1. Stochastic effects

3. Type of effect Dose - effect relation Somatic effect - induction of cancer –History –Selected types of cancer Hereditary effects

4. Type of effect. High doseLow dose High dose rateLow dose rate Deterministic effectsStochastic effects - cancer - hereditary Acute Late

5. Carcinogenesis

6. 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 Hyperproliferative epithelium Early adenoma Intermediate adenoma Late adenoma carcinoma Normal epithelium 5q Mutation FAP DNA methylation 12p Mutation KRAS 18q Loss DCC? 17p Loss p53

7. History. Exposure to X - rays = skin redness (HED = Haut Erythem Dosis) Development of skin cancer. (© Radiology Centennial Inc.)

8. History - skin cancer

9. History - Lack of protection Memorial to radiation martyrs, Sankt Georg Hospital, Hamburg. (© Radiology Centennial Inc.)

10. History - Radium girls

13. Age and gender dependency (After BEIR V)

14. Radiotherapy patients.

15. Leukemia after Chernobyl

17. Breast Cancer.

18. 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 ExamResulting Risk of Mammogram-Induced Breast Cancer. 30-34 range1 exam: 1 chance in about 1,100. 5 exams: 5 chances/1100, or 1 chance in 220. 35-49 range1 exam: 1 chance in about 1,900. 10 exams: 10 chances/1900, or 1 chance in 190. 50-64 range1 exam: 1 chance in about 2,000. 15 exams: 15 chances/2,000, or 1 chance in 133.

19. Thyroid cancer

20. Thyroid cancer post Chernobyl

21. Thyroid cancer

23. Modelling

24. Low Dose / Low Dose Rate Linear Non-threshold hypothesis Dose and Dose Rate Effectiviness Factor (DDREF) Radiation Hormesis Adaptive Response Bystander Effect Threshold ?

25. Hereditary effects.

26. Genetic defects Multifactorial (4 - 6%) Mendelian (2.4%) - multiple genetic - environment AutosomalautosomalX-linked Dominant recessive(0.15%) (1.5%)(0.75%) Visible at birth - congenital malformations Neurofibromatosis cystic fibrosis hemofilia Polycystic kidney homocysteïnuria fragile X Chromosomal (0.4%) 1 specific gene Developed later in life -diabetes, hypertension, cardiovascular

27. 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 ( ???)

28. RISK - ESTIMATION Studies in mouse Doubling dose = 1 Gy Human data ??? Doubling dose = 1 Gy

29. Multifactorial threshold model

30. = ------------------------------------------- Variance due to genetic effects Total variance (genetic + environment) = 0.3 tot 0.9

31. Mutation Component (MC) = relative change in disease-incidence per relative change in mutationfrequency MC = 1-(1-s) t MC = s(1-s) t-1 S = selection coëfficient, t = generation

32. 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

33. 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

34. DiseaseIncidence per million 1st generation Equilibrium Autosomal dominant * Severe * Moderately severe 2500 7500 5 tot 20 1 tot 15 25 75 X - linked400< 1< 5 Autosomal recessive2500< 10 Chromosomal Translocations trisomias 600 3800 < 5 < 1 … 10 tot 100 Congenital malformations 20000 - 300001010 tot 100 Other (diabetes, cardiovascular,....) 600000… (2 - 12)… Risk for a dose of 10 mSv (ICRP 1990)

35. ICRP (1990). Organdetriment (%/Sv) population detriment (%/Sv) occupational bladder0.290.24 Bone marrow1.040.83 Bone surface0.070.06 breast0.360.29 Large intestine1.030.82 liver0.160.13 lung0.80.64 esophagus0.240.19 ovarium0.150.12 skin0.040.03 stomach10.8 thyroid0.150.12 other0.590.47 gonads1.330.8 TOTAL7.35.6