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Long-term risks from medical ionizing radiation:
cancer and cardiovascular disease
Maria Grazia Andreassi,Unità Ricerca Genetica,
IFC-CNR, Fondazione Toscana Gabriele Monasterio, Ospedale G. Pasquinucci, Massa
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Sustainability of Medical Imaging: The Radiation Issue
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Diagnostic exposure to radiation is a public health issue
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Modified and updated (Regulla D 2005, and Mettler FA 2007)
Picano E. BMJ, March 6 2004
“Medical exposures now dwarfs that of all other sources” June 19th, 2007
~ 600% increasefrom 1980 to 2006
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Millions
of
proc
edur
es
Coronary Angiography
PCI Stent coronarico
‘92 93 94 95 96 97 98 99 00 01
Interventional procedurescontribute to about 20% of the total collective dose
per head per yearPicano et al. Int J Cardiovasc Imaging 2006
The use of procedures continues to grow steadily,
including pediatric cardiologyPatel and Hijazi Pediatric catheter interventions:
a year in review 2004-2005. Curr Opin Pediatr. 2005
Coronary procedure in Europe
Togni M et al. Eur Heart J 2004
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ICRP report 85 (2001): Avoidance of Radiation Injuries from Interventional Procedures
Ulcer 21 months afterfirst procedure,base of ulcer
exposes spinous process
Cataract in eye of interventionalistafter improper working
conditions related to high levels ofscattered radiation.
Interventional procedures may give rise to deterministic effects
FDA 1994: Public Health Advisory. Induced skin injuries in patient during fluoroscopically guided procedures
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Doses in interventional procedures
Not knownNot knownNot knownSkin cancer
50>1 year10Telangiectasia
90>6 weeks18Ulcer
704 weeks14Dry desquamation
353 weeks 7Permanent epilation
10Hour 2 Transient erythema
Minutes fluoro at 0.2 Gy/min
Approx. onset
Threshold dose (Gy)Effect
(Modified from Rehani, 2002; Hirschfeld, 2005; and Einstein, 2007)
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Biological effects of radiation
Cancer, genetic effectsErythema, ulcersClinical effects
DNA damageCell DeathCell Biology
NoYesThreshold dose
LongShortOccurrence time
LowMedium-HighDose
Stochastic effects Deterministic effects
Ris
k
Dose
Threshold dose
Dose
Ris
k
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Stochastic effects:DNA is the most important target of IRDNA is the most important target of IR
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Att
ribu
tabl
e c
ance
r ri
sk
(%)
1981 1991 19960.5
1.5
3.0
5.0
10.0
2006
Source: Doll R and Peto R,
1981
Berrington de Gonzales and Darby,
LANCET, 2004
From medical radiation dose to cancer risk
?
Picano E, Lancet, letter 2005
Update radio
Add nuclear
Accept BEIR VII
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The BEIR series are widely accepted as
primary source of radiation risk estimates and
protective regulations
BEIR VII report : the most up-to-date, comprehensive estimates for risk for cancer from
low-dose radiation
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50 500 1000
1 on 10,000
1 on 1,000
1 on 500
Risk of cancer (fatal and non-fatal) for exposure to one 15 mSv MSCT Elderly: 1 in 1,500Adult man: 1 in 750Adult woman: 1 in 500Male child (<1 year): 1 in 200Female child (<1 year): 1 in 100
Addi
tiona
l ris
k of
can
cer/e
xam
MRI, US
Equivalent number of chest x-rays
750
Elderly
Adul
t wo
man
Adult
man
Mal
e ch
ild <
1 ye
ar
Fem
ale
child
<1
year
250
Picano E, BMJ 9 October 2004, updated with BEIR VII, 2006
(Einstein A, et al. JAMA 2007)
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Risk increases with decreasing age
Brenner and Hall. Computed tomography--an increasing source of radiation exposure. N Engl J Med. 2007
Children exposed toionizing radiation have a (3-4 times) greater cancer risk than adults, as they have more rapidly dividing cells
and have longer life expectancy.
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BEIR VII: Research Need
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Cumulative patient effective dose in children with congenital heart disease
Ait-Ali et al. ESC Congress 2008, Munich
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Methods: Lifetime radiological estimated dose
Dose Reference values in pediatric cardiology
From Bacher et al. Patient-specific dose and radiation risk estimation in pediatric cardiac catheterization. Circulation 2005 Martinez LC, Vano E, et al. Patient doses from fluoroscopically guided cardiac procedures in pediatrics. Phys. Med. Biol. 2007, Brody et al. American Academy of Pediatrics Section on Radiology. Radiation risk to children from computed tomography. Pediatrics. 2007.
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Radiological exposure
Total examinations :1548 Mean examinations :26.2 ±26.3 per patient
1%2.5%3.5%
93%
41%
43%
11%
5%
X-rays
Diagnostic cathInterventional cath
Computed Tomography
Frequency of examinations Total collective dose
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Cumulative Effective Dose and Lifetime Attributable Risk of Cancer
02468
101214161820
0 5 10 15 20
% mortality excess
Age of exposure
Mortality excess per Sv all cancers (BEIR VII)
Males
Females
Effective dose,mSvmedian (25th-75th)
7.1 (5.1-12.5)
9.4 (6.5-18.1)
(LAR <1 year)
1 in 156 (1in 239-1in 83)
1 in 282 (1in 431-1in 117)
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R. Padovani – SENTINEL Project: Interventional Radiology and Cardiology Course, Budapest, 5 6 July 2006
Eg. Exposure from 300 procedures/year
Effective dose 9-44 mSv/year (lead protective apron)
4- 20 mSv/year
(protective apron+thyroid shield)
Exposure for cath lab workers
Nuclear Physicians
InterventionalCardiologists
0
50
100
150
Orthopedists Radiologists
Ches
t x-
rays
per
hea
d/pe
r ye
ar
(1 mSv)
(2 mSV)
(3 mSv)
200
250
300
(4mSv)
(5 mSv)
(6 mSv)
Vano E et al. Br J Radiol. 1998; 71:954-60
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0%
20%
40%
60%
80%
100%
Nothreshold
>1 >2 >3 >6
OthersNuclear MedicineAnesthesiologyOrthopedicsRadiologyUrologyCardiac cath lab
(mSv)Yearly exposure
(360) (60) (37) (6)(5,164)
Dose exposure in all medical staff censored in Tuscany (Florence-Pisa) Health Physics data bank year 2006
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Cancer risk from professional exposure in staff working in cardiac catheterization laboratory
Median LAR= 1 in 192 (range= 1 in 137-1in 370)
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42 spontaneous
cancers
+ 1, Radiation induced
100 mSv for 100 patients
BEIR VII, 2006
Range of uncertainty
(1 in 100)
(
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• An epidemiological study of 5
million people is required to
quantify directly the risk of
cancer from exposure of 10
mSv (500 chest X-rays) or
less.
Uncertainties from epidemiology estimates
Brenner DJ et al. Cancer risks attributable to low doses Brenner DJ et al. Cancer risks attributable to low doses of ionizing radiation:assessing what we really know of ionizing radiation:assessing what we really know
PNAS, 2003PNAS, 2003
BEIR VII, 2006
Range of uncertainty
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Research priorities
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Biodosimetry shrinks uncertainty
• 15% increase in adult patients after invasive cardiovascular interventions (Andreassi MG et al. Eur Heart J, 2007)
2
• 200% long-term increase in children with congenital heart disease (Andreassi MG et al. Eur Heart J 2006)
H
• 50% increase in interventional cardiologists (Andreassi MG et al, FASEB J, 2005)
2
Long-term predictor of cancer
Intermediate end-point for
carcinogenesis
Hagmar L et al. Cancer Res 1998Bonassi et al. C arcinogenesis 2006
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Chromosomal damage, radiation exposure and congenital heart disease
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Congenital Heart Disease, Cardiac Catheterization and Congenital Heart Disease, Cardiac Catheterization and
Chromosome Aberrations
200% long-term
increase in children
with CHD
Chromatid break
Mean cumulative estimated dose:19.4± 1.6 mSv (1000 Xrays ) per patient
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15 % increase in adult
patients after invasive
cardiovascular interventions
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50% increase in chromosomal DNA damage in interventional cardiologists
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DNA repair genes and cancer
Web registry on DNA repair polymorphisms and cancer risk: www.perseus.isi.it/huge
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XRCC3 gene polymorphism influence chromosomal DNA damage in Interventional Cardiologists
Accurate repair of DNA DSBs is critical in preserving the genomic
integrity of cells
Double-strand Break
Lethal chromosome damage
McKinnon and Caldecott KW. DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet, 2007
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Physical dosimetry
HIGHER RISK
LOWER RISK
FROM POPULATION RISK TO INDIVIDUAL RISK
BIOLOGICAL DOSIMETRY
Oxydant antioxydant balance ?
Genetic polimorphism ?
Micronutrients ?
-
Biomarkers of DNA damage susceptibility as Newton’s prism
(Andreassi MG et al, FASEB J, 2005)
A
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Volume 372, 30 August 2008-5 September 2008, Pages 697-699
Parveen Bhatti, Alice J Sigurdson and Kiyohiko Mabuchi
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1.58145234>15
1.4210615710-14
1.211451895-19
1.19180230<5
rightleft
Ratio left mortality vs right mortality
Cardiovascular MortalityYears of follow-up
CVD is probably associated with dose, volume and technique of irradiation. Actually, the average median dose is 2.3 Gy to the heart and 7.6 Gy to the left anterior descending coronary artery. However, part of the heart still receives >20 Gy.
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Cardiovascular mortality after radiotherapy for peptic ulcerCohort study on 1470 patients treated between 1936 and 1965 for peptic ulcer with radiotherapy compared with 1568 patients treated with drugs
Radiation doses to the stomach were 8 – 18 Gy in fractions of 1.5 GyRadiation doses to the heart were 1.6 – 3.9 Gy in fractions of 0.33 Gy
Significant trend with dose
Carr et al. Coronary heart disease after radiotherapy for peptic ulcer disease. Int.J.Radiat.Oncol.Biol.Phys. 2005; 61: 842 – 850
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Non-occupational Exposure:A-Bomb Survivors Circulatory Disease
Mortality 1968-1997Significant effect for both heart disease and stroke (whole-body uniform doses in the range 0-4 Sv)
Revealed a dosee esponse relationship that was highly significant statistically and appeared linear with no threshold, with each additional Sv of radiation increasing the mortality rate by a factor of 0.17
Prseton et al. Report 13: solid cancer and noncancer disease mortality: 1950e1997 Radiat Res 2003;
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McGale P, Darby SC. Radiation Res. 2005; 163: 247-57.
Occupational studies and circulatory disease mortality
*Excess relative risk
“No clear evidence in the range 0-4 Sv”
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Int J Epidemiol 2008; 37:506-518
For male radiation workers, there is an
apparent dose response for mortality from
circulatory system disease [P<0.001, ERR=0.65/Sv(90% CI 0.36–0.98)].
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Current State of KnowledgeEpidemiological evidence indicate radiation induced
cardiovascular effects for moderate doses (0.5 –2 Gy)
“whilst recognizing the potential importance of observations on non-cancer diseases -
particularly heart disease and stroke - the Commission judges that the present
available data does not allow for inclusion in the estimation of detriment following
radiation doses in the range up to few tens of mSv (100 ≤mSv)”
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Carotid IMT and risk in patients without history of CVD
0
5
10
15
20
25
30
35
40
45
1 2 3 4 5
CCA-IMTICA-IMTCCA + ICA IMT
Quintile Carotid IMT
Incidence MI/Stroke per
1000 Person-year
P < 0.001
O’ Leary et al. NEJM 1999; 340: 14 - 22
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Lerman A et al. Circulation, 2005
Endothelial dysfunction and CV events
n= 2500
CoronaryBrachial
Cuff inflation Cuff deflation
5 min
10
basal
0 min
11 16 17 20 26
Basal before nitrate
27 30
1‘
29 31
events 0.3 mg NGL
d=48 mm, %NMD=15d=46 mm, %FMD=11d=42 mm
Brachial endothelial function study
Cuff inflation Cuff deflation
5 min
10
basal
0 min
11 16 17 20 26
Basal before nitrate
27 30
1‘
29 31
events 0.3 mg NGL
d=48 mm, %NMD=15d=46 mm, %FMD=11d=42 mm
Brachial endothelial function study
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Atherosclerotic effects associated with environmental radiation exposure: the
Chernobyl cancer children study
Young adults (n=18, 25.3±2.7 y vs 10 controls) exposed as children to environmental
(Chernobyl area) and therapeutic (radioiodine ablation) radiation show
signs of early atherosclerosis, mirrored by
depressed FMD and increased CIMT
Venneri et al. preliminary results
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Cardiovascular effects associated with low RadRadiiatioon Doses assessed with an integrated clinical, cellular and experimental approach:
The Interventional Cardiologist Cardiologist Study
Cardiorad Study
Cath lab exposed workers(aged 26-60 yrs)
Bench
(>50 mSv lifetime
cumulative exposure)
Unexposed age and gender matched
controls
Primary endpoint:
% FMD and Carotid IMT
Potential mechanisms for atherosclerosis initiation:
a) inflammation-coagulation; b) apoptosis and oxyradical stress balance; c) genetic instability and d)
endothelial dysfunction.
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