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

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

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Page 1: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM

(LDRRP)IN THE DEPARTMENT OF ENERGY

OFFICE FORBIOLOGICAL AND ENVIRONMENTAL RESEARCH

Page 2: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH
Page 3: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH
Page 4: 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 risksfollowing radiation exposures of <100mSvusing 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 years05-07 – 19 in national labs @ $7.7M - 43 in universities and AMC @ $9.4M - 12 jointly funded with NASA

Page 5: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

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 estimatesat low doses

•Whether additional biological issues or technical hurdles remain before addressing regulatorypolicy

Page 6: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

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

Page 7: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

Finding 1A:

Program has played major role in world-wide changeof 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

Page 8: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

Finding 1B:

75% of 55 recent and current projects were rated good-to-excellent

Project Scores

0

5

10

15

20

25

30

Excellent Good Fair Poor

No

. of

Inv

es

tig

ato

rs

Page 9: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

Finding 1B:

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

Publication Profile (5 yrs)

0

5

10

15

20

25

0 1to5 6to10 11to15 16to20 21to25

Number of Papers

Inv

es

tig

ato

rs

Page 10: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

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

Page 11: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

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

Page 12: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

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

Page 13: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

Recommendations 3:

Establish a high-level advisory committee todevelop a roadmap for research with list ofpriorities 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.

Page 14: REVIEW OF THE LOW DOSE RADIATION RESEARCH PROGRAM (LDRRP) IN THE DEPARTMENT OF ENERGY OFFICE FOR BIOLOGICAL AND ENVIRONMENTAL RESEARCH

Summary:

1. 10 years have produced significant radio-biological findings on responses to <100mSv IR exposure.

2. 75% 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.