Intestinal Neoplasia in Min mice

1
Second Event Theory (SET) and the Reproductive
Cell Cycle
G2
G2 arrest point
M
S
G1 arrest point
G1
G0 (resting cells)
2
Sequential Beta Decay of Strontium-90 in a Mass
of Cells
1st 90Sr decay track range 50 cells
2nd 90Y decay track range 400 cells

• SET-specified dual events from 90Sr are rare
• (1.4 in 10,000 cells per mGy per year)

• SET-specified dual events from 1 mGy per year
  natural gamma occur at a similar frequency (1.1
  in 10,000 cells)

3
Biological Basis of SET (1)
Theory
A single ionising radiation track (1st hit) will
directly stimulate resting G0 cells to enter the
cell cycle
Published observations
No evidence found some evidence that irradiated
G0 cells are less responsive to stimulation
Comment
Data at doses gt0.5Gy (500 tracks/cell) - pilot
study at 1 track/cell Possible
mis-interpretations of the term
repair-replication
4
Biological Basis of SET (2)
Theory
All radiation stimulated G0 cells will arrest in
G2
Published observations
Not supported - no single arrest point, no
evidence of 100 G2 synchronization
Comment
Data at doses gt0.5Gy (500 tracks/cell) - pilot
study at 1 track/cell SET greatly
over-emphasizes G2 arrest sensitivity
5
Biological Basis of SET (3)
Theory
Synchronized G2 cells are extremely mutable by
radiation (ie second hit)
Published observations
G2 cells are often more mutable than others -
degree depends upon cell type and mutational end
point. Mutability increase is generally modest,
not gt1,000x
Comment
SET greatly over-emphasizes G2 mutability
6
SET and Particulate Alpha-Emitters

• Broad agreement on relatively high freguency
  of dual cellular hits local to Pu particles (0.5
  µm diam)
• SET conditions give dual events in cells with
  multiple hits (very high alpha doses)
• Cellular response dominated by cell killing
  not mutation

7
Alpha Decays from a Plutonium Oxide Particle in a
Mass of Cells
41,000 alpha traversals per year

• SET-specified dual events in 40-100 cells
  over 1 year

• Cellular alpha doses range from 34-470 Gy over
  1 year

8
Other SET-related Issues

• External review of additional biological data
• Discussion of possible future research