04 carcinogenesis

Ch 10 Radiation Carcinogenesis

A. Definition of late effects

1. Late effects are due to damage of cells that survive but retain some legacy of the radiation exposure.

a. germ cells → genetic mutation

b. somatic cell → leukemia or cancer

B. Stochastic effects

1. Genetic effects and carcinogenesis2. arise from the injury of a few cells, or a si

ngle cell, therefore has no dose threshold

3. All-or-none effect4. The probability of the biological effect oc

curing increases with dose, however, the severity of the biological effect when it occurs does not.

C. Deterministic (Nonstochastic) effect

1. Somatic effect

2. caused by damage of an increasing # of cells and amounts of tissue.

3. severity increases with increasing dose

4. degenerative, e.g. cataracts, organ atrophy, and fibrosis

5. There is a threshold dose

D. Carcinogenesis: The Nature of the Problem

Cancer induction is the most important somatic effect of low dose ionizing radiation.

1. Fig. 10-1, Fig. 10-2

2. Quantitative data on cancer induction by rad. come from pop’ns irradiated for medical purposes and exposed to nuclear weapons. (high d/r, short exposure time)

Marie & Irene Curie

(Both died of leukemia)

Hands of a dentist who held X-ray film in patients’ mouth for 35 yrs (thumb was partially amputated)

skin cancer

grafted skin

1. Skin cancer and Leukemia

Early X-ray workers, physicists and engineers for

accelerator

2. Lung cancer

Miners (radium)

3. Bone cancer

radium dial painters

4. Hepatoma

Thorotrast

Early human experience of radiation-induced cancer

E. The latent period1. There is a delay before the initially transformed

cell (cells) starts to divide and form a tumor. May be a further delay before the tumor assumes the malignant characteristics of growth and spread.

2. In general, three steps for cancer induction initiation → promotion → progression

3. Leukemia has the shortest latent period, a peak by 5-7 years, most occurs in the first 15 years.

4. Solid tumor have a longer latency, avg. 25 years (10-60 years).

F. Models for carcinogenesis1. Absolute risk model a. The risk from radiation is additional to

the natural incidence, e.g. leukemia due to external beams; bone cancer due to

ingestion of radionuclides.

b. Absolute risk = cancer risk in irradiated pop’n - cancer risk in the unirrad control pop’n

c. unit: # of cases of cancer/106 exposure persons/y/rem

2. Relative risk model:

Rad effect of cancer induction is to increase the natural incidence at all ages by a given factor.

Comittees Concerned with Risk Estamates

1. Scholarly United Nations Scientific Committee on the Effects of Atomi

c Radiation (UNSCEAR, established in 1955) BEIR committee (National Academy of Sciences in the United States, setup in

1976)

2. Comittees involved with radiation protection ICRP (International Commission on Radiological Protection) NCRP (National Council on Radiological Protection and Mea

surements)

Bone sarcoma in female dial painters

Relative risk (Straight line)

Estimated excess relative risk (ERR)

DDREF = 2

% increase in relative risk for sarcomas in or near the treatment fields for patients who received radiotherapy relative to those who underwent surgery for prostate cancers

Secondary Malignancy in RT Patients

G. Carcinogenesis in laboratory animals

1. Fig. 10-11, incidence of myeloid leukemia in RF male mice.

2. Characteristic of the curve-

the incidence of malignancy increases with dose up to a maximum, usually 3-10 Gy, followed by a subsequent decrease with further increases in dose.

Incidence of radiation-induced leukemia in RF male mice

The low-dose data ( 2 Gy) came from A-Bomb survivo≦rs; high-dose data refer to RT patients.

Excess Relative Risk for Leukemia

Excess Relative Risk for Solid Cancer

Ch 11 Hereditary Effects of Radiation

Lethal Chromosomal Damage

Lethal Chromosomal Damage

Non-lethal chromosome damage

Non-lethal chromosome damage

Translocation

(normal) (will survive due to genome balance, but abnormal)

Translocation

(die due to genome imbalance)

(die due to genome imbalance)