Transcript IX-(7)--Dose eff curves-Determ+Stoch effects

DOSE-EFFECT CURVES;
DETERMINISTIC AND STOCHASTIC
EFFECTS OF RADIATION
Module IX
Biological effects of radiation
in time perspective
Time scale
Effects
Fractions of seconds
Energy absorption
Seconds
Changes in biomolecules
(DNA, membranes)
Biological repair
Change of information in cell
Minutes
Hours
Days
Weeks
Months
Cell death
Mutations in a
Germ cell Somatic cell
Organ
death
Clinical
changes
Leukaemia
or
Cancer
Years
Decades
Module Medical IX.
Generations
Hereditary
effects
2
Radiation effects
Early
(deterministic only)
Local
Radiation injury of
individual organs:
functional and/or
morphological
changes within
hrs-days-weeks
Module Medical IX.
Common
Acute radiation disease
Acute radiation syndrome
(LD50/60 ~ 3.5Sv
LD ~ 5 Sv)
Late
Deterministic
(Above DQ, cummul.)
- Rad. Dermatitis
- Rad. Cataracta
- Teratogenic
(DQ,F~0,1Sv)
Stochastic
(Probability
increases
with dose)
- tumours,
leukaemia
- genetic effects
3
Deterministic (a) and stochastic (b) effects of
radiation
Det
Module Medical IX.
4
Sources of data on human effects of
radiation overexposure
Number x103
1
110
2
Occupational exposure
1.1 Early radiologist and medical physicists
1.2 Ra-dial painters
1.3 U-miners, nuclear industry workers
Medical overexposure
3
A-bomb victims
86.5
Overexposure due to nuclear weapons test
4.1. Inhabitants of Marshall Islands
4.2 Personnel of nuclear weapon tests (NWT)
4.3 Inhabitants living around NWT sites
5 Accidents – a) deterministic effects
5.1 Radiation accidents
5.2 Nuclear accidents (Chernobyl)
-stochastic effects
Registered thyroid cc.
6
Inhabitants of high natural background areas
Total number of registered overexposures
10
4
96
95
4
0.25
~ 100*
~ 500*
3
2.8
0.2
3
~600*
(~30M*)
(~60M*)
300
Note: *Effects of radiation exposure are not proved in these population groups, but
studied recently (M - million)
Module Medical IX.
5
Typical dose-effect relationships for
deterministic effects in population
Module Medical IX.
6
Threshold doses for some deterministic effects
in the most radiosensitive tissues
Tissue and
effects
Total dose
single brief
exposure (Gy)
Bone marrow
Depression of
haematopoesis
Annual dose rate received
in highly fractionated or
protracted exposure
for many years (Gy/y)
0.5
> 0.4
Temporary sterility
0.3
0.4
Permanent sterility
3.5-6.0
2.0
Testes
Module Medical IX.
7
Threshold doses for some
deterministic effects
Tissue and
effects
Total dose
received in
single brief
exposure
(Gy)
Annual dose rate
received yearly in
highly fractionated or
protracted exposure
for many years (Gy/y)
Ovaries
Sterility
2.5-6.0
> 0.2
Lens
Detectable opacities
2.0
> 0.1
Visual impairment
5.0
> 0.4
(cataract)
Module Medical IX.
8
Time of onset of clinical signs
of skin injury depending on
dose received
Symptoms







Dose range
(Gy)
Erythema
Epilation
Dry desquamation
Moist desquamation
Blister formation
Ulceration
Necrosis
3-10
>3
8-12
15-20
15-25
>20
>25
Time of onset
(day)
14-21
14-18
25-30
20-28
15-25
14-21
>21
Ref.: IAEA-WHO: Diagnosis and Treatment of Radiation Injuries.
IAEA Safety Reports Series, No. 2, Vienna, 1998
Module Medical IX.
9
Acute radiation syndrome
(ARS)

ARS is the most notable deterministic effect of ionizing radiation

Signs and symptoms are not specific for radiation injury but
collectively highly characteristic of ARS

Combination of symptoms appears in phases during hours to
weeks after exposure
- prodromal phase
- latent phase
- manifest illness
- recovery (or death)

Extent and severity of symptoms determined by
- total radiation dose received
- how rapidly dose delivered (dose rate)
- how dose distributed in body (whole vs partial body irradiation)
Module Medical IX.
10
Principle syndromes contributing to
death after acute whole body radiation
exposure
Whole body dose,
Gy
Syndrome
Time of death after the
exposure - days
3-10
bone marrow
30-60
10-30
gastrointestinal tract
10-20
>30
Module Medical IX.
neurovascular system
1-5
11
Special
deterministic effects
Teratogenic effects of radiation
Module Medical IX.
12
Frequency of severe mental retardation
in prenatally exposed survivors of
A-bombing in Hiroshima and Nagasaki
%
Sv
Module Medical IX.
13
Microcephaly:
Hiroshima data
45
40
35
%
30
25
20
15
10
5
0
0
10-90
100-190
200-290
300-490 500-1490
>1500
Foetal dose, mSv
Module Medical IX.
14
Stochastic effects
Cancer induction and genetic effects
Module Medical IX.
15
Phases of cancer induction
and manifestation
Norma l Ce lls
Initia tion
Muta te d Ce lls
Elimia tion Re pa ra tion
Pre -c a nc e r
Promotion
Minima l Ca nc e r
Clinic a l Ca nc e r
Progre ssion
Spre a ding
Module Medical IX.
16
Stochastic Effects of
Radiation Exposure

Frequency proportional to dose

No threshold dose

No method for identification of
appearance of effect of ionizing radiation
in individuals

Increase in occurrence of stochastic
effects provable only by epidemiological
method
Module Medical IX.
17
Stochastic effects of
radiation exposure
(continued)

Stochastic effects observed in animal
experiments

Dose-effect relationship for humans can be
studied only in human population groups

Dose-effect relationship in low dose range
(below 100 mSv) not yet verified

Extrapolation down to zero excess dose
accepted only for radiation protection and
safety
Module Medical IX.
18
Human data on
radiation cancerogenesis
Type or localization of cancer
Population
groups
A-bomb
survivors
Leukemia Thyroid
gland
+
+
Lung
Breast
+
+
Exposed in a
nuclear
accident
Module Medical IX.
Skin
+
Ra-dial painters
Early
radiologists
U-miners
Bone
+
+
+
+
19
Latency periods for
radiation-induced cancer
Module Medical IX.
20
Risk of leukaemia depending on
age at exposure to A-bomb
Module Medical IX.
21
Age dependency of incidence of leukaemia in
British population and radiotherapy patients
Leukaemia
per million/yr
10000
1000
100
10
1
10
20
30
40
50
60
70
AGE, years
General Population
Module Medical IX.
Radiotherapy patients
22
Cancer deaths attributable
to A-bomb
In 86 572 survivors of Hiroshima and Nagasaki, 7827
persons died of cancer in 1950-90
Observed
All tumours
7578
Leukaemia
249
All cancers
7827
Expected
7244
162
7406
Excess
(%)
334
(4.4)
87
(35.0)
421
(5.4)
Ref: Pierce et al, Rad.Res. 146: 1-27, 1996
Module Medical IX.
23
LEUKAEMIA CASES
per 100,000 person
per year
DOSE DEPENDENCE OF LEUKAEMIA IN
A-BOMB SURVIVORS
140
120
100
80
60
40
Hiroshima
20
0
Nagasaki
0
0.01-0.49
1.0-1.9
>4.0
ABSORBED DOSE, Gy
Module Medical IX.
24
Cancer mortality of
nuclear industry workers
Observed/Expected deaths
Dose ranges, mSv
<10
10-
20-
50-
100-
200-
400-
Total
Trend
number
test
of deaths
(p-value)
O/E number of deaths from cancers other than leukemia
2234/
462/
445/
276/
196/
161/
56/
2228.3
465.4
479.6
254.3
190.5
147.6
67.3
3830
-0.28
(0.609)
O/E number of deaths from leukemia other than CLL (chronic lymphocytic leukemia)
60/
19/
14/
8/
8/
4/
6/
62.0
17.2
17.2
9.0
6.4
4.7
2.3
119
1.85
(0.046)
The ERR (excess relative risk) per Sv among the 95,673 nuclear industry workers of Canada, UK and USA (having a mean cumulative
dose of 36.6 mSv in the combined cohort for the total period of observation, ie. 34 yrs in the USA and UK, and 29 years in Canada ) is
–0.07 for all cancers excluding leukemia, and 2.18 for leukemia excluding CLL.
Ref.: Cardis, E. et al: Combined Analyses of Cancer Mortality Among Nuclear Industry Workers in Canada, the UK and the USA. IARC
Technical Report No.25, Lyon, 1995
Module Medical IX.
25
Childhood leukaemia around
UK nuclear facilities





STUDY GROUP: 46 000 children (followed till the age of 25
yrs) born to parents working in nuclear industry
FINDINGS: 111 cases of acute leukaemia observed, i.e. fewer
than expected in a group of this size and age
Study found 3 cases of leukaemia in children of male workers
who had received a pre-conceptional exposure of 100 mSv or
more
Two of these three cases had already been identified in the 1990
Gardner report (proposed theory that paternal pre-conception
radiation leads to increased risk of leukaemia in offspring)
Conclusions
 No substantial evidence found to support Gardner’s theory
 Study did not confirm theory
Ref. ICRF, LSHTM & LRF: Nuclear Industry Family Study (NIFS). BMJ, 28-05-1999
Module Medical IX.
26
Lifetime mortality in population of
all ages from cancer
after exposure to low doses
Organ or tissue
Bladder
Bone Marrow
Bone Surface
Breast
Colon
Liver
Oesophagus
Ovary
Skin
Stomach
Thyroid
Remainder1
Total
Module Medical IX.
Fatal Cancer
Probability
Coefficient
-4
-1
(10 Sv )
30
50
5
20
85
15
30
10
2
110
8
50
500*
* For general public (all age
groups) only
Summary factor of cancer risk
for working population taken
to be 400x10-4 Sv-1
Reference ICRP, Publ. 60,
1991
27
Nominal probability coefficients
for stochastic radiation effects
Detriment (10- 2 Sv-1)
Exposed
population
Fatal
cancer
Non-fatal
cancer
Severe
hereditary
effects
Total
Adult workers
only
4.0
0.8
0.8
5.6
Whole population
(all age groups)
5.0
1.0
1.3
7.3
1
2
Rounded values
For fatal cancer, detriment coefficient is equal to
probability coefficient
Ref. ICRP, Publ. 60, 1991
Module Medical IX.
28
Genetic radiation damage

Increase of chromosome aberrations in human
spermatogonia following radiation exposure of
testes has been detected

inheritance of radiation damage in human
population (including A-bomb survivors) not yet
detected
Module Medical IX.
29
Review of topics discussed












Biological effects of radiation in time perspective
Main characteristics of deterministic and stochastic effects
Sources of data on human effects of radiation overexposure
Threshold doses of deterministic effects in the most radiosensitive
tissues
Teratogenic effects of radiation: severe mental retardation,
microcephaly
Phases of cancer induction
Sources of human data on radiation cancerogenesis (3 groups)
Latency periods of radiation induced cancers (lag 2 & 10 yrs)
Risk of cancer depending on age at exposure (reverse dependence)
Cancer deaths attributable to A-bombs – 5.4% in 40-yr follow up
Cancer mortality studies of nuclear industry workers and offspring –
leukaemia probable in workers
Genetic effects of radiation – not proved in human population
Module Medical IX.
30