Increased radiation sensitivity in newborns and children under 5 years of age compared to adults after in vitro CT exposure

Transcription

1 Increased radiation sensitivity in newborns and children under 5 years of age compared to adults after in vitro CT exposure

2 Background High number of CT-examinations (11,3 Mill/Jahr 2011) ca. 1% in children in Germany Relatively high organ doses compared to conventional Xray diagnostic (in few cases 500times increased) 60% Head CT: doses between 2-15 mgy 40% of children CT in the age group from 0-5 Jahren Presumably most sensitive age window

3

4 Age dependent radiation sensitivity Epidemiological evidence The U.S. Environmental Protection Agency (EPA) recommends (U.S. EPA, 2003a) 10-times risk adjustment for the first 2 years of age, 3-times adjustment in the age groupe from 3-15 years (Chemical noxes and radiation) Epidemiological studies (BEIRVII): 2-10times increased tumor risk after age of exposure < 5 Contradictory results for low doses: Recently 3 CT studies confirmed a small but definite cancer risk induced by CT scans early in life (UK, Australia, Taiwan)

5

6 Experimental in vivo studies In vivo studies: internal exposure after Chernobyl fall out Chromosome aberrations after in vivo CT examinations Problem: dosimetry to the blood

7 What are the reasons for an increased sensitivity in children? Scanners are not well adapted to the body proportions Tissues with higher cell division rate Increased numbers of stem cells in tissues Longer life time expectancy Unclear: Intrinsic cellular radionsensitivity?

8 In vitro pilot-ct Studie: Radiosensitivity in different age groups (Ethik-Kommission der Bayerischen Ärztekammer) according to 18 of the Professional Code of Conduct for Doctors in Bavaria (Berufsordnung für die Ärzte Bayerns) In vitro CT-study on repair of radiation-induced DNA-damage as a function of age and sex. Ethik-Kommsion Nr

9 Umbilical cord blood Children (0-5 years) Adults (> 20 years) In vitro CT irradiation Study Design GammaH2AX Dicentrics

10 Characterization of the study groups Adults N=17 Umbilical Cord N=15 Children N=15 Ethnicity Caucasians Caucasians Caucasians, 1 African Response Rate 100% 20%-90% (depending on the hospital) 80% Smoking Non-smokers: 14 Smokers: 3 Non-smoking parents: 13 Smoking parents: 1 Not reported: 1 Non-smoking parents: 5 Smoking parents: 9 Not reported: 1 Regular medication Histaminblocker (1), Thyronajod (1), Domperidon (1), ASS Atid (1), Pantoprazol (1), Simvabeta - No Diseases Allergy: 6 Hyperthyreosis: 1 - Circumcission (11) Inguinal hernia (2) Hydrocele (2) Dicentric Assay N=12 N=11 N=10 GammaH2AX N=12 N=11 N=13 Both Assays N=12 N=11 N=8

11 Irradiation Conditions 0 mgy (sham exposure), 41 mgy (± 0.5 mgy) and 978 mgy dose (± 16 mgy) Controlled by LiF Thermoluminecence Voltage: 120 kvp, Current: 400 ma (high dose) and 50 ma (low dose) Dynamic Scan within 15 sec. or 3 x 15sec Homogeneous dose distribution Spiral-CT-Scanner Toshiba Aquilion/LB Modell TSX-201A/1K

12 Characteristics of the applied biomarker Highly radiation specific (Dicentrics) Highly sensitive for low dose exposure (GammaH2AX) Low intra individual variation (Dicentrics, GammaH2AX?) Low inter indivdual variation (Dicentrics, GammaH2AX?) In vivo exposure is comparable to in vitro exposure (Dizentrics)

13 Principle of the GammaH2AX-Test 2. antibody Y 1. antibody Y P Cell nucleus

14 Frequencyt in % Microscopical Analysis Number of GammaH2AX-Foci in correlation to dose and time 0 Gy < Number of gammah2ax-foci 0.5 Gy 0Gy 8Gy 15min 8Gy 4h 8Gy 24h 3 Gy

15 Sensitivity of automatic and manual scoring foci 5,00 4,50 4,00 Integer 3,50 3,00 2,50 manual No 2,00 1,50 1,00 0,50 Vandervoorde et al. accepted 0,00 0,000 0,010 0,020 0,030 0,040 0,050 0,060 0,070 0,080 0,090 0,100 dose in [Gy]

16 0 Gy Gy Gy 0 Gy Gy Gy

17 Initial radiation damage (30 min) in different age groups 0 Gy 0.04 Gy 1.0 Gy

18 Damage after 24 h repair in different age groups 0 Gy 0.04 Gy 1.0 Gy 0.04 Gy 1.0 Gy

19 Principle of Dicentric Analyses Karyotype

20 Cells analysed (BfS and STUK) at dose... Adults (A) Children (C) Cord Blood (N) BfS STUK BfS STUK BfS STUK 0 mgy 3/1201 2/1200 3/1002 0/1000 1/1100 0/ mgy 7/1205 4/1139 3/1002 2/1000 3/1101 3/ mgy 144/ / / / / /1100

21 dic/100 cells Increased numbers of dicentrics in children and cord blood 25 adult (n = 12) 20 umbilical cord blood (n = 11) children (n = 10) ,7 0,6 0,5 0,4 0,3 0,2 0, dose [Gy]

22

23 Relative Risk for children Anzahl Dizentrischer/Zelle Anzahl ungeschädigter Zellen Kinder a c Erwachsene b d

24 What can we learn for the low dose exposure?

25 110,000 cells

26 Summary Increased cellular radiation sensitivity in male children from 0-5 years of age For Umbilical Cord Blood also confirmed by Bakhmutsky 2014

27

28 Bahmutsky et al.; Rad Res 2014

29 Summary Increased cellular radiation sensitivity in male children from 0-5 years of age For Umbilical Cord Blood also confirmed by Bakhmutsky 2014 Dicentric assay is the biomarker of choice! GammaH2AX highly sensitive but not for age related radiation sensitivity

30 Future Research What is going on in the low dose range? Are there sex differences? Definition of the exact age window?

31 Thanks to the partners Nabelschnurblut TUM (Frauenklinik) Dr. med. Markus Niemeyer LMU (Klinik und Poliklinik- Großhadern) PD Dr. med Uwe Hasbargen Blut von gesunden Kindern Dr. med Hans-Joachim Kirlum Kinderchirurgie in derau CT-Bestrahlung LMU (Klinik und Poliklinik für Strahlentherapie Großhadern) Prof. Belka Peter Lang, Klement Neumaier Statistik BfS (AG-SG1.3) Dr. Linda Walsh Universitätsmedizin Göttingen Mag. Albert Rosenberger

32 Thanks to BfS Blood Donors

33 BfS Blutspender Kinderchirurgie in der Au

34