If bystander effects for apoptosis occur in spleen
after low dose irradiation in vivo then the magnitude
of the effect fal...
Current radiation risk regulation
uses the
Linear No-threshold Model
LNT
LNT model of risk assessment
• Risk is directly proportional to dose
• Even the tiniest dose of radiation is
harmful
– ↑ca...
Cancer

DNA
damage
Radiation dose
LNT states that cancer risk is directly
proportional to dose
high exposure
Death
Cancer...
Low dose radiation phenomena
which do not follow LNT
• Adaptive Response
• Bystander effects
Adaptive Response
• According to LNT, doses must be
directly additive
Adaptive response
Low dose protects from a high dose
Low dose protects from endogenous damage
Mutationfrequency
conditioni...
Adaptive responses
↓ Risk
in vitro and in vivo
Adaptive responses do not necessarily overly concern
regulators because the...
Bystander Effect
• According to the LNT model “unhit” cells
cannot respond to radiation
BYSTANDER EFFECTS – IN VITRO
1 cell hit → many cells respond
Bystander effects at low doses?
• These worry regulators because they may
be under-protecting the population
• ↑ Risk or ↓...
Bystander effect at low doses in vivo?
• Can’t tell which cells have received direct hit
• At low doses, expected increase...
Our approach to study bystander effects at
very low doses in vivo
• Whole animal – mouse
• Whole body X-irradiation
• Low ...
0, 0.01, 1 or 1000 mGy
(n= 10‐16/group)
Detection of apoptosis in mouse spleen after
single whole body X-irradiation
7 h, ...
Development of sensitive method of apoptosis in
spleen in vivo
• in situ
• Minimum of 110,000 cells studied in spleen/mous...
Temporal study of apoptosis frequency in spleen
after low dose X-radiation
7 hours 1 day
3 days 7 days
N ≥ 10, Experiments...
You need a very large number of mice to detect apoptotic
changes based on LNT at these low doses
Even a substantial bystander effect will fall
within the homeostatic apoptosis range
25-fold25-fold
10-fold
Staudacher et ...
Summary
• Bystander effects have been observed in vitro which
could indicate a greater risk than predicted by LNT
• Do the...
Summary (cont)
• No significant changes in apoptosis detected at low
doses in temporal studies
• Expected apoptosis change...
Flinders University
and Medical Centre
Present members:
Pamela Sykes
Ben Blyth
Alex Staudacher
Rebecca Ormsby
Mark Lawrenc...
P. Sykes
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If bystander effects for apoptosis occur in spleen after low dose irradiation in vivo then the magnitude of the effect falls within the range of normal homeostatic apoptosi sykes

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If bystander effects for apoptosis occur in spleen after low dose irradiation in vivo then the magnitude of the effect falls within the range of normal homeostatic apoptosi sykes

  1. 1. If bystander effects for apoptosis occur in spleen after low dose irradiation in vivo then the magnitude of the effect falls within the range of normal homeostatic apoptosis Pamela J Sykes SA Pathology Flinders University and Medical Centre Can we see radiation bystander effects in vivo at low doses?
  2. 2. Current radiation risk regulation uses the Linear No-threshold Model LNT
  3. 3. LNT model of risk assessment • Risk is directly proportional to dose • Even the tiniest dose of radiation is harmful – ↑cancer • Everyone must be protected from tiny doses – Billions of $’s
  4. 4. Cancer  DNA damage Radiation dose LNT states that cancer risk is directly proportional to dose high exposure Death CancerData Data??? LNT = Linear no-threshold <100 mSv
  5. 5. Low dose radiation phenomena which do not follow LNT • Adaptive Response • Bystander effects
  6. 6. Adaptive Response • According to LNT, doses must be directly additive
  7. 7. Adaptive response Low dose protects from a high dose Low dose protects from endogenous damage Mutationfrequency conditioning dose Challenge dose Expected Observed Low High Radiation Dose
  8. 8. Adaptive responses ↓ Risk in vitro and in vivo Adaptive responses do not necessarily overly concern regulators because they may be over-protecting the public Identification of a safe threshold could save billions of dollars in unnecessary radiation exposure regulation
  9. 9. Bystander Effect • According to the LNT model “unhit” cells cannot respond to radiation
  10. 10. BYSTANDER EFFECTS – IN VITRO 1 cell hit → many cells respond
  11. 11. Bystander effects at low doses? • These worry regulators because they may be under-protecting the population • ↑ Risk or ↓ Risk ? • Do bystander effects occur – in vivo? – at relevant doses?
  12. 12. Bystander effect at low doses in vivo? • Can’t tell which cells have received direct hit • At low doses, expected increase in any biological end-point by direct effects would be very small – 1 mGy (most cells receive 1 electron track) – 0.01 mGy (1/100 cells receive an electron track) • However perhaps a bystander effect could be observed?
  13. 13. Our approach to study bystander effects at very low doses in vivo • Whole animal – mouse • Whole body X-irradiation • Low doses relevant to OH&S and population exposure – 0.01 mGy, 1 mGy • Biological End-point – Cell fate endpoint of apoptosis (programmed cell death) – Often used in In vitro studies • Spleen • In situ analysis • Temporal studies
  14. 14. 0, 0.01, 1 or 1000 mGy (n= 10‐16/group) Detection of apoptosis in mouse spleen after single whole body X-irradiation 7 h, 1, 3 or 7 days Remove spleen Stain for Apoptosis Alexander Staudacher PhD student
  15. 15. Development of sensitive method of apoptosis in spleen in vivo • in situ • Minimum of 110,000 cells studied in spleen/mouse • Precision of 0.001% • 14 experiments – mean sham-treated apoptosis = 0.27±0.005% – maximal difference of 1.2 apoptotic cells /1000 total cells between sham-treated groups
  16. 16. Temporal study of apoptosis frequency in spleen after low dose X-radiation 7 hours 1 day 3 days 7 days N ≥ 10, Experiments performed twice Total of 14 experiments 274 mice
  17. 17. You need a very large number of mice to detect apoptotic changes based on LNT at these low doses
  18. 18. Even a substantial bystander effect will fall within the homeostatic apoptosis range 25-fold25-fold 10-fold Staudacher et al, radiation Research, in press
  19. 19. Summary • Bystander effects have been observed in vitro which could indicate a greater risk than predicted by LNT • Do the in vitro results translate to in vivo? • Chose apoptosis as a bystander end-point based on in vitro studies • Chose spleen as organ of study as used in other in vivo low dose studies • Used a precise in situ method of analysis
  20. 20. Summary (cont) • No significant changes in apoptosis detected at low doses in temporal studies • Expected apoptosis changes due to direct effects based on LNT at these low doses – = small fraction of the natural variation in apoptosis – Prohibitive numbers of mice required • If bystander apoptotic effects exist in spleen – fall within the homeostatic range of apoptosis – may be a very specific sub-sets of cells affected? • Need for methods for studying rare irradiated cells in organs in vivo
  21. 21. Flinders University and Medical Centre Present members: Pamela Sykes Ben Blyth Alex Staudacher Rebecca Ormsby Mark Lawrence Monica Dreimanis Katrina Bexis Ami-Louise Cochrane Past members: Tony Hooker Tanya Day Guoxin Zeng Royal Adelaide Hospital Eva Bezac Kar Aun Giam Research Funded by the Low Dose Radiation Research program, Biological and Environmental Research, U.S. Department of Energy, grant #DE-FG02-01ER63227 and DE-FG02-05ER64104. Flinders Medical Centre Foundation Lovelace Respiratory Institute New Mexico Bobby Scott New Jersey Medical Centre Edouard Azzam Roger Howell University of Chicago David Grdina University of Freiburg Georg Bauer
  22. 22. P. Sykes

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