U.S. Low Dose Radiation Research Program

Transcription

1 U.S. Low Dose Radiation Research Program NF Metting, ScD, Program Manager EFCOG Radiation Protection Subgroup March 2012 Office of Science Office of Biological and Environmental Research

2 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) 2 Low Dose Program Mar 2012

3 History the Program was initiated in 1999 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 Low Dose Program Mar 2012

4 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 4 Low Dose Program Mar 2012

5 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 5 Low Dose Program Mar 2012

6 Twelve years later 2012 New Biological Paradigms: 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 6 Low Dose Program Mar 2012

7 Twelve years later 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 7 Low Dose Program Mar 2012

8 Twelve years later 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 8 Low Dose Program Mar 2012

9 Twelve years later 2012 Program Research Results Snapshot 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 dosedistribution. 9 Low Dose Program Mar 2012

10 An Adoptive Transfer Method to Detect Low-Dose Radiation-Induced Bystander Effects In Vivo Objectives Develop a method for studying low-dose and low-dose-rate radiation-induced bystander effects in vivo in an intact nonirradiated organ of a physiologically normal animal Test whether bystander effects are the same as seen in low-dose in vitro studies 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. Donor Mouse Recipient Mouse Spleen harvested Spleen harvested Donor Cells X-rays Image donor and bystander Cells 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)

11 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 11 Low Dose Program Mar 2012

12 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) 12 Low Dose Program Mar 2012

13 Why Epidemiology? 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 ) 13 Low Dose Program Mar 2012

14 Epidemiology Low Dose 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 14 Low Dose Program Mar 2012

15 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 1 st 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? 15 Low Dose Program Mar 2012

16 In Summary: 12 th year of Program Currently funded projects: University-based Three 5-yr Program Projects in 4 th year 21 radiobiology projects in 3 rd (last) year 7 of these are joint NASA-DOE Million U.S. Worker Study National Lab SFAs: LBNL, ORNL, PNNL >730 peer-reviewed publications ( Budget considerations Communication links with the public, science to inform public debate website, Workshop, dose range charts, etc. 16 Low Dose Program Mar 2012

17 17 Low Dose Program Mar 2012

18 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. ( mgy/yr )

19 Cosmic-ray exposure calculated from the topography Elevation data were taken from the world database of 1 km digital elevation and were regridded using a 2 km grid cell. Equations published by Boltneva, Nazarov, and Fridman (1974). ( mgy/yr )

20 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 ( mgy/yr ) Open-File Report Cancer Mortality Rates by County All Cancers, etc Deaths per 100,000 person-years

21 Cosmic-ray Exposure (calculated from the topography) ( mgy/yr ) U.S. Geological Survey Open-File Report Cancer Mortality Rates by County All Cancers, etc Deaths per 100,000 person-years

22 Cancer Mortality Rates by County All Cancers Deaths per 100,000 person-years U.S. average: 207 deaths/100,000 person-years highest 10%: deaths /100,000 p-y lowest 10%: deaths/100,000 p-y

23 Protective Action Guides for RDD or IND Incidents Federal Register August 2008 PAG= Protective Action Guides

24 Protective Action Guides for RDD or IND Incidents Federal Register August 2008 August 1, 2008 Table 1 Protective Action Guides for RDD and IND Incidents Sheltering or evacuation of public a 1-5 rem ( Sv) projected dose Relocation of public 2 rem (.02 Sv) projected dose 1 st year, subsequent 0.5 rem/yr (.005 Sv/yr)