Age-Time Patterns of Radiation-Related Cancer Risk

1. Age-Time Patterns of Radiation-Related Cancer Risk Donald A. Pierce Dale L. Preston RERF Hiroshima Michael Vaeth Aarhus University Denmark

2. Genesis 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

3. 1980’s and Still-Common Viewof the Relative Risk (ERR is the % increase in age-specific cancer rate)

4. But the Current Understanding is More as Shown Here Much of so-called exposure-age effect was due to variation with attained age

5. Reasons Why ERR Should Look Like This Considering malignancy of a cell as due to accumulated mutations, suppose as a substantial idealization that: • The spontaneous rate of the next mutation in a cell depends arbitrarily on its mutational status, but not otherwise on age • A brief radiation exposure causes mutations, i. e. momentarily increasing all relevant mutation rates by a factor

6. Implication 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

7. Simplest Evaluation of the Age-Increment Description The age increment removes the most basic evidence of a radiation effect on cancer rates

8. Same Results by Exposure Age Effect seen here is birth cohort variation in background cancer rates

9. Implications 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 ERR

10. Age-Change Result vs Description Theoretical result has no exposure age effect, an important issue with a variety of explanations

11. Several Refinements Will Explainthe 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

12. Effect of Slightly Higher Mutation Rates at Young Ages Solid: predicted Dashed: observed Mutation rate variation

13. More 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

14. Typical Result for Underground Miners and BEIR VI Models

15. Implications 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

16. Implications for Carcinogenesis in General of any 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

17. You Can Find Two Papers on This At http://home.att.ne.jp/apple/pierce/