2. Questions: Low Dose Effects and
Risk Assessment
• Is the nonthreshold, linear relationship of
ionizing radiation relevant at low doses?
• Is there sufficient repair at low doses to
impact DNA damage?
• Should regulatory agencies set a dose-
limit for ‘safe’ radiation exposure
• Is the nonthreshold linear model too
confining for environmental exposures?
4. Regulatory Agencies
• Agencies set limits based on both
stochastic and deterministic effects.
• Most total body exposure limits are based
on stochastic effects that have no
threshold.
• Most radiation limits are set based on high
dose high dose-rate exposures. Dose rate
has a significant impact on effects yet is
not considered for dose limits.
5. Tracks and Doses
• Public dose limit: 5mSv/y is about 1
track/year
• Occupational dose limit: 50mSv/y is about
10 tracks/year
• Single CT scan: range is 1-50 tracks/CT
scan
• A bomb survivors begin at range of
100mSv which is 100 tracks for the
exposure
• 1Gy gives about 1000 tracks
6. Radiation at Low Doses
1. Can radiation at the lowest doses produce damage to
chromosomes? Clustered damage to DNA is
possible with a single e- track, cannot be measured at
lowest doses.
2. Is such damage swamped out by endogenous DNA
damage (oxidative damage)? It is for simple dsbs by
at least 100x, but radiation is more damaging than
endogenous damage for causing complex DNA
damage.
3. Is chromosome damage the key event in
carcinogenesis? Possibly, shown in leukemias in
mice but not in other models or in humans.
4. Are dose-response relationships for dicentrics reliable
guides for understanding dose-response relationships
for carcinogenesis? Dicentrics are a poor surrogate
for viable aberrations. -from Dudley Goodhead
7. Issues that Question the
Conventional Paradigm
• Bystander Effects
• Induced Radiation Instability
• Adaptive Responses
• Hormetic Effects of radiation
• Cell signaling pathways/gene induction
• Germline minisatellite mutations
• Modifications to cell/tissue microenvironment
• Promotional effect of radiation
9. Endogenous (Oxidative)
Damage to DNA
• 50,000 lesions per day:
-20,000 ssbs
-10,000 depurination/depyrimidination
events
-5,000 alkylations
-2,000 oxidative lesions
-600 deaminations
-10-20 dsbs
-taken from Penny Jeggo
10. Adaptive Response
• A low (mGy) priming dose of radiation prevents damage
from a second challenging dose
• First observed in lymphocytes with regard to
chromosomal damage and mutation induction
• Now also observed in fibroblasts and whole animals
• Model: At low priming dose there is the induction of
repair/radioprotective compounds that allow for more
rapid or more accurate response to challenging dose
• Mechanism not known
• Evidence for high and low responders in people
• Candidates genes: PCNA, cytokines, other repair
enzymes, PKC
12. Bystander Effect
• An unirradiated cell in a population of irradiated
cells has responses like the irradiated cells.
Endpoints include gene induction, change in cell
cycle genes, increased chromosomal lesions.
• Some evidence for a trans-acting factor being
released into the medium.
• Some evidence for a role of gap junctions in the
process
• Recent idea that oxidative metabolites may be
involved
• Mechanism is not understood
26. Delayed Mutation Induction
• Delayed mutations do not occur in the irradiated
cells but rather in the progeny sometimes
several generations later (up to 13)
• May play a role in carcinogenesis: gene
amplification, cell transformation
• Appears to involve a nuclear signal
• Found in lymphocytes and fibroblasts
• Induced by both high and low LET radiation, but
more evidence for induction with high LET
• May involve the induction of a genetically
unstable state
31. Gene Induction
• Gene induction occurs at both high and low
doses of radiation; different genes can be
induced at different doses
• Genes induced vary from one cell type and
tissue type to another
• Not all genes induced by radiation are DNA
damage dependent
• Changes in gene expression often are
associated with changes in cell signal
transduction
32. Time course of Gene Expression following stress responses
33. Tannock IF, Hill RP, Bristow RG and Harrington L: The Basic Science of
Oncology
Figure 14.23. Pathways involved in tumor cell radioresistance amenable to molecular targeting in
addition to radiotherapy. A number of oncogenic pathways are abnormal in radioresistant tumor cells
leading to abnormal cell proliferation, DNA repair, cell death responses or angiogenesis. Specific agents
that target these pathways have been used in preclinical and clinical studies as a means of overcoming
this resistance. In this figure, pathways relating to increased radioresistance in vitro and in vivo are
presented as altered growth factor (i.e., EGFR, VEGF) PI-3K/PTEN-AKT and RASRAF intracellular
signaling and abnormalities in angiogenesis. Selected agents can lead to radiosensitization by blocking
receptors with competing antibodies or inhibiting intracellular Signaling cascades. These approaches are
discussed in more detail in Section 14.4.4. (Reproduced with permission from Ma et ai., 2003.) (See color
plate.)
50. Individual Susceptibility
• Are there subpopulations of people who are inherently (genetically)
sensitive to radiation exposure but who are generally phenotypically
normal?
• AT patients are sensitive but not normal; AT heterozygotes may
show sensitivity
• Background mutation frequencies in individuals are highly variable
(by as much as a factor of 10)
• Factors which MAY influence mutation frequency: chronic diseases,
increased cell division, smoking, age, infections
• RT does NOT cause a systemic increase in mutation frequency
• Some mutator phenotypes have been found in the population.
These are people who have a high mutation rate in the absence of
apparent induction pressure. Causes are not always known, but
some involve changes in particular genes.
51. Dose Rate Effects
• Most data are from acute exposures
• Most people are exposed environmentally
(Rn in the home, etc.)
• How much are high dose rate data
extrapolatable to low dose rates?
• Do different mechanisms occur at low
dose rates?
55. Summary
• Low dose responses include the bystander
effect, adaptive responses, delayed
genomic instability, and others
• Transcriptional changes occur at high and
low radiation doses
• Low dose rate responses are generally
determined by extrapolating from high
doses.
