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Non-Linear Biological Responses to Low Dose Radiation - Risk May Not be Proportional to Dose

Douglas R. Boreham, Professor

AAPM 2014, Austin Texas

Professor Northern Ontario School of Medicine

Bruce Power Chair in Radiation and Health

McMaster University

CANADA

Radiation Risk:

LNT Hypothesis

• Dose is additive.

• Dose is a surrogate for risk.

• Risk is proportional to dose without a

threshold.

• Everyone is the same with respect to risk

and dose.

• Biology does not influence risk.

The New England Journal of Medicine D. Brenner and E. Hall

November 29, 2007 Vol. 357:2277-2284

“2% of all cancers in North America over the next

decade will be caused by CT Scans”

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American Journal of Physicians and Surgeons

B. Scott, C. Sanders, R. Mitchel and D. Boreham

March 2008

“Cancer risk in North America may be reduced

by 2% over the coming decades because of low-dose medical CT exposures”

Computerized Tomography (10-40 mGy)

ROS Endogenous Damage and Radiation: What’s the Link?

H2O2

O2.-

OH. OH.

H2O2

O2.-

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Endogenous Free Radicals (ROS)

• A 10 mGy CT scan would be equate to an average of 10 photon tracks per cell in the body.

• Every hour, mammalian cells have 50-100 times as much spontaneous DNA damage as they would if they had 10 mGy dose of low-LET radiation (a CT scan).

Endogenous Free Radicals (ROS)

• There are 10,000 measurable DNA alterations per hour in each mammalian cell due to intrinsic causes (oxidative metabolism and ROS).

• Radiation literature states that 100 or fewer DNA alterations occur per 10 mGy (a CT Scan) of low LET radiation per mammalian cell.

Daniel Billen (1990) in Radiation Res. 1990 Nov;124(2):242-5 [7]

•Single cell organisms

•Insects

•Plants

•Lower vertebrates

•Mammalian cells including human

•Mammals

This is an Evolutionarily

Conserved Response

Adaption to radiation shown in:

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The Adaptive Response

Cellular response to an environmental

stress that induces a mechanisms that

confers resistance to subsequent stress.

Signal Time Resistance

Spontaneous level changes

Endogenous Damage

YEAST

INSECTS

PLANTS

CELLS

MAMMALS

HUMANS

Stress Hyperthermia Chemical Radiation

Mic

ronu

cleu

s fr

eque

ncy

(%)

0

20

40

60

80

100

120

Con

trol

4 G

y

1 m

Gy

- 3h

- 4 G

y

500

mG

y - 3

h - 4

Gy

1 m

Gy

500

mG

y

5 m

Gy

25 m

Gy

100

mG

y

5 m

Gy

- 3h

- 4 G

y

25 m

Gy

- 3h

- 4 G

y

100

mG

y - 3

h - 4

Gy

Ability to Repair Broken Chromosomes in Cells

Adapted by Exposure to Low Doses

60Co-γ

Broome, Brown and Mitchel. Radiat. Res. 158, 181-186 (2002)

C3H-10T1/2 Cell Transformation Assay

Type III Foci

Azzam, de Tolido, Raaphorst and Mitchel, Radiat. Res. 146:369-373 (1996)

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Low Dose -Rays Reduces the Spontaneous

Transformation Frequency in Mouse Embryo

Cells

20

10

Tra

ns

form

ati

on

Fre

qu

en

cy

(x 1

0,0

00

ce

lls

)

Azzam et al., Radiat. Res. (1996) control ray

0

1

2

3

4

5

6

7

0.0 0.04 0.1 0.4 4.0 9.0 18.0 36.0

Dose (cGy)

Tra

ns

form

ati

on

Fre

qu

en

cy

(x

10

5)

Effect of Low Doses of 60 kVp X-Rays on Neoplastic Transformation of Human Hybrid Cells in vitro

+/- 95% C.I.

Redpath JL et al. 2000

Fig. 4A Mitchel et al.

TIME (days)

0 200 400 600 800 1000

SU

RV

IVA

L P

RO

BA

BIL

ITY

0.0

0.2

0.4

0.6

0.8

1.0

Low Dose Radiation Improved Survival of

Myeloid Leukemia in Genetically Normal Mice

Control

and 1 Gy ML Neg.

1 Gy

ML Pos.

100 mGy + 24h + 1 Gy

ML Pos.

Trp53+/+

Mitchel, Jackson, McCann and Boreham, Radiat. Res. 152:273-279 (1999)

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TIME (days)

0 200 400 600 800 1000

SU

RV

IVA

L P

RO

BA

BIL

ITY

0.0

0.2

0.4

0.6

0.8

1.0

B

1 Gy

WBH (40oC, 60 min) + 1Gy

Mitchel, Jackson, McCann and Boreham, Radiat. Res. 152:273-279 (1999)

Mild Hyperthermia Improved Survival of

Myeloid Leukemia in Genetically Normal Mice

Role of Radiation and Risk - p53 “Knockout” Mouse Model

Normal p53

Two good copies

Homozygous

> 100 Weeks

no tumours

4 Gy

> 100 Weeks

no tumours

No p53

Two Bad Copies

Knockout

21 weeks

tumors

1 Gy

14 Weeks

tumours

Kemp et al. Nature Genetics 8:66-69, 1994

One bad p53 copy

One good copy

Heterozygous

70 weeks

tumours

4 Gy

40 Weeks

tumours

One bad p53 copy

One good copy

Heterozygous

70 weeks

tumours

4 Gy

40 Weeks

tumours

Lymphoma Latency

Tumor Latency (days)

0 200 400 600 800

Nu

mb

er

of

Tu

mo

rs

0

10

20

30

40

0 Gy Trp53 +/-

10 mGy Trp53 +/-

100 mGy Trp53 +/-

0 Gy Trp53 +/+

Mitchel, Jackson, Morrison and Carlisle, Radiat. Res. 159:320-327 (2003)

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CT and PET Lifetime Cancer Risk

Groups (Hets)

Controls

1 CT

1 PET

4 Gy (WT)

4 Gy

1 CT + 4 Gy

1 PET + 4 Gy

4 Gy + CTs

Do diagnostic CT and PET scans increase cancer risk?

Breeding

Male Breeders - B6.129S2 (Trp53 Heterozygous +/-)

Female Breeders – 129X1/SvJ (Trp53 Wild-type +/+)

X 64 870 X

3689 Female Mice (F1)

3500+ Male Mice Culled (21 days)

1867 Female Trp53 Heterozygous mice

1822 Female Trp53 Wild-type mice

CT X-rays and Anti-Promotion Low Dose Radiation?

Initiator High Dose 4 Gy

Low Dose CT X-ray 10 mGy

Time (Latency Period)

Cancer Later

Cancer

High Dose Acute

Cancer Later

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A single CT scan did not increase risk?

P = 0.002

7-8 Weeks Old

4 weeks

10 weeks Female Trp53+/-

4 Gy

Start Weekly

SHAM CT scans Daily Health Monitoring

Strict Objective Criteria for

Endpoint

Necropsy Analyses

Histopathology Examinations

7-8 Weeks Old

4 weeks

Start Weekly

10 mGy CT scans

10 weeks

Experimental Setup

Female Trp53+/-

4 Gy Daily Health Monitoring

Strict Objective Criteria for

Endpoint

Necropsy Analyses

Histopathology Examinations

Lymphoma Latency (days at risk)

0 100 200 300 400

Su

rviv

al

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.04 Gy4 Gy + Rpt CTs

Log rank statistics p = 0.040

Multiple CT scans did not increase risk (significant increase in life span).

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Lymphoma Latency

Age (days)

50 100 150 200 250 300 350 400

Nu

mb

er

of

Lym

ph

om

a T

um

ors

0

10

20

30

40

50

60

70

80

90

100

110

120

130

4Gy

4Gy+CT scans

Conclusions

• Cellular Mechanism do not respond linearly to low dose radiation

• Risk from low doses is not linear • A single CT scan increases lifespan in cancer prone mice

• Multiple CT scans after radiation-induced cancer initiation extends lifespan

• The effect is seen primarily in lymphoma and carcinoma not sarcoma

• The mechanism is independent or upstream of p53

• Multiple CT scans are not detrimental under these conditions.

Acknowledgements

US DOE

NSERC/McMaster University

Bruce Power

Colleagues: (M-E. Cybulski, N. McFarlane

L. Laframboise

Students (N. Phan, K. Taylor)

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0.00

5.00

10.00

15.00

20.00

25.00

30.00

35.00

Dose (Gy)

Control

Exercise

CT

CT+Ex

Apoptosis (Cell Death)