radiation
~ 2.4 mSv/year
Increase of CT scans
BEIR V, NRC, 1990
What is the risk?
Concept of dose
Absorbed dose: 1 Gray (Gy) = 1J/kg - physical unit, no idea of biological effects
Since alpha and neutron radiation produce more biological damage
QUALITY FACTOR of a radiation type is defined as the ratio of the biological
damage produced by the absorption of 1 Gy of that radiation to the
biological damage produced by 1 Gy of X or gamma radiation. biological damage produced by 1 Gy of X or gamma radiation.
Radiation Energy Q
Gamma, all 1
Beta, all 1
Neutrons, slow 5
Neutrons, fast 20
Alpha, all 20
An equivalent dose of one SIEVERT (Sv) represents that
quantity of radiation dose that is equivalent, in terms
of specified biological damage, to one gray of X or
gamma rays.
H (Sv) = D (Gy) x Q
Since not all tissues are equally sensitive to the same radiation dose
Concept of dose
Effective dose (E) corresponds to the sum of equivalent doses (H
T
)
relative to each organ multiplied by a weight factor W
T
specific for
each organ or tissue.
E= H x W E= H
T
x W
T
Organ WT
Gonads 0.20
Bone marrow,
Colon, lung, stomach 0.12
Bladder, breast, liver, thyroid 0.05
Skin, bone 0.01
ICRP
Sources of radiation exposure data
Principal toxic effects
Acute exposure Protracted exposure
Radiation exposure
High dose Low dose High dose Low dose
Immediate effects
Delayed effects
Immediate effects
Delayed effects
Whole body exposure
Classic paradigmof radiation injury
Ionizing
radiation
DNA
damage
DNA
repair
Cell
death
Late effects
Developmental
effects
Ionization
(free
radicals)
< 1 second min - hours days weeks months years generations
Stable mutations
Early effects
Radiation sickness
Cancer
Heritable
effects
Germ-line
Somatic
Metting, 2005; Little, 2003
Stochastic effects Non-Stochastic effects
Severity independent of dose
(both somatic and genetic)
Severity varies with magnitude
of dose, above a threshold
dose (somatic)
Cancer
Mental retardation
Hereditary effects
Skin erythema
Acute effects
Cataracts
Fertility impairment
SKIN EFFECTS
Acute radiation dermatitis (single exposure RX)
> 2 - 3 Gy
Epilation (temp.; def > 7 10 Gy)
> 3 Gy
Erythema (> 1 week)
Heals with (dry) desquamation and
hyperpigmentation hyperpigmentation
> 10 - 20 Gy
Erythema, oedema, large painful blisters,
wet desquamation, ulceration (weeksmonths),
radionecrosis.
Heals slowly with atrophy, telangiectasia, irregular
pigmentation
Some lesions may never completely heal chronic
stage
Acute radiation dermatitis
6,5 h. local exposure to Iridium-192 source
Turai e.a., BMJ 2004, 328: 568-572
day 2: early blister, erythema day 9: extended erosion, inflammation
Acute Radiation Syndrome
The body consists of cells of different radiation sensitivity, a large
dose of radiation delivered acutely does larger damage than the
same does delivered over a long period of time.
The body response to a large acute dose manifests itself in the
acute radiation syndrome.
DEVELOPMENT EFFECTS
Gestation: high cellular proliferation and differentiation
Effects depend on the gestational phase and time of exposure:
Pre-implantation (0 - 9 days) death of the
embryo
Organogenesis (10 days - 6 weeks) Growth delay
and/or teratogenic effects (malformation) and/or teratogenic effects (malformation)
Fetal (from6 semanas) growth delay
Observed effects depend on absorbed dose and dose rate.
> 0,1 Sv (in utero exposure), between 10 days and 26 weeks, risk is
high.
Mental retardation observed in children exposed in utero in Japan
FERTILITY EFFECTS
Doses, in general, lower than 10% of lethal doses induce alterations in
the reproductive organs
Female Sex:
Greater probability of sterility in older women.
Doses of 3 Gy (gonads) can provoke temporary sterility
in young women but permanent in older women. in young women but permanent in older women.
Doses > 4 Gy (gonads) provoke permanent sterility
regardless of age.
Male Sex:
Temporary sterility and qualitative alterations in sperm
with doses of 0,15 Gy (gonads).
Permanent sterility with doses between 3,5 and 6 Gy
(gonads).
GENETIC (HEREDITARY ) EFFECTS?
No radiation induced genetic (hereditary) effects have been
observed in humans
Cardiovascular effects have been observed in the atom bomb
survivors and offspring
CANCER EFFECTS
Significant risk at doses
50 100 mSv (acute
For X rays or rays
What is the lowest dose of x- or -radiation for which evidence
exists of increased cancer risks in humans?
50 100 mSv (acute
exposure)!
Significant risk at doses
10 50 mSv (protracted
exposure)!
Brenner, PNAS, 2003
Relative contribution to dose fromCT compared to other
radiological examinations
Pediatric CT Scans
1989: ~4% of all CT scans
1993: ~6%
UNSCEAR 2000; Brenner, D.
1993: ~6%
2000: ~11%
About 2.7 million CT exams /yr
in the US are on children under 15
Relevant dose: 6 100 mSv
Parry, Radiographics, 1999
Chernobyl
60
80
N

m
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r
o

d
e

c
a
n
c
r
o
s

d
a

t
i
r

i
d
e
Bielorssia (2.000.000)
Ucrnia (11.000.000)
Bryansk (300.000)
Orel-Tula-Kaluga (800.000)
Nmero de casos de cancro da tiride em crianas <15 anos na altura do
diagnstico (vrias fontes):
1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998
0
20
40
N

m
e
r
o

d
e

c
a
n
c
r
o
s

d
a

t
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i
d
e
Ano
As taxas de cancro da
tiride nas regies mais
afectadas pelas
radiaes comearam a
subir em 1990 (i.e. 4
anos aps o acidente)
comparado com 12 anos
aps as exploses de
Hiroshima e Nagasaki.
Population (years exposed) number
Average total in 20yrs
(mSv)
1
Liquidators (19861987)
(high exposed)
240 000 >100
Evacuees (1986) 116 000 >33
Residents SCZs (>555
kBq/m2)(19862005)
270 000 >50
Total average effective doses accumulated over 20 years by
the highest Chernobyl exposed populations
Residents low contam. (37
kBq/m2) (19862005)
5 000 000 1020
Natural background
2.4 mSv/year (typical
range1-10, max >20)
48
Approximate typical doses from medical x-ray exposures per procedure:
whole body CT scan 12 mSv
mammogram 0.13 mSv
chest x-ray 0.08 mSv
[1] These doses are additional to those from natural background radiation.
WHO, 2006
Dose (Gy) Persons 1950-1997
Deaths Expected
background
Fitted excess
< 0.005 37,458 3833 3844 0
0.0050.1 31,650 3277 3221 44
Observed and expected solid cancer deaths 19501997
by dose group (Life Span Study)
0.0050.1 31,650 3277 3221 44
0.10.2 5732 668 622 39
0.20.5 6332 763 678 97
0.51 3299 438 335 109
12 1613 274 157 103
2+ 488 82 38 48
Total 86,572 9335 8895 440
(Kodama, ICS, 2007; Preston, Rad. Res., 2003)
Biological effect as a function of dose
B
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o
g
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a
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e
f
f
e
c
t
Dose
B
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o
g
i
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a
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e
f
f
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t
Between 1944 and 2002:
420 incidents worldwide
134 deaths (28 deaths Chernobyl 1986)
50% radiations incidents in industry (NDC)
Global statistics and main causes of radiation
accidents
50% radiations incidents in industry (NDC)
10% medical incidents (diagnosis/therapy)
50% of fatal exposures due to calibration errors in
medical equipment or because of insecure storage
of spent sources for radiotherapy
Turai E.A., BMJ, 2004
CELLULAR AND MOLECULAR EFFECTS
Biomarkers of exposure Biomarkers of exposure
DNA LESIONS
Ionizing
Radiation
(DSB)
High LET
Multiple damaged
sites
(clustered damage)
difficult to repair
Low LET
Howmany DNA lesions occur?
J.-P. Pouget, S. J. Mather, Eur J Nucl Med (2001) 28:541561
Repair of DSB
More than 100 genes
Jan H. J. Hoeijmakers Nature 411, 366-374 (2001)
More than 100 genes
Involved in DNA repair
(a)
Normal
(f)
Tetraradial
(e)
Ring
(d)
Dicentric
(c)
Chromosome
break
(b)
Chromatid
break
Chromosomal aberrations
Biomarkers of exposure






break break
N.G.Oliveira, (2003)
Ring
Chromosomal aberrations
Dicentric
Fragment
Fragment
Octvia M.Gil et al, 2002
Tetraradial
Fragment
Dicentric
Dicentric
Dose response curve Chromosomal aberrations
Lonard, A. 2006
Gold standard!
Cytogenetic biomarkers -particles
tetraradial
triradial
Human melanoma cells
induction of micronuclei
V79 cells induction of
chromosomal aberrations
dicentric
tetracentric
dicentric
tetracentric
ring
ring
Acentric
fragment
tricentric
(1) (2) (3)
N.Oliveira et al, 2002
30
40
50
60
70
D
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t
r
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s
/
1
0
0

c
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l
s
Case study accidentally irradiated worker
Average whole body dose: ~ 5 Gy
Head: 2 Gy
Left Foot: 50 Gy
0
10
20
0 50 100 150 200 250
D
i
c
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n
t
r
i
c
s
/
1
0
0

c
e
l
l
s
Time after exposure (months)
Micronucleus assay
Cytochalasin B
N.Oliveira et al, 2002
Micronucleus
Micronucleus
Micronucleus assay
Octvia M.Gil et al, 2002
Oxidative DNA
damage: production
of breaks
Radiation
Dose
Comet assay
Transient effects
(Hours after exposure)
(DSB)
Translocations/FISH
www.genome.gov
Translocations/FISH
Octvia M.Gil et al, ITN
H2AX phosphorylation
Fernandez-Capetillo JEM, 199 199 199 199, 1671-1677 (2004)
No possvel apresentar a imagem. O computador pode no ter memria suficiente para abrir a imagem ou a imagem pode ter sido danificada. Reinicie o computador e, em seguida, abra o ficheiro novamente. Se o x vermelho continuar a aparecer, poder ter de eliminar a imagem e inseri-la novamente.
H2AX phosphorylation
Control
No possvel apresentar a imagem. O computador pode no ter memria suficiente para abrir a imagem ou a imagem pode ter sido danificada. Reinicie o computador e, em seguida, abra o ficheiro novamente. Se o x vermelho continuar a aparecer, poder ter de eliminar a imagem e inseri-la novamente.
After exposure
Transient effects
(Hours after exposure)
-H2AX
-PFGE
H2AX and radiation
No possvel apresentar a imagem. O computador pode no ter memria suficiente para abrir a imagem ou a imagem pode ter sido danificada. Reinicie o computador e, em seguida, abra o ficheiro novamente. Se o x vermelho continuar a aparecer, poder ter de eliminar a imagem e inseri-la novamente.
DSB induction in MRC-5 cells. -H2AX foci were
counted 3 min after irradiation
-PFGE
Rothkammand Lobrich, PNAS, 100, 5057-5062 (2003)
CASE STUDIES
1
1,2
1,4
1,6
D
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c

n
t
r
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o
s

(
%
)
Dicntricos em doentes com cancro da tiride
aps tratamento com
131
I (2590 MBq)
Dose (Gy) calculated by dicentric analysis: 200 300 mGy
0
0,2
0,4
0,6
0,8
T0 T1 T6 T24
D
i
c

n
t
r
i
c
o
s

(
%
)
O.Monteiro Gil et al., Mutagenesis, 15, 69-75,2000
Meses aps terapia
Abandoned medical clinic in Goinia contained 1,400 Curie
radioactive cesium 137 source
The radioactive sources were stolen, broken open, and
dispersed
112000 people (10 % of the total population) were monitored
250 were identified as contaminated
20 people were hospitalized or transferred to special housing with
medical and nursing assistance
Four fatalities (2 men, 1 woman and 1 child)
Goinia
Four fatalities (2 men, 1 woman and 1 child)
Radiation induced skin injuries observed in 28 patients
14 patients developed bone marrow depression
8 had classical signs and symptoms of ARS
4 died due to bleeding and infection (sepsis)
Chromosomal aberrations (CAs) in individuals
exposed to
137
Cs in Goinia, Brasil (soon after
exposure)
Dose estimate by analysis of CAs
129 individuals evaluated
5 dose > 3 Gy
16 dose > 1Gy
24 dose > 0.5 Gy
IAEA, 1988
Translocations in individuals exposed to
137
Cs in
Goinia, Brasil (10 years after exposure)
12
14
16
18
20
T
r
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s
l
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a

e
s
/
1
0
0
0

c

l
u
l
a
s
/
1
0
0
0

c
e
l
l
s
0.8 Gy
0.8 Gy
1.5 Gy
0.9 Gy
1.9 Gy
0.8 Gy
1.0 Gy
0.8 Gy
M.L. Camparoto et al. / Mutation Research 530 (2003) 17
0
2
4
6
8
10
I1 I1 I3 I4 I5 I6 I7 I8 I9 I10 C1 C2 C3 C4 C5
T
r
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e
s
/
1
0
0
0

c

l
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a
s
Indivduos estudados
controls
T
r
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s
l
o
c
a
t
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n
s
/
1
0
0
0

Dose (Gy) calculated by dicentric analysis
Dose (Gy) calculated by translocation analysis
<0.3 Gy
0.3 Gy
0.8 Gy
0.8 Gy
0.9 Gy
0.9 Gy
1.5 Gy
1.9 Gy
1.9 Gy
0.2 Gy
0.2 Gy
0.8 Gy
0.5 Gy
0.2 Gy
0.4 Gy
Radiao em Portugal?
Cartografia do Cartografia do rado rado em em
Portugal Portugal
60 % habitaes com < 50 Bq/m
3
2,6 % habitaes com > 400 Bq/m
3
A Unio Europeia (Directiva
90/143/EURATOM) recomenda que para
habitaes j construdas as concentraes
mdias anuais no ultrapassem os 400 Bq/m
3
< 25
25 - 50
50 - 200
Locais com concentraes superiores a 400 Bq/m
3
.
Legenda: Rado (Bq/m
3
)
[mdias anuais por concelho]
mdias anuais no ultrapassem os 400 Bq/m
3
e que para futuras construes os nveis de
rado sejam mantidos abaixo dos 200 Bq/m
3
.
Instituto Tecnolgico e Nuclear Instituto Tecnolgico e Nuclear
Departamento de Proteco Radiolgica Departamento de Proteco Radiolgica
e Segurana Nuclear e Segurana Nuclear