GSF 2004 1

Age-Time Patterns of Age-Time Patterns of Radiation-Related Cancer RiskRadiation-Related Cancer Risk

Donald A. Pierce

Dale L. Preston

RERF Hiroshima

Michael Vaeth

Aarhus University Denmark

GSF 2004 2

Genesis of Considerations HereGenesis of Considerations Here

• Initially, most thought an single exposure would cause a “wave” of excess cancer, vanishing after 20 years or so

• But by about 1985, we found that age-specific cancer rates were elevated for most or all of lifetime

• Why should this be? Insufficient attention was given to the implications, for both radiation-related cancer and carcinogenesis in general

GSF 2004 3

1980’s and Still-Common View1980’s and Still-Common Viewof the Relative Riskof the Relative Risk

ERR / 100 mSv

0

0.1

0.2

0.3

35 45 55 65 75 85

Age (at risk)

ER

R

Agex 5

Agex 15

Agex 30

Agex 55

(ERR is the % increase in age-specific cancer rate)

GSF 2004 4

But the Current Understanding But the Current Understanding is More as Shown Hereis More as Shown Here

ERR / 100mSv

0.0

0.1

0.2

0.3

35 45 55 65 75 85Age (at risk)

ERR

Agex 5

Agex 15

Agex 30

Agex 55

Much of so-called exposure-age effect was due to variation with attained age

GSF 2004 5

Reasons Why ERR Reasons Why ERR Should Look Like ThisShould Look Like This

Considering malignancy of a cell as due to accumulated mutations, suppose as a substantial idealization that:

A. The spontaneous rate of the next mutation in a cell depends arbitrarily on its mutational status, but not otherwise on age

B. A brief radiation exposure causes mutations, i. e. momentarily increasing all relevant mutation rates by a factor (1 )d

GSF 2004 6

Implication of ThisImplication of This

• Cancer rate following exposure to dose d is

• Aside from the idealized assumptions, this describes remarkably well the actual radiation cancer risks for A-bomb survivors

• The age increase is about 2-3 days per mSv

0( ) ( )d da a d

GSF 2004 7

Simplest Evaluation of the Age-Simplest Evaluation of the Age-Increment Description Increment Description

Sex-Averaged Cancer Rates by Dose Groups

0

0.01

0.02

0.03

0.04

0.05

30 40 50 60 70 80

Age

Can

cer

Rat

e

< 0.005

0.005 - 0.50

0.50 - 1.0

1.0 - 2.5

Same on On Transformed Age ScaleMen: age + 4.75 dose (Sv)

Women: age + 9.9 dose (Sv)

0

0.01

0.02

0.03

0.04

0.05

30 40 50 60 70 80

Age Transformed

Can

cer

Rat

e

The age increment removes the most basic evidenceof a radiation effect on cancer rates

GSF 2004 8

Same Results by Exposure AgeSame Results by Exposure AgeCA Rates for Age-at-Exposure Groups <20. 20-40, >40Solid Lines Entire Cohort on Transformed Age Scale

Dashed Lines Unexposed Group on Regular Age Scale

0

0.01

0.02

0.03

30 40 50 60 70 80

Age Transformed

Ca

nc

er

Ra

te

Effect seen here is birth cohort variation in background cancer rates

GSF 2004 9

Implications for Relative RiskImplications for Relative Risk

• The relation involves no assumption regarding some number of required mutations

• But for whatever reason, during most of life natural cancer rates take form

• Thus the RR could be expected to take form

0 ( ) pa a

( )(1 / ) 1 /

pp

p

a dRR d a p d a

a

0( ) ( )d da a d

ERR

GSF 2004 10

Age-Change Result vs DescriptionAge-Change Result vs Description

0

0.05

0.1

0.15

0.2

0.25

0.3

35 45 55 65 75 85

Age

ER

R /

100

mS

v

Result of Age Change

Agex 5 Description

Agex 15

Agex 30

Agex 55

Theoretical result has no exposure age effect, an important issue with a variety of explanations

GSF 2004 11

Several Refinements Will ExplainSeveral Refinements Will Explainthe Modest Age-at-Exposure Effectthe Modest Age-at-Exposure Effect

• Slight improvement in characterizing birth cohort variations in background rates

• Allowing that part of the birth cohort effect acts additively with radiation

• Modest increase at young ages of mutation rates per unit time

GSF 2004 12

Effect of Slightly Higher Mutation Effect of Slightly Higher Mutation Rates at Young AgesRates at Young Ages

0

0.05

0.1

0.15

0.2

0.25

0.3

35 45 55 65 75 85

Age

ER

R /

100

mS

v

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 10 20 30 40 50 60

Age

Va

ria

tio

n

Mutation rate variation

Solid: predicted Dashed: observed

GSF 2004 13

More Immediate EffectsMore Immediate Effects• Those results are for well after end of

exposure (following latent period between malignant cell and cancer)

• Exposure could cause final required mutation and allowing for this we have (but with latent period smoothing)

• This added factor can be important

( ) {1 ( ) / } {1 ( )}pRR a D a a d a

GSF 2004 14

Typical Result for Underground Typical Result for Underground Miners and BEIR VI ModelsMiners and BEIR VI Models

Exposed age 35 to 40

0

1

2

3

4

20 30 40 50 60 70 80

age

ER

R

Mutation model

BEIR 6 model no duration

BEIR 6 model duration

GSF 2004 15

Implications for Radiation & CancerImplications for Radiation & Cancer

• In this way of thinking, radiation does not “induce” cancers, but contributes to the natural process– can explain very simply why naturally why

risk persists for lifetime, but ERR decreases with age

• The “cancer age increase” interpretation can be useful, for analysis and communication

• Suggests substantial commonality between radiation-induced and spontaneous mutations

GSF 2004 16

Implications for Carcinogenesis in Implications for Carcinogenesis in General of General of anyany Multi-Mutation Model Multi-Mutation Model

• Accumulation of required mutations probably begins at a very early age

• Very large numbers of cells would acquire the first several mutations, and thus this would be quite stable from person-to-person

• Most of the person-to-person variation would be due to the long waiting time for the final one or two of required mutations

GSF 2004 17

You Can Find Two You Can Find Two Papers on This AtPapers on This At

http://home.att.ne.jp/apple/pierce/