Radiation Carcinogenesis

Martin Brown

Two types of late effects of irradiation

• Deterministic (non-stochastic) effects– Severity increases with dose. There is a threshold.

Eg tissue fibrosis, cataracts.– Mechanism involves effects (often cell kill) on

many cells.• Stochastic Effects

– No threshold, probability increases with dose but severity is independent of dose (eg cancer and genetic effects)

Both Marie Curie (the discoverer of radium) and her daughter Irene died of leukemia - probably due to their radiation exposures

It was known early after the discovery of radiation that it could cause cancer

Mutations produce Cancer

• H J Muller (1927) found that X-rays induce gene mutations in Drosophila (fruit flies) and that they do so linearly with dose.

“The effect of X-rays, in occasionally producing cancer, may also be associated with their action in producing mutations”.

• Bruce Ames. 1970’s: developed test in bacteria for potency of chemicals to cause mutations - these correlated with potency to cause cancer in rodents. Simple idea: mutagens = carcinogens.

Radiation induced cancers

• Spectrum of cancers is same as that occurring naturally.

• Severity of induced cancer is independent of dose.

• Probability of cancer induction increases with dose with no threshold.

• This is known as stochastic effect

• Mechanism is that cancer can arise from a single mutation in a single cell.

Risk Estimates for Radiation Induced Cancers

Information principally from…

• Occupationally Exposed: e.g., radium dial painters, uranium miners, early x-ray users.

• Medically Exposed: e.g., ankylosing spondylitis, tinea capitis, tuberculosis patients, children irradiated for enlarged thymus

• Atomic Bomb Exposed: e.g., Hiroshima and Nagasaki survivors.

Occupational exposure: Bone cancer developed in the “radium dial painters”

Thyroid cancer development in individuals given X-irradiation for enlarged thymus in childhood

Hiroshima immediately after the bomb

Hiroshima chamber of Commerce- before 1945

The A-bomb dome today

Latent Periods

• For leukemias: Rise started 2 yrs after bomb and reached peak 7-12 yrs after bomb. Most cases observed by 15 yrs

• Solid Cancers: Excess risk started about 10 years after bomb, excess still continues 60 years after bomb. Thyroid cancer in children has shorter latent period of ~5 yrs.

Breast cancer in A-bomb survivors 1958-1998

Preston et al, Rad Res.168 1-64,2007

Breast cancer in various irradiated populations

Relative vs Absolute Risk

A-bomb survivors1950-1990

Dose response curve (relative risk) for all cancers in A-bomb survivors 1958-1998

Preston et al, Rad Res.168 1-64,2007

Data consistent with linear dose response curve

Compared to the number of people in H & N killed outright (~100,000) the number of

cancer deaths attributable to the radiation dose is small

Preston et al, Rad Res.168 1-64,2007

Shape of dose response curve

A linear, non threshold model is assumed for risk estimates and for

radiation protection

Dose Rate Effectiveness Factor (DREF) = Ratio of cancer risk at high compared to low dose or low dose rate.

Best overall estimate of total radiation induced cancer mortality

10% per Sv (high doses/dose rates)

US Normal is ~ 16% for all cancers

Does this agree with 10% per Sv?

Cancer Risk after Radiotherapy 1

Increase in Relative Risk after Radiotherapy for Prostate Cancer

Second Cancers after Radiotherapy for Cervix Cancer (Boice et al, 1985)

Boice et al: JNCI: 74.955, 1985

Cancer risk is relatively independent of dose for high doses (Hall 2003)

Estimating cancer risk in any organ after radiotherapy

• Using a combination of the linear, non threshold estimates from the A-bomb survivors and actual cancer risk from Hodgkin’s disease patients treated at high doses (~ 40Gy), Schneider et al (Theoretical Biology and Medical Modelling 2011, 8:27), constructed dose response data for all organs. Below is the one for all cancers. They considered 3 different models:

Organ doses from Medical Radiation

Brenner & Hall, NEJM, 2007

Cancer incidence from CT scans

Brenner & Hall, NEJM, 2007

Of the 62 million CT scans, 4 million are on small children.4 x 106 x 0.1% = 4 x 103 excess ca deaths per year

Summary• Radiation is both a mutagen and a carcinogen• Human risk estimates are based on a linear, non

threshold assumption for the dose response curve• Human risks are based largely on the data from the

A-bomb survivors.• Rule of thumb: 1 Sv (= 1Gy of X-rays) gives 10%

cancer death rate over spontaneous rate. Reduce by factor of 2 for low doses and/or low dose rates.

• Radiation induces genomic instability by as yet unknown mechanisms