Office of Science

Office of Biological and Environmental Research

U.S. Low Dose Radiation Research

Program

NF Metting, ScD, Program Manager

EFCOG Radiation Protection Subgroup 13-15 March 2012

U.S. Department of Energy • Office of Science • Biological and Environmental Research 2 Low Dose Program Mar 2012

DOE’s Low Dose Program:

Is unique within the U.S. government in focusing on low dose

biological research aimed at informing current and future

national radiation risk policy for the public and the workplace

• DOE focuses on worker safety from low dose x- and gamma-ray

exposures encountered in energy production and environmental

cleanup

In contrast:

• NASA focuses on astronaut safety from high energy particulate

radiation exposures encountered in space flight

• NIH, specifically through NCI, NIEHS, and NIAID, focuses research on

high dose clinically-relevant exposures (200 rads and higher)

U.S. Department of Energy • Office of Science • Biological and Environmental Research 3 Low Dose Program Mar 2012

“The lowest dose at which a statistically

significant radiation risk has been shown

is ~ 100 mSv (10 rem) of x-rays.”

Bridging Radiation Policy and Science

An international meeting of experts, held

at Airlie House Conference Center

1 – 5 December 1999

History– the Program was initiated in 1999

U.S. Department of Energy • Office of Science • Biological and Environmental Research 4 Low Dose Program Mar 2012

In 1999, research needs were identified in five interrelated areas:

• Low dose radiation vs. endogenous oxidative

damage -- the same or different?

• Understanding biological responses to radiation

and endogenous damage.

• Thresholds for low dose radiation -- fact or fiction?

• Genetic factors that affect individual susceptibility

to low dose radiation.

• Communication of research results.

The challenge: Do research at 10 rad or less

U.S. Department of Energy • Office of Science • Biological and Environmental Research 5 Low Dose Program Mar 2012

Radiation physics (energy deposition) dictates a

linear induction of initial events as a function of dose

Radiation biology shows us that the subsequent

biological response is much more complex

DNA repair

Cell apoptosis

Cell/tissue growth and replacement

Immune system surveillance

U.S. Department of Energy • Office of Science • Biological and Environmental Research 6 Low Dose Program Mar 2012

• Different processes are induced:

• By high vs. low dose,

• By high vs. low dose rates

• Highly dependent on the cell microenvironment, tissue

type, health of subject, diet, …

• Some processes are protective:

• Immune system is stimulated

• Homeostatic mechanisms, DNA repair more efficient

This raises the question of whether health

consequences at very low doses can be

extrapolated from high-dose cancer rates

New Biological Paradigms:

Twelve years later – 2012

U.S. Department of Energy • Office of Science • Biological and Environmental Research 7 Low Dose Program Mar 2012

• Research now focused on – • Cellular and molecular responses within normal tissues

• After x- or gamma- radiation exposures

• For doses at or near current workplace exposure limits

• Million U.S. Worker Study • Research to enable mechanism-based models that incorporate

both radiobiology and epidemiology –

• From cellular and molecular actions within tissues

• To the evolution of cancer as a multi-cellular disease

• In human populations

• Improved models to facilitate incorporation of new biological

paradigms into the regulatory process

Twelve years later – 2012

U.S. Department of Energy • Office of Science • Biological and Environmental Research 8 Low Dose Program Mar 2012

• Joint funding of research with NASA’s Space Radiation

Research Program • Cellular and molecular responses in normal tissues

• After high LET radiation exposures

• At fluences approximating the space environment (high single-cell

doses but low tissue doses)

• Re-analysis of Radiobiology Archive data at Northwestern

University The Woloschak laboratory hosts several radiobiology

archives containing data and tissues from radiobiology mega (mouse,

dog) studies conducted in the second half of the 20th century

• Communication links with the public, science to inform

public debate –website, Workshop, dose range charts

Twelve years later – 2012

U.S. Department of Energy • Office of Science • Biological and Environmental Research 9 Low Dose Program Mar 2012

• Biological systems can detect and respond to very low doses of radiation

• Cells not directly exposed can show a biological response to the low dose radiation exposure of neighboring cells

• Cell-cell and cell-matrix communication are critical in the total response to radiation, resulting in whole tissue responses as compared to individual cell responses

• Different molecular-level mechanisms of action result in responses to low doses of radiation vs. high doses of radiation

• Many cellular responses demonstrate non-linear responses with respect to radiation dose

• In addition to radiation-induced DNA damage, other processes are induced by radiation that participate in the prevention of the development of cancer, as a function of radiation exposure parameters including dose, dose-rate and dose-distribution.

Program Research Results – Snapshot

Twelve years later – 2012

Objectives

• Develop a method for studying low-dose

and low-dose-rate radiation-induced

bystander effects in vivo in an intact non-

irradiated organ of a physiologically

normal animal

• Test whether bystander effects are the

same as seen in low-dose in vitro studies

Results/Impact • The novel method is robust, reproducible and allows

study of variations in exposure time, dose rate,

radiation source, etc.

• First results show that neither the local area

surrounding lodged donor cells nor the spleen as a

whole showed a change in apoptosis or proliferation

• These results suggest that if bystander effects

are occurring in vivo, they may not pose as

large a concern to radiation risk estimation as

in vitro studies might predict.

(Blyth, et al., Radiation Research, 2010)

An Adoptive Transfer Method to Detect Low-Dose

Radiation-Induced Bystander Effects In Vivo

Spleen section of

recipient mouse.

Donor cell (red,

arrowed) lodged in

local field.

Proliferating cells

stained (green).

Tissue section is

counterstained

with DAPI (blue).

Scale bar = 50 µm.

Spleen

harvested

Donor Mouse

Recipient Mouse

Donor Cells

Spleen

harvested

Image donor and

bystander Cells

X-rays

U.S. Department of Energy • Office of Science • Biological and Environmental Research 11 Low Dose Program Mar 2012

Major Focus Areas

• Systems biology / tissue microenvironment

• Regard the tissue / organ / organism as the primary responder

• Allows rational study of homeostatic mechanisms

• Will resolve issues and bring about consensus

• Human inter-individual variability • Adaptive responses

• Mechanisms (protein complexes, signaling, networks, …)

• Modes of action (immune function, other homeostatic mech)

• Epigenetic regulation

• The interface between environment and the genome

• Cell differentiation / Imprinting / Tissue specificity

• Molecular and cellular hallmarks of aging

• Systems genetics – mouse

• Intersection of biology with epidemiology • The human population as the system

U.S. Department of Energy • Office of Science • Biological and Environmental Research 12 Low Dose Program Mar 2012

Why Adaptive Responses?

• The adaptive response is initiated by very low dose, and

a beneficial effect is seen most clearly in normal healthy

organisms

• This response is the strongest argument for not

extrapolating from high dose effects to low dose risk

• Therefore, we need to know the mechanism(s)

• Protection by Selective Deletion of Aberrant Cells

• Transformed cells are selectively deleted by signals from normal cells and

low dose irradiation augments the efficacy of normal cells (Bauer, 1996;

Portess et al. 2007; Redpath, 2008)

• Radiation-induced TGFb mediates surveillance of genomically unstable

cells in vitro and in vivo (Maxwell et al, 2008)

• 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 (Sykes, et al., 2010)

U.S. Department of Energy • Office of Science • Biological and Environmental Research 13 Low Dose Program Mar 2012

• Major radiation biology paradigm shifts have not yet affected regulatory principles

• Debate on whether the ‘new’ effects are positive or negative, big or small

• Therefore, there is a need to tie experimental data and modeling to epidemiology (the ultimate systems biology)

• Increased interaction with epidemiologists will be needed

• Significant effects seen in human epidemiological studies should be

focus of biological studies (age and gender)

• Need clearer understanding of the biological assumptions underlying

epidemiological analysis (dose lagging, time lagging, binning by

dose and/or cancer type …)

Why Epidemiology?

U.S. Department of Energy • Office of Science • Biological and Environmental Research 14 Low Dose Program Mar 2012

• Low Dose Epidemiology Workshop

• “…There is a pressing need, and a golden opportunity , to

obtain more information on the long-term effects of relatively

low doses, delivered over protracted periods by pooling and

updating the data for the various groups of occupationally

exposed U.S. nuclear workers…” (Hall, et al., Rad. Res., 2009)

• Million U.S. Worker Study

• “Epidemiological Study of One Million U.S. Workers and

Military Veterans Exposed to Ionizing Radiation” (Boice)

• Established cohort studies to be updated to the present

• (Some of the cohorts have not been updated for almost 30 years)

• Dosimetry to be validated

• Cohorts to be integrated into one large study for analysis

Epidemiology – Low Dose

U.S. Department of Energy • Office of Science • Biological and Environmental Research 15 Low Dose Program Mar 2012

Epidemiology – Million U.S. Worker Study • 2010—Office of Science funded Pilot Study

• DOE’s Office of Health, Safety and Security (HS) approved Dr. Boice’s

request to access data on DOE workers

• Co-managed by

• Noelle Metting, ScD, Senior Radiation Biologist (SC)

• Bonnie Richter, PhD, Senior Epidemiologist (HS)

• NCI separate funding to study Atomic Vets

• 1st Paper: No detectable increase in cancer for Rocketdyne workers

(Boice, et al., 2011)

• New application - Interagency support:

• (NCI—Atomic Vets)

• DOE-Office of Science

• DOE-Office of Health, Safety and Security

• US-NRC– interagency agreement in process

• NASA, EPA, DOD…?

U.S. Department of Energy • Office of Science • Biological and Environmental Research 16 Low Dose Program Mar 2012

• 12th year of Program

• Currently funded projects:

• University-based

• Three 5-yr Program Projects in 4th year

• 21 radiobiology projects in 3rd (last) year –

• 7 of these are joint NASA-DOE

• Million U.S. Worker Study

• National Lab SFAs: LBNL, ORNL, PNNL

• >730 peer-reviewed publications (www.lowdose.doe.gov)

• Budget considerations…

• Communication links with the public, science to inform

public debate –website, Workshop, dose range charts, etc.

In Summary:

U.S. Department of Energy • Office of Science • Biological and Environmental Research 17 Low Dose Program Mar 2012

Gamma-ray dose rates,

derived from

measurements taken

by airborne gamma-ray

spectrometry (AGRS).

Grids of 5-20 km flight

paths across U.S. and

Canada. Elements of

most importance:

potassium, thorium, and

uranium.

http://pubs.usgs.gov/of/2005/1413/

( 0.1 - 0.7 mGy/yr )

Cosmic-ray exposure

calculated from the

topography

Elevation data were

taken from the world

database of 1 km digital

elevation and were re-

gridded using a 2 km

grid cell. Equations

published by Boltneva,

Nazarov, and Fridman

(1974).

http://pubs.usgs.gov/of/2005/1413/

( 0.4 - 0.8 mGy/yr )

http://ratecalc.cancer.gov/ratecalc/index.jsp

Cancer Mortality Rates by County

All Cancers, etc.…

1970-2004

Deaths per 100,000 person-years

http://pubs.usgs.gov/of/2005/1413/

Gamma-Ray Absorbed Dose

Duval, J.S., Carson, J.M., Holman, P.B., and Darnley,

A.G., 2005, Terrestrial radioactivity and gamma-ray

exposure in the United States and Canada

U.S. Geological Survey

Open-File Report 2005-1413. ( 0.1 - 0.7 mGy/yr )

Cancer Mortality Rates by County

All Cancers, etc….

1970-2004

Deaths per 100,000 person-years

http://ratecalc.cancer.gov/ratecalc/index.jsp

http://ratecalc.cancer.gov/ratecalc/index.jsp

http://pubs.usgs.gov/of/2005/1413/

Cosmic-ray Exposure

(calculated from the topography)

U.S. Geological Survey

Open-File Report 2005-1413. ( 0.4 - 0.8 mGy/yr )

Cancer Mortality

Rates by County All Cancers

1970-2004

Deaths per 100,000

person-years

U.S. average:

207 deaths/100,000

person-years

highest 10%: 223 – 326 deaths /100,000 p-y

lowest 10%: 0 - 173 deaths/100,000 p-y

http://ratecalc.cancer.gov/ratecalc/index.jsp

Protective Action Guides for RDD or IND Incidents

Federal Register—August 2008

PAG= Protective Action Guides

1- 5 rem (.01-.05 Sv) projected dose Sheltering or evacuation

of public a

2 rem (.02 Sv) projected dose 1st year,

subsequent 0.5 rem/yr (.005 Sv/yr)

Relocation of public

August 1, 2008

Protective Action Guides for RDD or IND Incidents

Federal Register—August 2008

Table 1 – Protective Action Guides for RDD and IND Incidents