How Might Basic Research on Low Dose Ionizing Radiation Influence Future Radiation

Protection ProgramsWilliam F. Morgan, Ph.D., D.Sc.

Biological Sciences DivisionPacific Northwest National Laboratory

Richland, WashingtonUSA

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 importantMy research interestsFuture directions

Mans Radiation Burden

Cosmic raysAir (radon)Building materialWaterFoodEarth

Air travelTesting falloutTV & luminous watchesNuclear power plants (20%)Radioactive wasteDiagnostic & therapeutic radiation*

*> 200 million procedures/year (USA), 2 billion worldwide

Computerized Tomography (10-30 mGy)

Hair Loss From Excessive Dose Of A CT Angiogram

CT Over-Exposure To A Young PatientFell from bed and complained of neck pain the following morningPlain 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 hourThe 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

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

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?

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

Radiation Effects Research Foundation (Hiroshima) a unique resource~ 43% survivors still aliveIn the laboratory acute exposures practical and convenient

Radiation Dose

Effe

ct

?

Chernobyl, 1986Protracted exposure (contamination)

Research InterestsUnderstanding 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.

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

.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

Rad

iatio

n R

elat

ed C

ance

r Ris

k

Radiation Protection ConsiderationsScience is only one input to risk managementWhat are the other inputs?TraditionNot scaring peoplePoliticsSocial valuesEconomic considerationsTechnological considerationsWe have a long legacy of mistrust to deal with!Plus some widely diverging opinionsHormesis - tolerance - acceptance - total denial

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).

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.

The Radiendocrinator (ca. 1930)Gold plated Radiendocrinator sold in its velvet lined pocket for $150. Beta-

gamma GM detector ~ 200 mR/hr.

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Societies Perception of Risk Differs

Epidemiology versus BiologyEpidemiology 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?

Any exposure has the potential for risk

GeneticsEnvironmentDietLifestyle

The Current Paradigm For Risk

Conventional paradigm for radiation effects

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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

Radiation-Induced Genomic InstabilityIncreased rate of genomic alterations in the

progeny of irradiated cells

Irradiation

Manifests as:chromosomal rearrangementsmicronucleianeuploidydelayed mutation

(spectrum different)gene amplificationcell killing

Non clonal - not necessarily a fixed genetic change that is passed on.

Clonally expand

IrradiateClonally expand

Metaphase analysis of clonally expanded cells

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

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 irradiatedSingle

particle

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 expressionmutationtransformationmicronucleicell killing

Why?

Bystander effects in an in vivo human skin model (3D).Belyakov et al. PNAS 102, 14203-7 (2005)

Beneficial? Eliminating damaged or initiated cellsDetrimental? Inducing damage in non-irradiated cells

Implanted LLC cells

Abscopal “Anti-Tumor” Effects In Vivo

5 x 10Gy12 x 2Gy

fractionated

Significant delay in LLC cell growth.Camphausen et al. Cancer Res. 63, 1990-1993 (2003)

76 year old male with back painThoracic and abdominal CT scans thoracic vertebral bone metastasis and hepatocellular carcinoma36Gy to the bone massregression 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

AbscopalEffects:

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

Clastogenic Factors In Plasma From:Accidentally irradiated individuals

Goh & Sumner, Radiation Res. 35, 171-181 (1968)

Therapeutically irradiated individualsHollowell & Littlefield, PSEBM. 129, 240-244 (1968)

A-bomb survivorsPant & Kamada, Hiroshima J. Med. Sci. 26, 149-154 (1977)

Chernobyl clean up workersEmerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561 (1994)

Children exposed after ChernobylEmerit et al., Mutation Res. 373, 47-54 (1997)

CF-Nelson ratsFagnet et al., Cancer Genet. Cytogenet. 12, 73-83 (1984)

Patients with chromosome fragility syndromesBloom syndrome, Fanconi anemia, XP and AT

.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

Rad

iatio

n R

elat

ed C

ance

r Ris

k

Linear Non-Threshold is a Model/Hypothesis:As such it has been used and abused!Goal: public and worker protectionAssumes: Correctly that

Tissues/organs differentially sensitiveRisk varies with

AgeSexSocio economic statusDiet and lifestyleGenetic makeup and raceDose and dose rateRadiation quality

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

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?

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 politiciansPoliticians dictate policyRegulators have to implement the policySo where is the science?Lets take for example the increasing use of CT scans

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)

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

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 modelLife is dangerous - keep radiation in perspective.

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.

Computation and information management

High-throughput technologies

Hypothesis

Analysis Experiment

Why PNNL? Established effort enables system’s biologyTo understand organisms from a “systems perspective” we must integrate

experiments, analysis and modeling in a recursive manner

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:

Expertisebiologists, chemists, physicistsinstrumentation & applied technology specialistsmathematicians & computational scientistsskilled laboratory techniciansTime - infrastructure and expertiseTechnologies & developmentEgo suppression

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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

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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

Integrated Data Management

Data Storage

Data Discovery(finding what is stored)

Data Integration and Analysis

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Key Event Networks connect molecular networks to population dynamics

Edwards & Preston (2008), Tox Sci, 106(2):312-318

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

And you  don’t  believe the  media ??

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

Comments and Questions?

wfmorgan@pnl.gov