As a simple demonstration of the shape of the EPR spectrum and the adequacy of the spectral model, a set of spectra were collected in vivo for inserted molar teeth with doses of 0 Gy, 2 Gy, 5 Gy, and 7.5 Gy. The averaged EPR spectra and the non-linear least squares fits to the data are shown in . These spectra demonstrate a largely consistent spectral shape for the tooth signal across doses and lack of regular structure in the residuals, which support the use of the developed spectral model. Distortion of the baseline signal, which is independent of the tooth and reference samples and related to modulation of the electrical properties of the resonator during data collection, gives rise to spectral features that do not match the shape defined by the spectral model. In spectra with considerable baseline distortion, spectral fitting with a restrictive model provides an effective, but imperfect, means to distinguish between the desired EPR signals and the variable baseline. Through spectral fitting the effects of features of the baseline distortion which do not match those defined within the model are minimized, however, baseline features which do resemble those in the modeled spectrum directly effect the estimated spectral parameters.
Spectral fitting of (a) 0 Gy, (b) 2 Gy, (c) 5 Gy and (d) 7.5 Gy in vivo data. The black smooth line is a fit to the underlying experimental spectrum.
Measurements in Molar Teeth
In vivo measurements were made using non-irradiated volunteers with inserted molar teeth that were irradiated to doses up to 30 Gy in order to facilitate the development of the EPR techniques and instrumentation. When grouped by date, to account for developmental variations in the spectrometer and the resonators, consistent dose responses have been observed across subjects. In a study involving 2 subjects with unique sets of 6 molar teeth irradiated to doses between 0 Gy and 30 Gy, measurements averaged across 3 separate days provided statistically indistinguishable linear dose responses (F-test, p=0.34) with a joint slope of 0.028 AU/Gy and an intercept of 0.152 AU. The SEP values were estimated to be 1.2 Gy and 1.52 Gy based on individual calibrations, and 1.72 Gy using the jointly derived calibration.
In addition to calibration of the dose response over this wide range, experiments have been performed that focus on lower doses, in the range for which decisions regarding treatment of acute radiation syndrome are expected to focus. The measurements with lower doses summarized here were made with inserted irradiated teeth in two volunteer subjects, on three different days for each subject, using separate sets of teeth that had received absorbed doses of 0, 2, 5, 7.5 and 10 Gy. The results are summarized in () and . The results show that the in vivo dose responses measured under consistent experimental conditions, but with different subjects and different inserted teeth, give rise to consistent dose calibrations that can be applied across individuals. The dose response relationships had linear regressions that were not statistically different according to the F-test (p-value >0.6). Included in () are SEP estimates for both individual measurements of each subject and after the 3 measurements for each subject had been averaged together. Consistent with previously published results (Demidenko et al. 2007
), based on averages for both the in vitro and in vivo results, the SEP for individual measurements is approximately 1.5 Gy and the SEP for averaged measurements is reduced to near 1 Gy. Based on the SEP values for the joint calibrations, for which the greatest number of measurements are included in the analysis, errors in the estimated doses are similar for in vivo and in vitro studies, though there is presently an approximate factor of 2 decrease in the EPR signal amplitude for in vivo measurements relative to those done in vitro. The similarity in SEP estimates reflects a concomitant decrease in baseline noise when measurements are made in vivo . These results indicate that doses could be resolved with sufficient accuracy and precision to perform screening and assist during triage to separate the population into groups identified for additional interrogation or broad treatment categories.
In Vivo Molar Dose Response Parameters and SEP Values
Fig. 4 In vivo and in vitro dose response relationships for molar teeth for two volunteers subjects. Error bars denote the SD of the data at each dose. The calibration lines for the individual volunteers and the calibration for the combined data were not statistically (more ...)
Measurements in Premolar Teeth
Dose responses were measured for a common set of premolar teeth, acquired both in vitro and inserted in vivo for a single volunteer. The SEP values based on data averaged across 3 independent measurements was 0.9 Gy in vitro and 2.7 Gy in vivo. The dose response in vitro had a slope of 0.07 AU/Gy and intercept of 0.24 AU, and the in vivo measurements had slope of 0.03 AU/Gy and intercept of 0.19 AU. While the SEP value observed in vivo is larger than expected, these results are consistent with other data, demonstrating that linear dose responses are observed and a factor of ~2 difference in the slopes of the dose responses observed in vivo and in vitro. These measurements were performed with a different resonator than that used for molar teeth, so identical dose responses are not expected across these measurements. Eight additional sets of in vivo measurements with premolar teeth were made with a different volunteer and a similar dose response was observed (slope = 0.04 ± 0.01, intercept = 0.1 ± 0.2), consistent with there being a universal calibration for similarly executed measurements in premolar teeth.
Measurements in Incisor Teeth
illustrates a representative result where a 30 Gy incisor was measured using a 10 mm loop resonator and compared to the measurement of a similarly irradiated molar using the standard 12 mm loop resonator. Resonator dimensions were chosen to match the sizes of the respective teeth and optimize sensitivity. The resonators were placed over the biting surface of the molar tooth and on the lingual surface of the incisor. While the amplitude measured here from the incisor is approximately 35% lower than that of the molar, this result is a key indicator that it may be feasible to make the desired in vivo measurements in teeth other than molars, including incisors.
Fig. 5 Spectra recorded for molar and incisor teeth that had been irradiated to equal doses of 30 Gy, each with an appropriate size resonator, have comparable EPR signal amplitudes. The incisor amplitude is 70% of the amplitude for the molar. No size correction (more ...)
Measurements in Teeth Irradiated In situ
In addition to the in vivo dose response studies with volunteer subjects and inserted teeth described above, measurements have been performed using natural teeth in the mouths of volunteer patients who have received radiation therapy. Some patients have volunteered for repeated measurements, as illustrated in the three examples below. The measurements in these patients presented a special challenge because none had molar teeth suitable for measurements and therefore we had to adapt the method to measure in their canine or premolar teeth. While this problem is less likely in a normal population, there clearly is a need to be able to adapt the technique for the types of teeth that are present and satisfactory for EPR dosimetry (i.e. intact, with no or minor amounts of restorations).
In one series of measurements a resonator with a large detection loop, designed for molar teeth, was placed over neighboring premolar and canine teeth in a single patient on seven different days and the dose was calculated using the calibration curve derived for the same resonator from measurements in the normal volunteers who had irradiated single molar teeth placed in their mouths. As usual, a correction was applied to account for the size of the teeth being measured. Based on this independent calibration, the dose to the patient’s teeth was estimated to be 25±5 Gy (n=7). The dose delivered to the teeth was estimated from the radiation treatment plan to be 25.5±0.8 Gy, so even under these less than ideal developmental conditions, the absolute dose estimate provided by in vivo EPR was in agreement with the delivered dose.
Measurements were made on teeth in two patients, referred to as Patient A and Patient B, whose treatment plan and remaining dentition provided the potential for measuring different doses in the mouths of the individual subjects. These data summarize multiple measurements in different canine teeth in two patients. These result shown in and Fig. indicate that the doses as measured were consistent with the doses that were calculated by the medical physicists and that the relationship between dose and EPR signal is linear, as expected. The quantitative results for the several teeth and in the two different patients suggest that a universal calibration may exist. Based on the joint calibration, the standard error of prediction is 2.4 Gy, which may be higher than is required for the goals of screening and triage, but this is not surprising in view of the rather irregular size and shape of whole canine teeth and state of development of the measurement technique at the time.
Canine tooth doses for patients A and B based on treatment planning and EPR dosimetry. Doses are given in Gy and EPR estimates are given as the mean with SE.
An extensive set of measurements was recently performed on 2 lower canine teeth, #22 and #27, of a patient volunteer receiving radiation treatment involving fractionated irradiation of the oral cavity. The treatment was delivered in 31 fractions over a period of 43 days, with the lower canines each receiving volumetric mean doses of 1.0 Gy (SD ±0.1 Gy) per fraction. Based on modeling within the treatment planning system, the gradient in dose spanned ±12% for #22 and ±30% for #27, with the maximum doses at the bases of the teeth and the minima at the tips. This highlights the inhomogeneity of the dose within single teeth, a situation that is not expected to occur in the mass exposure scenario. The standard EPR measurement procedure was used throughout the course of radiation treatment and measurements were tolerated with no complications. EPR dosimetry measurements were performed for each tooth four times each week and analyzed to estimate the RIS and dose response. Given the large degree of heterogeneity in dose across the teeth, the dose response analysis was performed Responses for both teeth are shown in Fig‥ Based on individual analyses of each tooth, the SEP values were 2.1 Gy and 2.5 Gy.