Stochastic effects
M. van Eijkeren
Dpt. Of Radiation Oncology
Ghent University Hospital
Stochastic effects
• Type of effect
• Dose - effect relation
• Somatic effect - induction of cancer
– History
– Selected types of cancer
• Hereditary effects
Type of effect.
High dose
High dose rate
Low dose
Low dose rate
Deterministic effects
Stochastic effects
- cancer
- hereditary
Acute
Late
Carcinogenesis
Carcinogenesis a multistep process
1954: Armitage and Doll cancer incidence = C*[age]β
β=4-6
1988: Moolgavkar - Venzon - Knudson model
1990: Vogelstein model for colon cancer
12p
5q
Mutation
FAP
Normal
epithelium
Hyperproliferative
epithelium
DNA
methylation
Early
adenoma
Mutation
KRAS
Intermediate
adenoma
18q
Loss
DCC?
17p
Loss
p53
Late
adenoma
carcinoma
History.
Exposure to X - rays = skin redness
(HED = Haut Erythem Dosis)
Development of skin cancer.
(© Radiology Centennial Inc.)
History - skin cancer
History - Lack of protection
Memorial to radiation martyrs, Sankt Georg
Hospital, Hamburg.
(© Radiology Centennial Inc.)
History - Radium girls
History - Radium girls
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Excess risico op kankermortaliteit
9
8
7
6
5
4
3
2
1
0
-1
Leukemie
Vaste Tumoren
8
-7
74
19
4
-7
70
19
0
-7
66
19
6
-6
62
19
2
-6
58
19
8
-5
54
19
4
-5
50
19
Age and gender dependency
(After BEIR V)
Radiotherapy patients.
Leukemia after Chernobyl
Breast Cancer.
Mammography.
Basis:
Exam is done at an accredited mammography facility.
Mean glandular x-ray dose per view = 0.1 rad (0.1 centi-gray, cGy).
There are two views of each breast per exam.
Combined mean glandular dose to each breast = 0.2 rad (0.2 cGy).
Unrepaired damage to genes from xrays accumulates. Therefore, the risk
from multiple mammograms is the sum of the risk from each individual
exam.
Risks below refer to incidence of cancer; risk of mortality is 4x lower.
Age at Exam
Resulting Risk of Mammogram-Induced Breast Cancer.
30-34 range
1 exam: 1 chance in about 1,100.
5 exams: 5 chances/1100, or 1 chance in 220.
1 exam: 1 chance in about 1,900.
10 exams: 10 chances/1900, or 1 chance in 190.
1 exam: 1 chance in about 2,000.
15 exams: 15 chances/2,000, or 1 chance in 133.
35-49 range
50-64 range
Thyroid cancer
Thyroid cancer post
Chernobyl
Thyroid cancer
Modelling
Lineair
Kwadratisch
Lineair-kwadratisch
Dosis (Gy)
Low Dose / Low Dose Rate
Linear Non-threshold hypothesis
Dose and Dose Rate Effectiviness Factor (DDREF)
Radiation Hormesis
Adaptive Response
Bystander Effect
Threshold ?
Hereditary effects.
Genetic defects
Chromosomal (0.4%)
Mendelian (2.4%)
Multifactorial (4 - 6%)
- multiple genetic
- environment
Visible at birth
Autosomal
Dominant
(1.5%)
Neurofibromatosis
Polycystic kidney
autosomal
recessive
(0.75%)
cystic fibrosis
homocysteïnuria
- congenital malformations
Developed later in life
-diabetes, hypertension,
cardiovascular
1 specific gene
X-linked
(0.15%)
hemofilia
fragile X
Effects after Chernobyl
• Down - syndroom
– Dec 86: Bavaria - 4 cases but in very low
dose area.
– Jan 87: West - Berlin: 12 cases when 3
expected
– European studie (jan - maart 87): no
difference
• Minisatellite mutations
– If exposed: x 2 ( ???)
RISK - ESTIMATION
Studies in mouse
Doubling dose = 1 Gy
Human data ???
Doubling dose = 1 Gy
Multifactorial threshold model
Multifactorial threshold model
Variance due to genetic effects
= ------------------------------------------Total variance (genetic + environment)
= 0.3 tot 0.9
Mutation Component (MC)
MC = 1-(1-s)t
MC = s(1-s)t-1
= relative change in disease-incidence per relative
change in mutationfrequency
S = selection coëfficient, t = generation
Potential Recoverability Factor
Induced mutations have to be compatible with life and
are to some extent recoverable in offspring
PRCF
= 0.15 - 0.3 for autosomal dominant & X-linked
= 0.02 - 0.09 for chronic multifactorial
Risk per dose unit =
= P x (1/DD) x MC x PRCF
Chronic exposure
650000 10-6 x 1 x 0.02 x (0.02 - 0.09) = 250 - 1200 10-6
Risk for a dose of 10 mSv (ICRP 1990)
Disease
Incidence per 1st
million
generation
Equilibrium
Autosomal dominant
* Severe
* Moderately severe
2500
7500
5 tot 20
1 tot 15
25
75
X - linked
400
<1
<5
Autosomal recessive
2500
<1
0
Chromosomal
•Translocations
• trisomias
600
3800
<5
<1
…
10 tot 100
Congenital
malformations
20000 - 30000
10
10 tot 100
Other (diabetes,
cardiovascular, ....)
600000
… (2 - 12)
…
ICRP (1990) .
Organ
detriment (%/Sv)
population
detriment (%/Sv)
occupational
bladder
0.29
0.24
Bone marrow
1.04
0.83
Bone surface
0.07
0.06
breast
0.36
0.29
Large intestine
1.03
0.82
liver
0.16
0.13
lung
0.8
0.64
esophagus
0.24
0.19
ovarium
0.15
0.12
skin
0.04
0.03
stomach
1
0.8
thyroid
0.15
0.12
other
0.59
0.47
gonads
1.33
0.8
TOTAL
7.3
5.6