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

Sustainability of Medical Imaging: The Radiation Issue

Diagnostic exposure to radiation is a public health issue

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

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

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

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)

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

Stochastic effects:DNA is the most important target of IRDNA is the most important target of IR

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

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

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)

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.

BEIR VII: Research Need

Cumulative patient effective dose in children with congenital heart disease

Ait-Ali et al. ESC Congress 2008, Munich

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.

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

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)

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

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

Cancer risk from professional exposure in staff working in cardiac catheterization laboratory

Median LAR= 1 in 192 (range= 1 in 137-1in 370)

42 spontaneous

cancers

+ 1, Radiation induced

100 mSv for 100 patients

BEIR VII, 2006

Range of uncertainty

(1 in 100)

(

• 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

Research priorities

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

Chromosomal damage, radiation exposure and congenital heart disease

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

15 % increase in adult

patients after invasive

cardiovascular interventions

50% increase in chromosomal DNA damage in interventional cardiologists

DNA repair genes and cancer

Web registry on DNA repair polymorphisms and cancer risk: www.perseus.isi.it/huge

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

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

Volume 372, 30 August 2008-5 September 2008, Pages 697-699

Parveen Bhatti, Alice J Sigurdson and Kiyohiko Mabuchi

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.

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

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;

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”

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)].

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)”

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

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

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

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.