Stochastic effects

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 Low doseHigh dose rate Low dose rate

Deterministic effects Stochastic effects

- cancer - hereditary

Acute Late

Carcinogenesis

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

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 aTIFF (LZW) decompressor

are needed to see this picture.

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

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.

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.

Thyroid cancer

Thyroid cancer post Chernobyl

Thyroid cancer

Modelling

Dosis (Gy)

Kans o

p e

ffect

Lineair

Kwadratisch

Lineair-kwadratisch

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

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

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)

= 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

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

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

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)

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