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