1. How Might Basic Research on
Low Dose Ionizing Radiation
Influence Future Radiation
Protection Programs
William F. Morgan, Ph.D., D.Sc.
Biological Sciences Division
Pacific Northwest National Laboratory
Richland, Washington
USA

2. Disclosures:
Member of NCRP, ICRP and
consultant for UNSCEAR - vested
interest in this issue.
But these are my opinions!
Outline of presentation:
Why it is important
My research interests
Future directions

3. Mans Radiation Burden
Cosmic rays
Air (radon)
Building material
Water
Food
Earth
Air travel
Testing fallout
TV & luminous
watches
Nuclear power
plants (20%)
Radioactive waste
Diagnostic &
therapeutic
radiation*
*> 200 million procedures/year (USA), 2 billion worldwide

4. Computerized Tomography (10-30 mGy)

5. Hair Loss From Excessive Dose Of A CT Angiogram

6. CT Over-Exposure To A Young Patient
Fell from bed and complained of neck pain the following morning
Plain x-rays and then a CT scan of neck ordered by ER
CT table did not index (move) and radiologic technologist manually instituted 151 slices over a
period of more than 1 hour
The patient was successfully rescanned by another technician
About 2-3 hours after the first CT attempt he developed a red line around his face at the level of
the 151 CT scan slices

7. US scientists are
warning that radiation
from controversial full-
body airport scanners
has been dangerously
underestimated and
could lead to an
increased risk of skin
cancer - particularly in
children.
http://www.news.com.au/travel/news/naked-
scanners-may-increase-cancer-risk

8. This is why we have radiation
protection programs and what
radiation protection is all about!
So where does the information
regarding the health effects of
ionizing radiation come from?

9. Most of our understanding of radiation effects
comes following a single acute exposure

10. Radiation Effects Research Foundation
(Hiroshima) a unique resource
~ 43% survivors still alive
In the laboratory acute exposures
practical and convenient
Radiation Dose
Effect
?

11. Chernobyl, 1986
Protracted exposure (contamination)

13. Research Interests
Understanding effects of exposure
to low dose (<100mGy), low dose
rate ionizing radiation, the potential
consequences of such exposure(s)
and how to translate these data to
radiation risk.

14. 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?
Questions In the Context
Of Radiation Protection

15. .01 .05 .1 101.0 4.0 100
A-bomb Survivor data
Supra-linearity
Dose (Sv)
Background
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.
Sub-linearity
Hormesis
LNT
RadiationRelatedCancerRisk

16. Radiation Protection Considerations
Science is only one input to risk management
What are the other inputs?
Tradition
Not scaring people
Politics
Social values
Economic considerations
Technological considerations
We have a long legacy of mistrust to deal with!
Plus some widely diverging opinions
Hormesis - tolerance - acceptance - total denial

17. 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).

18. 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.

20. The Radiendocrinator (ca. 1930)
Gold plated Radiendocrinator sold in its velvet lined pocket for $150. Beta-
gamma GM detector ~ 200 mR/hr.

21. 21
Societies Perception of Risk Differs

22. Epidemiology versus Biology
Epidemiology is fraught with
uncertainties…..So what is the
biological data (presumably the
mechanisms) that can help us
understand the potential effects
of exposure to ionizing radiation?

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

24. Conventional paradigm for radiation effects

25. 25
In addition to targeted effects we must
consider the impact of non-targeted effects
Targeted cell
Survives and
proliferates
Secreted / shed factors
gap junction
communication
Bystander cell

26. 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.

28. Clonally expand
Irradiate
Clonally expand
Metaphase analysis of
clonally expanded cells

31. Radiation-Induced Instability Can
Occur In Non-Targeted Cells:
Instability observed in cells not traversed
by an alpha particle
Kadhim et al. Nature 355, 738-40 (1992)
Shielded grid experiment
Lorrimore et al. PNAS 95, 5730-3 (1998)
secreted factor?
cell to cell gap junction communication*?
dead / dying cells*?
*Not in our cell system

32. 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

33. 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
gene expression
mutation
transformation
micronuclei
cell killing
Why?

34. Bystander effects in
an in vivo human
skin model (3D).
Belyakov et al. PNAS 102,
14203-7 (2005)
Beneficial? Eliminating damaged or initiated cells
Detrimental? Inducing damage in non-irradiated cells

35. Implanted
LLC cells
Abscopal “Anti-Tumor” Effects In Vivo
5 x 10Gy
12 x 2Gy
fractionated
Significant delay in LLC cell growth.
Camphausen et al. Cancer Res. 63, 1990-1993 (2003)

36. 76 year old male with back pain
Thoracic and abdominal CT scans
thoracic vertebral bone metastasis
and hepatocellular carcinoma
36Gy to the bone mass
regression of hepatic lesions
Ohba et al. Gut 43, 575-577, (1998)
Retrospective
analysis of
serum
concentration
s of IL-1 beta,
IL-2, IL-4, IL-6,
HGF, and
TNF-alpha
Abscopal
Effects:

37. Precedent For Secreted Factor(s) In
Humans - Clastogenic Factors

38. Clastogenic Factors In Plasma From:
Accidentally irradiated individuals
Goh & Sumner, Radiation Res. 35, 171-181 (1968)
Therapeutically irradiated individuals
Hollowell & Littlefield, PSEBM. 129, 240-244 (1968)
A-bomb survivors
Pant & Kamada, Hiroshima J. Med. Sci. 26, 149-154 (1977)
Chernobyl clean up workers
Emerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561 (1994)
Children exposed after Chernobyl
Emerit et al., Mutation Res. 373, 47-54 (1997)
CF-Nelson rats
Fagnet et al., Cancer Genet. Cytogenet. 12, 73-83 (1984)
Patients with chromosome fragility syndromes
Bloom syndrome, Fanconi anemia, XP and AT

39. .01 .05 .1 101.0 4.0 100
A-bomb Survivor data
Supra-linearity
Dose (Sv)
Background
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.
Sub-linearity
Hormesis
LNT
RadiationRelatedCancerRisk

40. 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
Diet and lifestyle
Genetic makeup and race
Dose and dose rate
Radiation quality

41. Questions: How to design a system that limits risk?
How do we assign a potential human health risk?
Caveats: This system must take into account :
The most sensitive organ (breast)*?
The most sensitive individual*?
Where do you draw this line for regulatory purposes?
* Ethical and legal questions
Radiation
resistant
Radiation
sensitive

42. 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?

43. How do you communicate radiation risk when
the “so called experts” do not agree?
Disasters/crises make the news!
The public reads/listens to the news.
The public votes for politicians
Politicians dictate policy
Regulators have to implement the policy
So where is the science?
Lets take for example the increasing use of
CT scans

44. Brenner & Hall; “Computed tomography - An increasing source of radiation
exposure” NEJM 357, 2277-2284 (2007)
Scott, Sanders, Mitchel & Boreham; “CT scans may reduce rather than
increase the risk of cancer” J. Amer. Phys & Surg. 13, 8-11 (2008)

45. What About in the Low Dose Region?
BEIR VII cited 1386 peer reviewed publications
French Academie des Sciences cited 306 publications
Overlap in publications cited = 68

46. My thoughts.
Epidemiology is unlikely to provide definitive
information - always “uncertainty”.
Radiobiology - mechanisms not risk.
The current system works - mortality data from
nuclear power workers - “healthy workers”
Hard to fault regulatory bodies for endorsing the
middle ground of a LNT cancer risk model
Life is dangerous - keep radiation in perspective.

47. OK - but given ionizing radiation is
probably the best studied human
carcinogen, how can we understand
its mechanism of action?
The Pacific Northwest National Laboratories
Integrated Systems Biology Approach to
Understanding Potential Effects Associated
with Exposure to Ionizing Radiation.

50. Computation and
information
management
High-throughput
technologies
Hypothesis
Analysis Experiment
Why PNNL? Established effort enables system’s biology
To understand organisms from a “systems perspective” we must integrate
experiments, analysis and modeling in a recursive manner

51. What is Systems Biology?
The quantitative study of biological networks and
pathways as integrated systems rather than as a
set of isolated parts.
Requires a long term investment in:
Expertise
biologists, chemists, physicists
instrumentation & applied technology specialists
mathematicians & computational scientists
skilled laboratory technicians
Time - infrastructure and expertise
Technologies & development
Ego suppression

52. 52
A System Is A Result Of Interacting Parts:
An “interesting” part is one
for which the
consequences of
interaction is non-trivial
The sum of the system is
greater than the sum of
the parts.
Biological systems are
defined by multiple
redundant and
interdependent signaling
networks and metabolic
pathways

53. 53
Context Cannot Be Accurately Predicted
Without Multiple Sources Of Data
Well-designed studies with
appropriate controls
Gene expression data does
not predict protein
abundance
Protein abundance data does
not predict protein function
Single time points do not
provide directionality for
correlation to functional
outcomes
Network reconstruction requires
heterogeneous data for dose and
dose rate-dependent and temporal
measurements

54. Integrated Data Management
Data Storage
Data Discovery
(finding what is stored)
Data Integration
and Analysis

55. 55
Key Event Networks connect molecular
networks to population dynamics
Edwards & Preston (2008), Tox Sci, 106(2):312-318

56. Hopefully PNNL’s systems
radiation biology program will
contribute to understanding the
long term health effects of
exposure to ionizing radiations
But even if we do - will protection
standards ever be based on
scientific evidence?

58. And you
don’t
believe the
media ??

59. Quiz: Which one is the child of
radiation exposed parent?

60. Comments and Questions?
wfmorgan@pnl.gov