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The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron activation analysis (PGNAA) following gadolinium-based contrast-enhanced MRI
Radiation Physics and Chemistry ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Radiation Physics and Chemistry journal homepage: www.elsevier.com/locate/radphyschem
The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron activation analysis (PGNAA) following gadolinium-based contrast-enhanced MRI F. Mostafaei a,n, F.E. McNeill a, D.R. Chettle a, M.D. Noseworthy b, W.V. Prestwich a a b
Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, ON, Canada Biomedical Engineering, McMaster University, Hamilton, ON, Canada
H I G H L I G H T S
The feasibility of using a 238Pu/Be based prompt in vivo neutron activation analysis (IVNAA) system for measuring Gd in bone was investigated. The observed detection limit was poor: approximately 150 ppm. We verified the poor detection limit using an alternative method in the McMaster Nuclear Reactor (MNR). We compared the performance of this prompt gamma neutron activation analysis (PGNAA) system against an XRF system. Our conclusion is that this particular system is not suited to detection of Gd in bone.
art ic l e i nf o
a b s t r a c t
Article history: Received 29 July 2014 Received in revised form 17 March 2015 Accepted 23 April 2015
The feasibility of using a 238Pu/Be-based in vivo prompt γ-ray neutron activation analysis (IVNAA) system, previously successfully used for measurements of muscle, for the detection of gadolinium (Gd) in bone was presented. Gd is extensively used in contrast agents in MR imaging. We present phantom measurement data for the measurement of Gd in the tibia. Gd has seven naturally occurring isotopes, of which two have extremely large neutron capture cross sections; 155Gd (14.8% natural abundance (NA), s¼ 60,900 barns) and 157Gd (15.65% NA, s¼ 254,000 barns). Our previous work focused on muscle but this only informs about the short term kinetics of Gd. We studied the possibility of measuring bone, as it may be a long term storage site for Gd. A human simulating bone phantom set was developed. The phantoms were doped with seven concentrations of Gd of concentrations 0.0, 25, 50, 75, 100, 120 and 150 ppm. Additional elements important for neutron activation analysis, Na, Cl and Ca, were also included to create an overall elemental composition consistent with Reference Man. The overall conclusion is that the potential application of this Pu–Be-based prompt in vivo NAA for the monitoring of the storage and retention of Gd in bone is not feasible. & 2015 Elsevier Ltd. All rights reserved.
Keywords: Neutron activation analysis In vivo Gadolinium MRI
1. Introduction Gd is commonly used as the basis of contrast agents in MRI imaging. The Gd3 þ ion interacts with the magnetic field and shortens the tissue relaxation times (T1 and T2). Parts of the body with enhanced uptake of the Gd-based agent will show shorter relaxation times. This can be used, for example, to map blood flow. An association between Gd-based contrast agents (GBCA) and nephrogenic systemic fibrosis was shown in patients with renal
n
Corresponding author. Fax: þ 1 905 522 5982. E-mail address: [email protected] (F. Mostafaei).
disease several years ago, and exposure to GBCA has been an issue in patients with advanced renal failure since that time (Grobner and Prischl, 2007; Grobner, 2006). Free Gd is very toxic and it has been hypothesized that the Gd may be detaching from the chelate (the imaging agent), especially in patients with renal disease, thus leading to health issues. There is some evidence to support this hypothesis. Traces of Gd have been found in bone-biopsy samples obtained from people under-going hip replacement surgery who had been previously administered a Gd-based agent. There is therefore some concern about the detachment of Gd from the chelate and subsequent retention of Gd in the body, even in the general patient population (Darrah et al., 2009; White et al., 2006). We have previously shown that the high thermal neutron capture
http://dx.doi.org/10.1016/j.radphyschem.2015.04.016 0969-806X/& 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
F. Mostafaei et al. / Radiation Physics and Chemistry ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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cross-sections of 155Gd and 157Gd, 60,900 and 254,000 barns respectively, permit the prompt γ neutron activation analysis (PGNAA) to be measurement of Gd in the lower leg muscle painlessly and non-invasively in humans (Gräfe et al., 2011; Gräfe et al., 2010). We showed that irradiation with a neutron beam from a 238 Pu/Be source and measurements of Gd γ- and x-rays resulted in a minimum detectable limit (MDL) of 2.3370.08 ppm in the lower leg. However, there is evidence that Gd accumulates in bone over time. If low MDLs in bone were achievable, this would permit monitoring of Gd accumulation. This study assessed the feasibility of the PGNAA method for detection of Gd in bone. Since the lower leg is placed away from the radiosensitive organs and tissues of the body, the effective radiation dose is low, 0.6 μSv, for a single leg neutron scan in comparison to the annual natural background radiation exposure level in North America which is approximately 3000 μSv (ICRP 1991).
2. Methods The source is 238Pu mixed with beryllium powder which results in neutron emission from the 9Be(α,n)12C reaction. This produces a high energy neutron spectrum which extends to a maximum of 11 MeV with an average neutron energy of approximately 4 MeV (Block et al., 1967). The system therefore pre-moderates and multiplies the neutron beam using Be filters (via the 9Be(n,2n)8Be reaction). This leads to better thermalization of the neutron beam in the body and a lower dose per unit activation to the person being measured (Franklin et al., 1990). The neutron sources are contained in a neutron shielding and collimating box (Fig. 1). The box material includes alternating sheets of steel (and polyethylene, a central steel tube (9 cm inner diameter) collimator encased in graphite, and high-Z γ-ray shielding materials such as tungsten, bismuth and lead. Iron was chosen because of the large cross section for inelastic scatter of fast neutrons by 56Fe. This creates an excited state of 847 keV, leading to a neutron energy loss of 1 MeV or more per collision (Franklin et al., 1990). Graphite encases the steel tube to reflect and collimate the neutrons along the central axis of the shielding apparatus. Polyethylene is used in the system as a moderator due to the hydrogen content and its flexibility. The efficiency of hydrogen in moderating the neutron is based on the single proton nucleus which approximately has the same mass as a neutron. The partially assembled collimator, with visible steel and graphite cylinder, and alternating steel and polyethylene plates is shown in Fig. 1. 10B has a relatively large thermal neutron absorption cross section of 3800 barns. To prevent neutron leakage at the system edges, the entire system is covered in borated resin shielding. This is topped with a vinyl cover. The box is 1 m3 in size (Gräfe et al., 2011; Gräfe et al., 2010). Gd detection system: The thermal neutron capture reactions on Gd result in the production of the compound excited state nuclei
Fig. 1. Portable
238
Table 1 Net thermal flux at various phantom positions. Positions Total net count
1 2 3 4
Net counts with cadmium wrapped BF3
1.028 105 7 320 2623 7 51 5.902 104 7 243 7517 27 2.702 104 7 164 3147 18 4.319 104 7 208 6777 26
Thermal neutrons' net counts 1001777 316 28269 7 168 26706 7 163 425137 206
156 Gd* and 158Gd*. These decay by prompt γ-ray emission to the stable 56Gd and 158Gd isotopes, respectively. The excited states of these isotopes have half-lives on the order of picoseconds, so the emission of γ-rays following neutron capture takes place almost simultaneously with the neutron capture. Therefore, irradiation and counting must take place at the same time. The most dominant Gd prompt γ-rays emitted following neutron capture and have energies of 79.5 and 181.9 keV with emission probabilities per neutron capture of 10% and 18%, respectively. These γ-rays are measured on a hyper-pure Germanium (HPGe) semiconductor detector. HPGe is employed because a detector with high-energy resolution at low energy γ-ray energies is the best option for Gd detection. The spectrum can be quite complicated, with a number of emission lines from different elements which need to be resolved. It is essential for the detector to have an adequate thickness to detect the primarily low energy γ-rays following Gd neutron capture efficiently. However, a down side to these detectors is that neutron damage can occur while the detector is subject to repeated neutron exposure. Regular annealing is required to try and maintain the detector resolution which degrades due to longterm exposure of the detector to neutrons. Even with repeated annealing, the detector resolution worsens over time. A small coaxial n-type HPGe low-energy photon detector (10% relative efficiency, model LOAX- 51700/20-S, ORTEC) was used in this system to detect the characteristic γ-rays from Gd. Measurements were performed on a ‘bare bone’ phantom with soft tissue equivalent plastic to simulate the overlying tissue in the leg in an in vivo measurement. In order to simulate the human bone, compounds of NaNO3 (1.25 g of Na), NH4Cl (1.19 g of Cl), CaCO3 (14.9 g of Ca) were included in the phantoms in order to maintain a trace element composition consistent with Reference Man (Mostafaei et al., 2013a; 2013b; ICRP 1975). These phantoms were doped with varying concentrations of Gd: seven concentrations were made using pure Gd powder as the doping agent. Phantoms were made which were equivalent to 0.0, 25, 50, 75, 100, 125 and 150 ppm (where ppm means mg Gd per g of phantom material). Phantoms were measured for 2100 s real time.
3. Results and discussion Although the system is pre-moderated and multiplied, there is
Pu/Be neutron source shielding apparatus.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
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Fig. 3. PGNAA spectra from 150 ppm Gd phantom, ((a) 72.8 keV Pb kα2, (b) 75 keV Pb kα1, (c) 84.5 keV Pb Kβ3 þ85 keV Pb Kβ1 and (d) 87.3 keV Pb Kβ2 ).
Fig. 2. Optimizing the phantom placement.
a significant fast neutron component to the neutron field at the exit to the box. Measurements were performed to determine the best position for the bone within the phantom during measurement. This was assumed to be the location with the highest thermal neutron flux. Measurements were performed using a BF3 detector both bare and cadmium wrapped; the cadmium difference technique being commonly-used to determine the relative contributions of thermal and epithermal neutrons. The neutron capture cross section for Cd at neutron energies below 0.4 eV is very large. Thicknesses of the order of 0.5 mm of Cd acts as a filter, blocking neutrons with energies below 0.4 eV (Knoll, 2000). By subtracting the Cd wrapped signal from the bare signal the thermal neutron component can be assessed. The detector was placed in four different positions and the signals from the BF3 detector were processed with digital pulse processing systems (DSPEC plus) and logged into separate spectra in a computer. The measurement positions of the BF3 detector are shown in Fig. 2. Position 1 had the highest number of thermal neutrons compared to the other positions. Data are shown in Table 1. Adding pre-moderators to the system: A series of measurements were performed to determine whether an additional pre-moderator would increase the thermal neutron flux in the bone phantoms, and thus improve the measurement of Gd. Paraffin wax is a popular neutron moderator, being relatively cheap and easy to shape. Different thicknesses (2, 4, 6, 8, 10 cm) were placed in front of the phantoms. The wax was positioned inside the shielding hole in front of the 238Pu/Be source, after the Be disc. Measurements were recorded using the BF3 detector. Table 2 has shown the net counts with and without the cadmium wrapping. 2 cm of wax was determined to be the best pre-moderator thickness. Comparison with previous Gd measurement: After this optimization, the Gd phantom with a concentration of 150 ppm (i.e. the highest concentration phantom) was examined. The spectrum is shown in Fig. 3. It can be seen that the Gd peaks at 79.5 and
181.9 keV are, at best, barely detectable. In the previous study performed by Gräfe et al., the feasibility of using this PGNAA system for measuring Gd in the lower leg muscle was determined. The MDL was found to be 2.337 0.08 ppm in the lower leg. This was an MDL obtained in a 2 kg water-based phantom. Converting this to an MDL in units of total Gd mass results in an MDL of 4.7 mg Gd. If this mass of Gd was measured in the leg phantom constructed here, it would equate to an MDL of approximately 110 ppm. Previous work therefore would suggest that a nearly observable peak should be seen, as was indeed the case. In order to examine whether higher levels of Gd can be observed, a phantom with 1500 ppm Gd concentration was measured. Fig. 4 shows a comparison of a 1500 ppm and 150 ppm signal. This figure shows that a small peak can be observed in the 1500 ppm phantom, but is hardly discernible in the 150 ppm spectrum. This spectrum does imply that the MDL of the system approaches 150 ppm. This detection limit suggests that the system is not worth pursuing as a measure of Gd in vivo, especially as, we have shown in other work that a K x-ray fluorescence (K-XRF) system has a detection limit estimate that is nearly an order of magnitude better than observed here (Mostafaei et al., 2015). In order to determine further whether this MDL estimate is valid, some measurements were performed using PGNAA at McMaster Nuclear Reactor (MNR). MNR has a thermalized neutron beam with a dedicated PGNAA system (Shaw, 1999). This is used for both academic and commercial studies, mostly for boron (B) analysis, but also for Gd, samarium (Sm) and hydrogen (H). The thermal flux at the sample position is about 6 l07 n cm 2s 1. Only small samples can, at present, be measured in the PGNAA line. Samples are irradiated in polyethylene containers which can hold up to 1 g of powder. The γ-rays are detected in an Ortec 15% efficient intrinsic n-type HPGe detector. The detector is enclosed within extensive shielding to protect it from fast neutrons and
Table 2 Net epithermal neutron’ counts. Paraffin thickness (cm)
Total net count Net counts with cadmium wrapped BF3
0 2 4 6 8 10
4858127 697 5126787 716 3931927 627 3697157 608 3251367 570 295885 7 544
27505 7166 28249 7168 21567 7147 16367 7128 12104 7110 11339 7106
Thermal neutrons' net counts 4583077 677 484429 7 696 371625 7 610 353348 7 594 313032 7 559 284546 7 533
Fig. 4. PGNAA spectra from gadolinium concentration of 1500 ppm.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
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measurement, the present system has apparent limited utility for measurements of bone.
Acknowledgments The authors would like to thank Justin Bennett, for his assistance. Funding was provided by the Natural Sciences and Engineering Research Council of Canada.
References Fig. 5. 181.9 keV calibration lines for the bone phantom.
reduce the signal from γ-rays in the shielding. Fig. 5 shows a calibration line obtained using small bone phantom materials doped with Gd in the MNR PGNAA reactor system. A set of six phantoms was measured for 200 s each. Each phantom contained varied amounts of Gd (0, 20, 30, 40, 60 and 100 ppm) plus 0.93 g of CaCO3, 0.11 g of NaNO3 and 0.045 g of NH4Cl. Each phantom was irradiated and counted for 200 s three times to demonstrate the measurement reproducibility. The MDL for the phantoms was found to be 2.9 ppm. Converting to units of mass of Gd, the MDL was found to be 2.9 mg Gd. Using these data, we can determine a further estimate for in vivo Gd measurement using the Pu–Be based system. Previous data had estimated a neutron flux of 2000 n cm 2 s 1 immediately in front of the box. The MNR PGNAA line uses a neutron flux of 6 l07 n cm 2 s 1.This would estimate that based on neutron flux alone, the MDL for the box would be √(6 l07 200)/(2100 2000) ¼ approximately 53.5 times poorer. That is, this would estimate an MDL of a factor of 600 poorer in the Pu–Be system as compared to the MNR system. This would therefore estimate an MDL of 0.16 mg total mass Gd. This is an estimate that significantly better than the estimate from the lower leg detection limit. It predicts that Gd should be observable. This MNR-based estimate does not, however, account for the expected background signal due to hydrogen capture in the lower leg. This warrants further investigation.
4. Conclusions The feasibility of using a 238Pu/Be-based in vivo prompt γ NAA system for the detection of Gd in bone has been investigated. The results suggest that this system is not feasible for bone-Gd measurement, given that the MDL of a published XRF system are an order of magnitude lower. While an excellent system for soft tissue
Block, S., Bryan, J., Prevo, C., Montan, D., 1967. Laboratory sources enhanced in 0.5 eV to 200 keV neutrons for instrument evaluation. Health Phys. 13 (9), 1025–1031. Darrah, T.H., Prutsman-Pfeiffer, J.J., Poreda, R.J., Ellen Campbell, M., Hauschka, P.V., Hannigan, R.E., 2009. Incorporation of excess gadolinium into human bone from medical contrast agents. Metallomics : Integrated Biometal Sci. 1 (6), 479–488. Franklin, D.M., Armstrong, R., Chettle, D.R., Scott, M.C., 1990. An improved in vivo neutron activation system for measuring kidney cadmium. Phys. Med. Biol. 35 (10), 1397–1408. Gräfe, J.L., McNeill, F.E., Byun, S.H., Chettle, D.R., Noseworthy, M.D., 2011. The feasibility of in vivo detection of gadolinium by prompt gamma neutron activation analysis following gadolinium-based contrast-enhanced MRI. Appl. Radiat. Isot. 69 (1), 105–111. Gräfe, J.L., McNeill, F.E., Byun, S.H., Chettle, D.R., Noseworthy, M.D., 2010. A benchmarked MCNP model of the in vivo detection of gadolinium by prompt gamma neutron activation analysis. Nucl. Instrum. Methods Phys. Res. Sect B: Beam Interact. Mater. Atoms 268 (15), 2451–2457. Grobner, T., Prischl, F.C., 2007. Gadolinium and nephrogenic systemic fibrosis. Kidney Int. 72 (3) 260–4. Grobner, T., 2006. Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol., Dial., Transplant. 21 (4), 1104–1108. ICRP, 1991. 1990 Recommendations of the International Commission on Radiological Protection. ICRP Publication 60. Ann. ICRP 21, no. (1–3). ICRP 1975 Report of the Task Group on Reference Man: A Report ICRP Publication 23 (Oxford: Pergamon). Knoll, G.F., 2000. Radiation Detection and Measurement, Third John Wiley & Sons, Inc., United States of America. Mostafaei, F., McNeill, F.E., Chettle, D.R., Prestwich, W.V., 2013a. Improvements in an in vivo neutron activation analysis (NAA) method for the measurement of fluorine in human bone. Physiol. Meas. 34 (10), 1329–1341. Mostafaei, F., McNeill, F.E., Chettle, D.R., Prestwich, W.V., Inskip, M., 2013b. Design of a phantom equivalent to measure bone-fluorine in a human’s hand via delayed neutron activation analysis. Physiol. Meas. 34 (5), 503–512. Mostafaei, F., McNeill, F.E., Chettle, D.R., Noseworthy, M.D., 2015. A feasibility study to determine the potential of in vivo detection of gadolinium by x-ray fluorescence (XRF) following gadolinium-based contrast-enhanced MRI. Physiol. Meas. 36 (1), N1–N13. Shaw, D., 1999. Prompt gamma neutron activation analysis. J. Neutron Res. 7 (3), 181–194. White, G.W., Gibby, W.A., Tweedle, M.F., 2006. Comparison of Gd (DTPA-BMA) (Omniscan) versus retention in human bone tissue by inductively coupled plasma mass spectroscopy. Investig. Radiol. 41 (3), 272–278.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
Contents lists available at ScienceDirect
Radiation Physics and Chemistry journal homepage: www.elsevier.com/locate/radphyschem
The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron activation analysis (PGNAA) following gadolinium-based contrast-enhanced MRI F. Mostafaei a,n, F.E. McNeill a, D.R. Chettle a, M.D. Noseworthy b, W.V. Prestwich a a b
Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, ON, Canada Biomedical Engineering, McMaster University, Hamilton, ON, Canada
H I G H L I G H T S
The feasibility of using a 238Pu/Be based prompt in vivo neutron activation analysis (IVNAA) system for measuring Gd in bone was investigated. The observed detection limit was poor: approximately 150 ppm. We verified the poor detection limit using an alternative method in the McMaster Nuclear Reactor (MNR). We compared the performance of this prompt gamma neutron activation analysis (PGNAA) system against an XRF system. Our conclusion is that this particular system is not suited to detection of Gd in bone.
art ic l e i nf o
a b s t r a c t
Article history: Received 29 July 2014 Received in revised form 17 March 2015 Accepted 23 April 2015
The feasibility of using a 238Pu/Be-based in vivo prompt γ-ray neutron activation analysis (IVNAA) system, previously successfully used for measurements of muscle, for the detection of gadolinium (Gd) in bone was presented. Gd is extensively used in contrast agents in MR imaging. We present phantom measurement data for the measurement of Gd in the tibia. Gd has seven naturally occurring isotopes, of which two have extremely large neutron capture cross sections; 155Gd (14.8% natural abundance (NA), s¼ 60,900 barns) and 157Gd (15.65% NA, s¼ 254,000 barns). Our previous work focused on muscle but this only informs about the short term kinetics of Gd. We studied the possibility of measuring bone, as it may be a long term storage site for Gd. A human simulating bone phantom set was developed. The phantoms were doped with seven concentrations of Gd of concentrations 0.0, 25, 50, 75, 100, 120 and 150 ppm. Additional elements important for neutron activation analysis, Na, Cl and Ca, were also included to create an overall elemental composition consistent with Reference Man. The overall conclusion is that the potential application of this Pu–Be-based prompt in vivo NAA for the monitoring of the storage and retention of Gd in bone is not feasible. & 2015 Elsevier Ltd. All rights reserved.
Keywords: Neutron activation analysis In vivo Gadolinium MRI
1. Introduction Gd is commonly used as the basis of contrast agents in MRI imaging. The Gd3 þ ion interacts with the magnetic field and shortens the tissue relaxation times (T1 and T2). Parts of the body with enhanced uptake of the Gd-based agent will show shorter relaxation times. This can be used, for example, to map blood flow. An association between Gd-based contrast agents (GBCA) and nephrogenic systemic fibrosis was shown in patients with renal
n
Corresponding author. Fax: þ 1 905 522 5982. E-mail address: [email protected] (F. Mostafaei).
disease several years ago, and exposure to GBCA has been an issue in patients with advanced renal failure since that time (Grobner and Prischl, 2007; Grobner, 2006). Free Gd is very toxic and it has been hypothesized that the Gd may be detaching from the chelate (the imaging agent), especially in patients with renal disease, thus leading to health issues. There is some evidence to support this hypothesis. Traces of Gd have been found in bone-biopsy samples obtained from people under-going hip replacement surgery who had been previously administered a Gd-based agent. There is therefore some concern about the detachment of Gd from the chelate and subsequent retention of Gd in the body, even in the general patient population (Darrah et al., 2009; White et al., 2006). We have previously shown that the high thermal neutron capture
http://dx.doi.org/10.1016/j.radphyschem.2015.04.016 0969-806X/& 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
F. Mostafaei et al. / Radiation Physics and Chemistry ∎ (∎∎∎∎) ∎∎∎–∎∎∎
2
cross-sections of 155Gd and 157Gd, 60,900 and 254,000 barns respectively, permit the prompt γ neutron activation analysis (PGNAA) to be measurement of Gd in the lower leg muscle painlessly and non-invasively in humans (Gräfe et al., 2011; Gräfe et al., 2010). We showed that irradiation with a neutron beam from a 238 Pu/Be source and measurements of Gd γ- and x-rays resulted in a minimum detectable limit (MDL) of 2.3370.08 ppm in the lower leg. However, there is evidence that Gd accumulates in bone over time. If low MDLs in bone were achievable, this would permit monitoring of Gd accumulation. This study assessed the feasibility of the PGNAA method for detection of Gd in bone. Since the lower leg is placed away from the radiosensitive organs and tissues of the body, the effective radiation dose is low, 0.6 μSv, for a single leg neutron scan in comparison to the annual natural background radiation exposure level in North America which is approximately 3000 μSv (ICRP 1991).
2. Methods The source is 238Pu mixed with beryllium powder which results in neutron emission from the 9Be(α,n)12C reaction. This produces a high energy neutron spectrum which extends to a maximum of 11 MeV with an average neutron energy of approximately 4 MeV (Block et al., 1967). The system therefore pre-moderates and multiplies the neutron beam using Be filters (via the 9Be(n,2n)8Be reaction). This leads to better thermalization of the neutron beam in the body and a lower dose per unit activation to the person being measured (Franklin et al., 1990). The neutron sources are contained in a neutron shielding and collimating box (Fig. 1). The box material includes alternating sheets of steel (and polyethylene, a central steel tube (9 cm inner diameter) collimator encased in graphite, and high-Z γ-ray shielding materials such as tungsten, bismuth and lead. Iron was chosen because of the large cross section for inelastic scatter of fast neutrons by 56Fe. This creates an excited state of 847 keV, leading to a neutron energy loss of 1 MeV or more per collision (Franklin et al., 1990). Graphite encases the steel tube to reflect and collimate the neutrons along the central axis of the shielding apparatus. Polyethylene is used in the system as a moderator due to the hydrogen content and its flexibility. The efficiency of hydrogen in moderating the neutron is based on the single proton nucleus which approximately has the same mass as a neutron. The partially assembled collimator, with visible steel and graphite cylinder, and alternating steel and polyethylene plates is shown in Fig. 1. 10B has a relatively large thermal neutron absorption cross section of 3800 barns. To prevent neutron leakage at the system edges, the entire system is covered in borated resin shielding. This is topped with a vinyl cover. The box is 1 m3 in size (Gräfe et al., 2011; Gräfe et al., 2010). Gd detection system: The thermal neutron capture reactions on Gd result in the production of the compound excited state nuclei
Fig. 1. Portable
238
Table 1 Net thermal flux at various phantom positions. Positions Total net count
1 2 3 4
Net counts with cadmium wrapped BF3
1.028 105 7 320 2623 7 51 5.902 104 7 243 7517 27 2.702 104 7 164 3147 18 4.319 104 7 208 6777 26
Thermal neutrons' net counts 1001777 316 28269 7 168 26706 7 163 425137 206
156 Gd* and 158Gd*. These decay by prompt γ-ray emission to the stable 56Gd and 158Gd isotopes, respectively. The excited states of these isotopes have half-lives on the order of picoseconds, so the emission of γ-rays following neutron capture takes place almost simultaneously with the neutron capture. Therefore, irradiation and counting must take place at the same time. The most dominant Gd prompt γ-rays emitted following neutron capture and have energies of 79.5 and 181.9 keV with emission probabilities per neutron capture of 10% and 18%, respectively. These γ-rays are measured on a hyper-pure Germanium (HPGe) semiconductor detector. HPGe is employed because a detector with high-energy resolution at low energy γ-ray energies is the best option for Gd detection. The spectrum can be quite complicated, with a number of emission lines from different elements which need to be resolved. It is essential for the detector to have an adequate thickness to detect the primarily low energy γ-rays following Gd neutron capture efficiently. However, a down side to these detectors is that neutron damage can occur while the detector is subject to repeated neutron exposure. Regular annealing is required to try and maintain the detector resolution which degrades due to longterm exposure of the detector to neutrons. Even with repeated annealing, the detector resolution worsens over time. A small coaxial n-type HPGe low-energy photon detector (10% relative efficiency, model LOAX- 51700/20-S, ORTEC) was used in this system to detect the characteristic γ-rays from Gd. Measurements were performed on a ‘bare bone’ phantom with soft tissue equivalent plastic to simulate the overlying tissue in the leg in an in vivo measurement. In order to simulate the human bone, compounds of NaNO3 (1.25 g of Na), NH4Cl (1.19 g of Cl), CaCO3 (14.9 g of Ca) were included in the phantoms in order to maintain a trace element composition consistent with Reference Man (Mostafaei et al., 2013a; 2013b; ICRP 1975). These phantoms were doped with varying concentrations of Gd: seven concentrations were made using pure Gd powder as the doping agent. Phantoms were made which were equivalent to 0.0, 25, 50, 75, 100, 125 and 150 ppm (where ppm means mg Gd per g of phantom material). Phantoms were measured for 2100 s real time.
3. Results and discussion Although the system is pre-moderated and multiplied, there is
Pu/Be neutron source shielding apparatus.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
F. Mostafaei et al. / Radiation Physics and Chemistry ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
Fig. 3. PGNAA spectra from 150 ppm Gd phantom, ((a) 72.8 keV Pb kα2, (b) 75 keV Pb kα1, (c) 84.5 keV Pb Kβ3 þ85 keV Pb Kβ1 and (d) 87.3 keV Pb Kβ2 ).
Fig. 2. Optimizing the phantom placement.
a significant fast neutron component to the neutron field at the exit to the box. Measurements were performed to determine the best position for the bone within the phantom during measurement. This was assumed to be the location with the highest thermal neutron flux. Measurements were performed using a BF3 detector both bare and cadmium wrapped; the cadmium difference technique being commonly-used to determine the relative contributions of thermal and epithermal neutrons. The neutron capture cross section for Cd at neutron energies below 0.4 eV is very large. Thicknesses of the order of 0.5 mm of Cd acts as a filter, blocking neutrons with energies below 0.4 eV (Knoll, 2000). By subtracting the Cd wrapped signal from the bare signal the thermal neutron component can be assessed. The detector was placed in four different positions and the signals from the BF3 detector were processed with digital pulse processing systems (DSPEC plus) and logged into separate spectra in a computer. The measurement positions of the BF3 detector are shown in Fig. 2. Position 1 had the highest number of thermal neutrons compared to the other positions. Data are shown in Table 1. Adding pre-moderators to the system: A series of measurements were performed to determine whether an additional pre-moderator would increase the thermal neutron flux in the bone phantoms, and thus improve the measurement of Gd. Paraffin wax is a popular neutron moderator, being relatively cheap and easy to shape. Different thicknesses (2, 4, 6, 8, 10 cm) were placed in front of the phantoms. The wax was positioned inside the shielding hole in front of the 238Pu/Be source, after the Be disc. Measurements were recorded using the BF3 detector. Table 2 has shown the net counts with and without the cadmium wrapping. 2 cm of wax was determined to be the best pre-moderator thickness. Comparison with previous Gd measurement: After this optimization, the Gd phantom with a concentration of 150 ppm (i.e. the highest concentration phantom) was examined. The spectrum is shown in Fig. 3. It can be seen that the Gd peaks at 79.5 and
181.9 keV are, at best, barely detectable. In the previous study performed by Gräfe et al., the feasibility of using this PGNAA system for measuring Gd in the lower leg muscle was determined. The MDL was found to be 2.337 0.08 ppm in the lower leg. This was an MDL obtained in a 2 kg water-based phantom. Converting this to an MDL in units of total Gd mass results in an MDL of 4.7 mg Gd. If this mass of Gd was measured in the leg phantom constructed here, it would equate to an MDL of approximately 110 ppm. Previous work therefore would suggest that a nearly observable peak should be seen, as was indeed the case. In order to examine whether higher levels of Gd can be observed, a phantom with 1500 ppm Gd concentration was measured. Fig. 4 shows a comparison of a 1500 ppm and 150 ppm signal. This figure shows that a small peak can be observed in the 1500 ppm phantom, but is hardly discernible in the 150 ppm spectrum. This spectrum does imply that the MDL of the system approaches 150 ppm. This detection limit suggests that the system is not worth pursuing as a measure of Gd in vivo, especially as, we have shown in other work that a K x-ray fluorescence (K-XRF) system has a detection limit estimate that is nearly an order of magnitude better than observed here (Mostafaei et al., 2015). In order to determine further whether this MDL estimate is valid, some measurements were performed using PGNAA at McMaster Nuclear Reactor (MNR). MNR has a thermalized neutron beam with a dedicated PGNAA system (Shaw, 1999). This is used for both academic and commercial studies, mostly for boron (B) analysis, but also for Gd, samarium (Sm) and hydrogen (H). The thermal flux at the sample position is about 6 l07 n cm 2s 1. Only small samples can, at present, be measured in the PGNAA line. Samples are irradiated in polyethylene containers which can hold up to 1 g of powder. The γ-rays are detected in an Ortec 15% efficient intrinsic n-type HPGe detector. The detector is enclosed within extensive shielding to protect it from fast neutrons and
Table 2 Net epithermal neutron’ counts. Paraffin thickness (cm)
Total net count Net counts with cadmium wrapped BF3
0 2 4 6 8 10
4858127 697 5126787 716 3931927 627 3697157 608 3251367 570 295885 7 544
27505 7166 28249 7168 21567 7147 16367 7128 12104 7110 11339 7106
Thermal neutrons' net counts 4583077 677 484429 7 696 371625 7 610 353348 7 594 313032 7 559 284546 7 533
Fig. 4. PGNAA spectra from gadolinium concentration of 1500 ppm.
Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i
F. Mostafaei et al. / Radiation Physics and Chemistry ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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measurement, the present system has apparent limited utility for measurements of bone.
Acknowledgments The authors would like to thank Justin Bennett, for his assistance. Funding was provided by the Natural Sciences and Engineering Research Council of Canada.
References Fig. 5. 181.9 keV calibration lines for the bone phantom.
reduce the signal from γ-rays in the shielding. Fig. 5 shows a calibration line obtained using small bone phantom materials doped with Gd in the MNR PGNAA reactor system. A set of six phantoms was measured for 200 s each. Each phantom contained varied amounts of Gd (0, 20, 30, 40, 60 and 100 ppm) plus 0.93 g of CaCO3, 0.11 g of NaNO3 and 0.045 g of NH4Cl. Each phantom was irradiated and counted for 200 s three times to demonstrate the measurement reproducibility. The MDL for the phantoms was found to be 2.9 ppm. Converting to units of mass of Gd, the MDL was found to be 2.9 mg Gd. Using these data, we can determine a further estimate for in vivo Gd measurement using the Pu–Be based system. Previous data had estimated a neutron flux of 2000 n cm 2 s 1 immediately in front of the box. The MNR PGNAA line uses a neutron flux of 6 l07 n cm 2 s 1.This would estimate that based on neutron flux alone, the MDL for the box would be √(6 l07 200)/(2100 2000) ¼ approximately 53.5 times poorer. That is, this would estimate an MDL of a factor of 600 poorer in the Pu–Be system as compared to the MNR system. This would therefore estimate an MDL of 0.16 mg total mass Gd. This is an estimate that significantly better than the estimate from the lower leg detection limit. It predicts that Gd should be observable. This MNR-based estimate does not, however, account for the expected background signal due to hydrogen capture in the lower leg. This warrants further investigation.
4. Conclusions The feasibility of using a 238Pu/Be-based in vivo prompt γ NAA system for the detection of Gd in bone has been investigated. The results suggest that this system is not feasible for bone-Gd measurement, given that the MDL of a published XRF system are an order of magnitude lower. While an excellent system for soft tissue
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Please cite this article as: Mostafaei, F., et al., The feasibility of in vivo quantification of bone-gadolinium in humans by prompt gamma neutron.... Radiat. Phys. Chem. (2015), http://dx.doi.org/10.1016/j.radphyschem.2015.04.016i