Keynote Lecture: Effects on Tissues and Organs (including hereditary and prenatal effects)

1. Keynote Lecture:Effects on Tissues and Organs(including hereditary and prenatal effects) Wolfgang-U. Müller Institute of Medical Radiation Biology University Hospital Essen Germany

2. Stochastic and deterministic effects

3. The cataract issue

4. Problem: • Until recently, it was thought that radiation-induced cataracts emerge only after exceeding a threshold dose of about 1 to 2 Gy (acute exposure) or 5 to 7 Gy (chronic exposure). • It was overlooked that latency period increases with decreasing dose. • Analyses show now that, if there is a threshold dose at all, then it will be, at least, tenfold lower than previously thought.

5. Animal experiments • Rodents are useful model systems for cataract research. • In rats, 100 mGy are cataractogenic. • Experiments with 25 and 50 mGy are in progress.

6. The cardiovascular issue

7. Cardiovascular Effects • Until recently, one assumed that cardiovascular damage occurs after high radiation doses only. • The most recent data from Hiroshima and Nagasaki show that effects on the cardiovascular system can be observed, at least, down to 0.5 Gy.

8. A possible mechanism for radiation induced cardiovascular problems Radiation may damage the lining of small vessels in the heart muscle leading to a low oxygen level locally, and, after many years, to slowly progressive fibrosis of the heart muscle.

9. method 1: method 2: Bystander effect X X medium-transfer X X X X X X X

10. A warning: Never look at one mechanism only! Some examples of important mechanisms: Adaptive response Apoptosis Bystander effect Genetic predisposition Genomic instability Immune defence Number of mutations required Repair Repair systems inactive?

11. Effects attributable to prenatal exposure: Teratogenesis and mental retardation

12. Pregnancy risks

13. Gastroschisis

14. The threshold question

15. Pregnancy risks

16. Exencephaly

17. Problem: Threshold dose?! • For humans there are too few data to answer the threshold dose question. • Many animal experiments were done with too few animals to obtain a meaningful answer. • The bigger studies point to threshold doses in the range of 50 to 250 mGy. • There are indications that sensitive sub-populations exist in the total population (small, plateau-like effects before the threshold dose is reached).

18. Threshold doses (ICRP 90) Organogenesis (malformations): 100-200 mGy

19. Pregnancy risks

20. Severe mental retardation; SMR [Source: ICRP 90 (2003) 105]

21. Threshold doses (ICRP 90) Fetogenesis (mental retardation): 8.-15. week 300 mSv(= lower 95% confidence limit of the point estimate of 600 mSv) 16.-25. week 300 mSv(= lower 95% confidence limit of the point estimate of 900 mSv)

22. IQ-Reduction • Not definitely clear whether a threshold dose exists or not. • IQ-reduction (without cases of severe mental retardation): 8.-15. Woche: 21 IQ-points/Gy 16.-25. Woche: 13 IQ-points/Gy

23. Hereditary risk

24. Problem: • For humans, we only have some data for the first and, partly, for the second generation after radiation exposure. • These data suggest a very low, if at all, hereditary risk. • We do not have any human data for the third and following generations.

25. Tissue weighting factor for gonads in the course of time ICRP 26 (1977): 0.25 ICRP 60 (1991): 0.20 ICRP 103 (2008): 0.08

26. The End