increased radiation sensitivity in newborns and children under 5 …€¦ · increased radiation...

Biomarker OPERRA Workshop 2015, Gomolka

Increased radiation sensitivity in newborns

and children under 5 years of age compared to adults

after in vitro CT exposure


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


• 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)

Age dependent radiation sensitivity – Epidemiological evidence


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


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?


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. 11083


Study Design

Umbilical cord blood

Children (0-5 years)

Adults (> 20 years)

In vitro CT irradiation

GammaH2AX Dicentrics


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

Characterization of the study groups


Irradiation Conditions

Spiral-CT-Scanner Toshiba Aquilion/LB Modell TSX-201A/1K

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


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)


Cell nucleus

P Y

1. antibody

2. antibody Y

Principle of the GammaH2AX-Test


0 Gy

0.5 Gy

3 Gy

0

20

40

60

80

100

Fre

qu

en

cyt

in %

0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 40<

Number of gammaH2AX-foci

0Gy 8Gy 15min 8Gy 4h 8Gy 24h

Microscopical Analysis Number of GammaH2AX-Foci in correlation to dose and time


Vandervoorde et al. accepted

Sensitivity of automatic and manual scoring

0,00

0,50

1,00

1,50

2,00

2,50

3,00

3,50

4,00

4,50

5,00

0,000 0,010 0,020 0,030 0,040 0,050 0,060 0,070 0,080 0,090 0,100

foci

dose in [Gy]

No

Integer

manual


0 Gy 0.041 Gy 0.978 Gy

0 Gy 0.041 Gy 0.978 Gy


0 Gy 0.04 Gy 1.0 Gy

Initial radiation damage (30 min) in different age groups


Damage after 24 h repair in different age groups

0 Gy 0.04 Gy 1.0 Gy 0.04 Gy 1.0 Gy


Principle of Dicentric Analyses

Karyotype


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 0/1100

41 mGy 7/1205 4/1139 3/1002 2/1000 3/1101 3/1100

978 mGy 144/1200 150/1200 193/1000 177/1000 232/1100 188/1100

Cells analysed (BfS and STUK)


Increased numbers of dicentrics in children and cord blood

0

5

10

15

20

25

0 0.04 1dose [Gy]

dic

/100 c

ell

s adult (n = 12)

umbilical cord blood (n = 11)

children (n = 10)

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0 0.04


Kinder Erwachsene

Anzahl Dizentrischer/Zelle

a b

Anzahl ungeschädigter Zellen

c d

Relative Risk for children


What can we learn for the low dose exposure?


110,000 cells


Summary

Increased cellular radiation sensitivity in male children from 0-5 years of age

For Umbilical Cord Blood also confirmed by Bakhmutsky 2014


Bahmutsky et al.; Rad Res 2014


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


Future Research

What is going on in the low dose range?

Are there sex differences?

Definition of the exact age window?


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


Thanks to

BfS Blood Donors


Kinderchirurgie in der Au

BfS Blutspender

increased radiation sensitivity in newborns and children under 5 …€¦ · increased radiation...

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