REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

Goal: To obtain a more robust estimate of health risks following radiation exposures of <100mSv using cellular, molecular and systems biological approaches Why? Most human exposures are in this dose range including medical, industrial, and environmental ones; epidemiologic estimates are uncertain How? 243 projects in 10 years – 19 in national $7.7M - 43 in universities and $9.4M - 12 jointly funded with NASA

Under Secretary’s Charge – Address: Scientific accomplishments, quality and technical innovation of the research Whether the Program is taking advantage of advances in biological research Whether growing body of knowledge from the Program justifies reconsidering risk estimates at low doses Whether additional biological issues or technical hurdles remain before addressing regulatory policy

Composition of the review sub-committee S. James Adelstein (Chair) - BERAC C. Norman Coleman - National Cancer Institute Shirley A. Fry - Formerly, Oak Ridge Associated Universities Dudley Goodhead - MRC Radiation and Genome Stability Unit John B. Little - Harvard School of Public Health Jac A. Nickoloff - University of New Mexico Julian Preston - US Environmental Protection Agency Thomas M. Roberts - Dana-Farber Cancer Institute Expertise in radiation biology & biophysics, molecular genetics, radiation oncology, epidemiology, cancer biology

Finding 1A: Program has played major role in world-wide change of direction in radiobiologic research with new emphasis on gene expression, adaptive responses, genomic instability, bystander effect, use of tissue and 3D models, employment of mutated vs. wt cell lines, as well as genetically modified animals Among results: DNA damage from IR differs from endogenous ROS Gene expression differs with hi & lo dose exposure Large no. genes responsible for variation in sensitivity 2D and 3D cell cultures differ in response to low doses ECM important in systems biologic response to IR

Finding 1B: 75% of 55 recent and current projects were rated good-to-excellent

Finding 1B: Fair-to-poor ratings were due to ● deficiencies in progress reports ● lack of peer reviewed papers

Recommendation 1: ● More explicit expectations and monitoring of progress during and at end of funded projects ● Require time-lines and milestones (mission- directed program) ● More specific format for annual and final progress reports ● Careful examination of proposals for relevance to program goals

Finding 2: PIs appear to be familiar with current technologies and approaches including ● microarrays ● proteomic profiling ● optical imaging ● DNA repair ● perturbation of signaling pathways ● single-cell mutagenesis ● epigenetic vs. genetic modifications Recommendation 2: Greater use could be made of ● gene silencing ● transgenic and knock-out animals

Finding 3: This mission-oriented program requires a roadmap that directs radiobiologic research to making risk estimates. Conceptually (for example): Phenomenologic biological observations → mechanistic (quantifiable) studies → health effects (esp. cancer) in experimental animals → risk estimates in humans (by modeling approaches and epidemiology) → regulatory adjustments

Recommendations 3: Establish a high-level advisory committee to develop a roadmap for research with list of priorities for future work ● calls for proposals would be based on the priorities ● monitoring of program progress would include milestones Encourage groups with differing expertise to work on same systems. LDRRP should cooperate with EU/Euratom low dose initiative.

Summary: 1.10 years have produced significant radio-biological findings on responses to <100mSv IR exposure % percent of recent projects were judged of high quality and productivity. 3. Greater emphasis in future should be placed on public written record. 4. Program investigators use a broad range of contemporary technologies. 5. Future focus should be on how findings impact on human health. 6. Planning for next phase of program will require a roadmap to guide investigators and monitor progress. 7. More important now than ever to understand the health implications of low dose exposures.