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Stochastic effects
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Stochastic effects
• Type of effect
• Dose - effect relation
• Somatic effect - induction of cancer– History– Selected types of cancer
• Hereditary effects
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Type of effect.
High dose Low doseHigh dose rate Low dose rate
Deterministic effects Stochastic effects
- cancer - hereditary
Acute Late
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Carcinogenesis
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Carcinogenesis - a multistep process
1954: Armitage and Doll cancer incidence = C*[age]
= 4 - 6
1988: Moolgavkar - Venzon - Knudson model
1990: Vogelstein model for colon cancer
Hyperproliferativeepithelium
Earlyadenoma
Intermediateadenoma
Lateadenoma carcinoma
Normal
epithelium
5qMutationFAP
DNAmethylation
12p
Mutation
KRAS
18qLossDCC?
17pLossp53
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History.
Exposure to X - rays = skin redness (HED = Haut Erythem Dosis)
Development of skin cancer.
(© Radiology Centennial Inc.)
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History - skin cancer
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History - Lack of protection
Memorial to radiation martyrs, Sankt Georg Hospital, Hamburg.
(© Radiology Centennial Inc.)
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History - Radium girls
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History - Radium girls
QuickTime™ and aTIFF (LZW) decompressor
are needed to see this picture.
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1950-54
1954-58
1958-62
1962-66
1966-70
1970-74
1974-78
-10
12
3
4
5
6
7
8
9
Excess risico op kankermortaliteit
LeukemieVaste Tumoren
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Age and gender dependency
(After BEIR V)
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Radiotherapy patients.
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Leukemia after Chernobyl
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Breast Cancer.
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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.
35-49 range 1 exam: 1 chance in about 1,900. 10 exams: 10 chances/1900, or 1 chance in 190.
50-64 range 1 exam: 1 chance in about 2,000. 15 exams: 15 chances/2,000, or 1 chance in 133.
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Thyroid cancer
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Thyroid cancer post Chernobyl
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Thyroid cancer
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Modelling
Dosis (Gy)
Kans o
p e
ffect
Lineair
Kwadratisch
Lineair-kwadratisch
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Low Dose / Low Dose Rate
Linear Non-threshold hypothesis
Dose and Dose Rate Effectiviness Factor (DDREF)
Radiation Hormesis
Adaptive Response
Bystander Effect
Threshold ?
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Hereditary effects.
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Genetic defects
Multifactorial (4 - 6%) Mendelian (2.4%)
- multiple genetic- environment Autosomal autosomal X-linked
Dominant recessive (0.15%)(1.5%) (0.75%)
Visible at birth
- congenital malformations
Neurofibromatosis cystic fibrosis hemofiliaPolycystic kidney homocysteïnuria fragile X
Chromosomal (0.4%)
1 specific geneDeveloped later in life
-diabetes, hypertension, cardiovascular
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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 ( ???)
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RISK - ESTIMATION
Studies in mouse
Doubling dose = 1 Gy
Human data ???
Doubling dose = 1 Gy
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Multifactorial threshold model
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Multifactorial threshold model
= -------------------------------------------Variance due to genetic effects
Total variance (genetic + environment)
= 0.3 tot 0.9
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Mutation Component (MC)
= relative change in disease-incidence per relativechange in mutationfrequency
MC = 1-(1-s)t
MC = s(1-s)t-1
S = selection coëfficient, t = generation
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Potential Recoverability FactorInduced 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
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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
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Disease Incidence per million
1st 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) …
Risk for a dose of 10 mSv (ICRP 1990)
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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