Radiation Carcinogenesis

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…

1. Occupationally Exposed: e.g., radium dial

painters, uranium miners, early x-ray users.

2. Medically Exposed: e.g., ankylosing spondylitis,

tinea capitis, tuberculosis patients, children

irradiated for enlarged thymus

3. 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 chamber of Commerce- before 1945 Hiroshima immediately after the bomb

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 survivors

1950-1990

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