EPR Dosimetry for Triage after a Major Radiation Event

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Reynold McKinney
5 years ago
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1 EPR Dosimetry for Triage after a Major Radiation Event Harold M. Swartz, M.D., Ph.D. Geisel School of Medicine at Dartmouth (perspectives include 10 yrs. experience as medical officer in USA army, involvement in radiation dosimetry/mitigation for about 50 years, for EPR biodosimetry 8 years ongoing support from NIAID CMCR program, 2 yrs. into active contract from BARDA & prior contracts from DARPA & DTRA)

2 KEY ISSUES FOR HANDLING A LARGE SCALE RADIATION EVENT MUST sort out those who are significantly exposed from those who are not in a group of up to 1,000,000 people! Triage needed for military and civilians but some significant differences Need to estimate dose at the level of the individual, i.e., need to know about each person Existing guidelines have very significant limitations for this scenario Biodosimetry will be part of the solution

3 Special aspects for defense forces Can preplan deployment, placing instruments within medical units and have prior training More likely to be able to measure sooner after the event More likely to have combined injury, requiring ability to make the measurements quickly on physically compromised subjects Could identify in advance individuals likely to be exposed and obtain background measurements, which would make it feasible to increase sensitivity for lower doses Pretreatment (radioprotectors) may be feasible Distribution of age and fitness differs from civilian population May decide to have short term continued deployment of affected individuals to advance the misssion 3

4 OVERALL GOAL OF THE DEVELOPMENTS AT DARTMOUTH To produce an effective prototype for one or more dosimetry devices that meets fully the need for effective triage after a large-scale radiation event, with operation by minimally trained personnel at the site of the incident The level of development should be sufficient to be the basis for rapid production of FDA approvable instruments by an appropriate large medical devices company (one device underway with G.E., under a contract from BARDA)

5 Our Approach Based on electron paramagnetic resonance (EPR or ESR). EPR specifically and sensitively responds to the presence of unpaired electrons. Ionizing radiation generates large numbers of unpaired electron species. While most of these react immediately and disappear, in some materials in which diffusion is limited, the unpaired electrons can persist for long periods. This phenomenon has been recognized to occur in bone, teeth, and nails for more than 50 years and has been shown to be a feasible method for retrospective dosimetry in teeth.

6 EPR dosimetry has some desirable characteristics No need to remove sample from subject No need for processing at a distant site The measurements can be made any time after the event Results are available immediately The measurements can be made in the field by personnel with no prior training Alternatively, fingernail clippings can be obtained and stored and/or processed at a distant site Capable of resolving the doses needed for effective triage Capable of providing information on homogeneity of exposure Unlike many biologically based dosimetry techniques, EPR dosimetry will not be affected by other factors such as stress, wounds, and pre-existing conditions

7 EPR dosimeters for partial body exposure (you carry your dosimeter with you at all times!) EPR can be measured in vivo in teeth and nails and/or in vitro using clipped nails or isolated teeth Finger- and toenails Finger- and toenails

8 AFTER-THE FACT DOSIMETRY BASED ON EPR MEASUREMENTS OF TEETH

9 (left) The existing deployable EPR tooth dosimeter, includes a self contained compact electronics and display unit and 60 lb. permanent magnet. (right) An integrated bite block and lip retractor is designed to provide optimal positioning and full comfort for the subject.

10 Current version of tooth dosimeter operated in field 10

11 Feasibility of In Vivo Measurements, using Existing Deployable EPR Dosimeter In vivo measurements of upper incisor teeth Uses the current version of the instrument and established methods to measure with EPR 59 total measurements in 46 people 18 measurements in 11 TBI patients (0 Gy x 2, 1.5 Gy, 2 Gy x 12, 12 Gy x 3). Resulting in vivo calibration curve with 1.25 Gy SEP For each subject, 3 5 independent sets of data were collected, data collection for each set required 60 seconds and the results from the sets were averaged to provide a single dose estimate. Illustrates the ability to make measurements in TBI patients and the current state of the art using dosimetry based on incisors measured in vivo 11

12 Current status of tooth dosimetry Excellent discrimination of triage dose with procedure that takes less than 5 minutes Advanced device development proceeding based on utilization of the upper incisors Good progress towards completing the remaining essential steps: Full automation Field testing of automated instrument Production of fully clonable instrumentation Achieving FDA approval Plan to utilize patients undergoing TBI for completion of developments, testing of automation, and obtaining data needed for approval by the FDA

13 Ex Vivo Nails aka nail clippings

14 MIS1 MIS2 MIS3 0.8 MIS base function N A MIS2 MIS1 (and RIS if irradiated) -0.4 N MIS A MIS D M MIS MIS1, MIS2 and MIS3 base spectra that are used in the base function fitting method. These smoothed curves are obtained from the average of many samples. THEY ARE THEN USED TO DECOMPOSE EXPERIMENTAL SPECTRA TO DETERMINE RIS, USING THE PROPORTIONALITY BETWEEN MIS-2 & MIS-1 AND MIS-3 & MIS-1 A

15 Original Spectrum Fitted Spectrum Fitted RIS Fitted MIS Relative Intensity Magnetic Field, [G] Representative EPR spectra from a sample with 6 Gy irradiation, immediately after cutting. The original spectrum is shown in blue, and the fitted spectrum using the new fitting model is in red. Relative Intensity Magnetic Field, [G] The Fitted MIS and RIS components from the same sample.

16 14 12 Estimated RIS Amplitude Irradiation Dose,[Gy] Dose response curve from 15 sets from individual donors. Each set received doses of 0, 1, 2, 4, 6 Gy. The error bar is the Standard Error of the Mean (SEM).

17 EPR Biodosimetry (Dose Calibration)

18 Current status of dosimetry based on clipped nails Excellent linearity of dose response observed over the desired range (0 to 10 gray) Variation among samples now understood, allowing detailed studies of effects of demographic variables and potential confounders to be studied Most likely utilization will be to process large numbers of samples at a remote site where steps to overcome the variability among samples can be utilized, especially using the dose added method and perhaps high frequency EPR Plans are to utilize nail clippings from patients undergoing TBI for further validation of the technique

19 IN VIVO MEASUREMENTS OF NAILS

20 In Vivo Measurements of Nails Eliminates problems of MIS signal introduced by clipping Technical challenge is to achieve a sufficiently localized field from the resonator so that the 9.5 GHz microwaves interact only with the keratinized fingernails and not the underlying soft tissues Configurations that would be very convenient for triage are readily envisioned

21 Measurements of nails in vivo Both Fingernail and Toenail measurements can be preformed simultaneously. The same kiosk could measure teeth All measurements could be performed without movement of the subject.

22 Photographs illustrating the position of fingers in resonators for in vivo nail dosimetry (A) the SRA resonator; (B) rectangular TE 102 cavity aperture resonator (AR); and (C) hemispherical TE 121 AR C A B

23 Current status of in vivo nail dosimetry. Both resonator geometries are in advanced stages of development. Dose-response measurements in cadaver fingers are underway Dose-dependent curve of 0, 5,10,20 & 30 Gy using the SRA has been achieved in an irradiated toenail backed by a tissue equivalent toe model An AR has been developed and is being tested with a dielectric insert for which simulations indicate a two-fold increase in sensitivity Measurements on fingernails of TBI patients are imminent

24 SUMMARY AND CONCLUSIONS - 1 In the event of an event in which large numbers of people are potentially exposed to levels of radiation that could lead to the ARS, it is essential to have a method to carry out effective and rapid triage The existing guidelines from official documents provide recommendations that are unlikely to be effective for large scale events Biodosimetry may be a important part the solution to meeting this very important gap It may be especially suitable for military 24

25 SUMMARY AND CONCLUSIONS - 2 Physical biodosimetry, specifically EPR based biodosimetry, appears to have the characteristics needed to fill the gap in triage Tooth dosimetry, using the upper incisors, is poised to be developed into a practical deployable capability In vivo nail dosimetry is likely also to provide the desired capabilities for in field dosimetry and also direct evidence on homogeneity of the exposure Dosimetry based on nail clippings is likely to be a valuable addition to the capabilities, especially to resolve inconsistencies in dose estimation

26 WHO REALLY DID THE WORK! Dartmouth EPR Center: H. Boyle, P. Calderon, J. Crist, E. Demidenko, R. Dong, M. Feldman, A. Flood, S. Geimer, B. Gimi, O. Grinberg, J. Gui, A. Gupta, X. He, H. Hou, N. Khan, K. Kobayashi, V. Krymov, M. Kmiec, P. Lesniewski, M. Mariani, T. Matthews, P. Meaney, J. Nicolalde, P. Pennington, S. Petryakov, T Raynolds, K. Rychert, A. Ruuge, Y. Sakata, I. Salikhov, W. Schreiber, D. Tipikin, T. Walczak, D. Wilcox, B. Williams Collaborators at other academic sites: B. Gallez (Belgium), G&S Eaton (USA), W. Froncisz (Poland), J. Hyde (USA), M. Krishna (USA), P. Kuppusamy (USA), J. Liu (USA), M. Sentjurc (Slovenia), S. Swarts (USA), M. Miyake and I. Yamaguchi (Japan) Commercial Collaborators: Clin-EPR, Resonance Research, Bruker, General Electric Support of research through grants and contracts: NIH, BARDA, DARPA, DTRA

27 THANK YOU FOR YOUR ATTENTION ANY QUESTIONS?

Retrospective Dosimetry Based on Long Lived Free Radicals

Retrospective Dosimetry Based on Long Lived Free Radicals Harold Swartz, M.D., Ph.D. Geisel Medical School at Dartmouth Region near Fukushima reactor site Dose distribution from fallout about May 1, 2011