William F. Morgan. Ph.D., D.Sc.

Transcription

1 Biological Responses at Low Radiation Doses: Advances in Radiation Biology and Potential ti Implications for Radiation Exposure Regulations. William F. Morgan. Ph.D., D.Sc. Pacific Northwest National Laboratory 1

2 Joe has outlined the reasons we need a radiation protection policy! Biological effects at low doses So what (if any) advances in the radiation sciences might impact on radiation exposure regulations?

3 The dilemma for radiation protection: what is the scientific basis for radiation standards to protect the public from exposures to low levels of ionizing radiation (<0.1 Sv) where there are considerable uncertainties in the epidemiological data. Ra adiation Related Ca ancer Risk A-bomb Survivor data Supra-linearity LNT Sub-linearity it Background Hormesis Dose (Sv)

4 4 Societies Perception of Risk Differs

5 Ionizing radiation Has The Potential To Cause Detrimental Effects: All radiation is bad and should be eliminated or reduced to a level as low as reasonably achievable (ALARA).

6 On the other hand - complex biological systems have physiological barriers against damage and disease. Primary damage linear with dose, secondary damage not. Cellular processes block damage propagation to clinical disease.

7

8 Questions In the Context Of Radiation Protection How to extrapolate biological effects at low doses to risk? Are extrapolations from high dose acute exposures appropriate when human exposure is primarily chronic low dose exposure?

9 Hot Topics - sponsored in large part by the US DOE Low Dose Radiation Research Program Low dose radiation hypersensitivity Adaptive responses Epigenetic modifications Non-targeted genomic instability Non-targeted bystander effects Non-cancer effects

10 The Current Paradigm For Risk Genetics Environment Diet Lifestyle Any exposure has the potential ti for risk

11 Hypersensitivity to Low Doses of Ionizing Radiation Joiner et al. I.J.R.O.B.P. 49; (2001) Failure of ATM-dependent repair processes to fully arrest the progression of damaged G 2 -phase cells harboring un-repaired DNA breaks entering mitosis. Well documented in vitro, also occurs in vivo How universal is low dose hypersensitivity, exception rather than the rule?

12 Chr romatid abe errations Adaptive Responses: Adapt Challenge Chromosome Low dose reducing high background analysis E O E O Radiation dose (mgy) Redpath et al., I.J. R.B. 79, (2003) Coleman et al., Rad. Res. 164; (2005)

13 Epigenetic Modifications DNA methylation Chromatin remodeling MicroRNAs

14 Radiation-Induced Genomic Instability Increased rate of genomic alterations in the progeny of irradiated cells Irradiation Manifests as: chromosomal rearrangements micronuclei aneuploidy delayed mutation (spectrum different) gene amplification cell killing Non clonal - not necessarily a fixed genetic change that is passed on.

15 Radiation Induced Bystander Effects: Effects observed in cells that were not irradiated but were bystanders at the time of irradiation Single cell microbeam irradiation 1 cell irradiated Single particle

16 Radiation induced bystander effects: Effects observed in cells that were not irradiated but were bystanders at the time of irradiation Single cell microbeam irradiation Why? 1 cell irradiated gene expression mutation transformation micronuclei cell killing

17 Bystander effects in an in vivo human skin model (3D). Belyakov et al. PNAS 102, (2005) Beneficial? Eliminating damaged or initiated cells Beneficial? Eliminating damaged or initiated cells Detrimental? Inducing damage in non-irradiated cells

18 In addition to targeted effects we must consider the impact of non-targeted t effects Targeted cell Survives and proliferates gap junction communication Secreted / shed factors Do hit and naive cells respond differently? Bystander cell Sowa & Morgan, PNAS:102, (2005) 18

19 Linear Non-Threshold is a Model/Hypothesis: As such it has been used and abused! Goal: public and worker protection Assumes: Correctly that Tissues/organs differentially sensitive Risk varies with Age Sex Socio economic status t Diet and lifestyle Genetic makeup and race Dose and dose rate Radiation quality Difficult to recapitulate in vitro

20 Questions: How to design a system that limits risk? How do we assign a potential human health risk? What science do you need to accomplish this? Caveats: This system must take into account : The most sensitive organ (breast)? The most sensitive individual? Radiation sensitive Radiation resistant Where do you draw this line for regulatory purposes?

21 Extrapolation From Experimental Systems: Cells tissues organs man What does in vitro cell culture tell us about a response in humans? What do in vivo models tell us about a response in humans - how do you extrapolate from an an animal model to the human population? Should you?

22 My thoughts. Epidemiology is unlikely to provide definitive information - always uncertainty. Radiobiology - mechanisms not risk. The current system (LNT) works, although the biology suggests all responses might not be linear - mortality data from nuclear power workers Hard to fault regulatory bodies for endorsing the middle ground of a LNT cancer risk model Life is dangerous - keep radiation in perspective.

23 Comments and / or questions wfmorgan@pnl.gov g 23