Opportunities to improve the in vivo measurement of manganese in human hands.

Manganese (Mn) is an element which is both essential for regulating neurological and skeletal functions in the human body and also toxic when humans are exposed to excessive levels. Its excessive inhalation as a result of exposure through industrial and environmental emissions can cause neurological damage, which may manifest as memory deficit, loss of motor control and reduction in the refinement of certain body motions. A number of clinical studies demonstrate that biological monitoring of Mn exposure using body fluids, particularly blood, plasma/serum and urine is of very limited use and reflect only the most recent exposure and rapidly return to within normal ranges. In this context, a non-invasive neutron activation technique has been developed at the McMaster University accelerator laboratory that could provide an alternative to measure manganese stored in the bones of exposed subjects. In a first pilot study we conducted recently on non-exposed human subjects to measure the ratio of Mn to Ca in hand bones, it was determined that the technique needed further development to improve the precision of the measurements. It could be achieved by improving the minimum detection limit (MDL) of the system from 2.1 microg Mn/g Ca to the reference value of 0.6 microg g(-1) Ca (range: 0.16-0.78 microg Mn/g Ca) for the non-exposed population. However, the developed procedure might still be a suitable means of screening patients and people exposed to excessive amounts of Mn, who could develop many-fold increased levels of Mn in bones as demonstrated through various animal studies. To improve the MDL of the technique to the expected levels of Mn in a reference population, the present study investigates further optimization of irradiation conditions, which includes the optimal selection of proton beam energy, beam current and irradiation time and the effect of upgrading the 4pi detection system. The maximum local dose equivalent that could be given to the hand as a result of irradiation was constrained to be less than 150 mSv as opposed to the previously imposed dose equivalent limit of 20 mSv. A maximum beam current, which could be delivered on the lithium target to produce neutrons, was restricted to 500 microA. The length of irradiation intervals larger than 10 min, was considered inconvenient and impractical to implement with Mn measurements in humans. To fulfil the requirements for developing a protocol for in vivo bone Mn measurements, a revised estimate of the dose equivalent has been presented here. Beam energy of 1.98 MeV was determined to be optimal to complete the irradiation procedure within 10 min using 500 microA beam current. The local dose equivalent given to hand was estimated as 118 mSv, which is lower by a factor of 1.5 compared to that of 2.00 MeV. The optimized beam parameters are expected to improve the currently obtained detection limit of 2.1 microg Mn/g Ca to 0.6 microg Mn/g Ca. Using this dose equivalent delivered to the central location of the hand, the average dose equivalent to the hand of 74 mSv and an effective dose of approximately 70 microSv will be accompanying the non-invasive, in vivo measurements of bone Mn, which is little over the chest radiograph examination dose.

Neutron microdosimetric response of a gas electron multiplier.

A new high-sensitivity tissue equivalent proportional counter (TEPC) on the basis of the gas electron multiplier (GEM) detector used in high-energy physics experiments has been designed, constructed and tested in a variety of neutron fields. The GEM-TEPC makes use of a lithographically produced strip readout system to achieve the equivalent of a large number of miniature TEPC detector elements. This new device could be used as the basis of an electronic personal dosemeter for gamma and neutron mixed radiation fields.

Monte Carlo simulation of neutron irradiation facility developed for accelerator based in vivo neutron activation measurements in human hand bones.

The neutron irradiation facility developed at the McMaster University 3 MV Van de Graaff accelerator was employed to assess in vivo elemental content of aluminum and manganese in human hands. These measurements were carried out to monitor the long-term exposure of these potentially toxic trace elements through hand bone levels. The dose equivalent delivered to a patient during irradiation procedure is the limiting factor for IVNAA measurements. This article describes a method to estimate the average radiation dose equivalent delivered to the patient's hand during irradiation. The computational method described in this work augments the dose measurements carried out earlier [Arnold et al., 2002. Med. Phys. 29(11), 2718-2724]. This method employs the Monte Carlo simulation of hand irradiation facility using MCNP4B. Based on the estimated dose equivalents received by the patient hand, the proposed irradiation procedure for the IVNAA measurement of manganese in human hands [Arnold et al., 2002. Med. Phys. 29(11), 2718-2724] with normal (1 ppm) and elevated manganese content can be carried out with a reasonably low dose of 31 mSv to the hand. Sixty-three percent of the total dose equivalent is delivered by non-useful fast group (> 10 keV); the filtration of this neutron group from the beam will further decrease the dose equivalent to the patient's hand.

Techniques for radiation measurements: microdosimetry and dosimetry.

Experimental microdosimetry is concerned with the determination of radiation quality and how this can be specified in terms of the distribution of energy deposition arising from the interaction of a radiation field with a particular target site. This paper discusses various techniques that have been developed to measure radiation energy deposition over the three orders of magnitude of site-size; nanometer, micrometer and millimetre, which radiation biology suggests is required to fully account for radiation quality. Inevitably, much of the discussion will concern the use of tissue-equivalent proportional counters and variants of this device, but other technologies that have been studied, or are under development, for their potential in experimental microdosimetry are also covered. Through an examination of some of the quantities used in radiation metrology and dosimetry the natural link with microdosimetric techniques will be shown and the particular benefits of using microdosimetric methods for dosimetry illustrated.

High and low fluences of alpha-particles induce a G1 checkpoint in human diploid fibroblasts.

The effects of exposure to high and very low fluence alpha-particles on the G1 checkpoint were investigated in human diploid fibroblasts irradiated and released from density-inhibited confluent cultures by the use of the cumulative labeling index method. Transient and permanent arrests in G1 occurred in fibroblast populations exposed to mean doses as low as 1 cGy, suggesting that nontraversed bystander cells may contribute to the low dose response. In cells exposed to high fluences, the G1 checkpoint is at least as extensive as in gamma-irradiated cells. In contrast to gamma-irradiated cells, neither repair of potentially lethal damage nor a reduction in the fraction of cells transiently or permanently arrested in G1 were observed in cells held in confluence for 6 h after alpha-particle irradiation. Studies with isogenic wild-type, p53-/-, and p21Waf1-/- mouse embryo fibroblasts exposed to either gamma or alpha-particle radiation revealed a total lack of G1 arrest in either p53-/- or p21waf1-/- cells, indicating that the G1 checkpoint in wild-type cells is p53-dependent and that p21Wf1 fully mediates the role of p53 in its induction. In contrast to human cells, mouse embryo fibroblasts do not undergo a permanent G1 arrest. Except under conditions favoring potentially lethal damage repair, a comparable expression pattern of p53, p21Waf1, and other cell cycle-regulated proteins (pRb, p34cdc2, and cyclin B1) was observed in alpha-particle or gamma-irradiated human fibroblasts.

Environmental microdosimetry: microdosimetric characterisation of low-dose exposures.

A number of researchers, as well as the International Commission on Radiation Units and Measurements, have described how concepts and quantities used in microdosimetry best capture the stochastic nature of low-level exposures in terms of cell hits and the fraction of cells affected within a tissue. However, the concepts of microdosimetry are not generally intuitive to the public or indeed to health physicists. In this article, the methods of conventional internal dosimetry was applied to different forms of radioactive iodine to derive cell-hit numbers and cell fractions affected by low-level exposures, and it is shown that microdosimetric analysis is compatible with conventional dosimetry but has the advantage of underscoring the stochastic nature of ionising radiation at low dose. The microdosimetric description of low-dose exposures derived in this work could be improved with the use of Monte Carlo track structure codes and more realistic models of different tissues and their cellular structure.

Measurements of neutron energy using a recoil-proton telescope and a high-pressure ionization chamber.

Two very different techniques for measuring the energy of neutrons in the energy range 0.1-10 MeV are presented and compared. A recoil-proton spectrometer is used to determine the energy spectra of neutrons produced by the d(4)-Be and p(4)-Be reactions down to the low-energy threshold of 0.7 MeV. The same radiation fields are also measured with a recently developed method using a high-pressure ionization chamber that can be used to determine the mean energy of the neutrons in a mixed neutron-gamma radiation field provided the gamma-ray absorbed dose fraction is determined independently. An intercomparison of the two methods shows that the high-pressure ionization chamber compares well and supplements the established recoil-proton spectrometer technique. The almost isotropic response of the chamber has enabled measurements to be made of the variation of mean neutron energy with depth in water for the two radiation fields.

Miniature tissue-equivalent proportional counters for BNCT and BNCEFNT dosimetry.

A dual miniature tissue-equivalent proportional counter (TEPC) system has been developed to facilitate microdosimetry for Boron Neutron Capture Therapy (BNCT). This system has been designed specifically to allow the analysis of the single event charged particle spectrum in phantom in high intensity BNCT beams and to provide this microdosimetric information with excellent spatial resolution. Paired A-150 and 10B-loaded A-150 TEPCs with 12.3 mm3 collecting volumes have been constructed. These TEPCs allow more accurate neutron dosimetry than current techniques, offer a direct measure of the boron neutron capture dose, and provide a framework for predicting the biological effectiveness of the absorbed dose. Design aspects and characterization of these detectors are reviewed, along with an exposition of the advantages of microdosimetry using these detectors over conventional dosimetry methods. In addition, the utility of this technique for boron neutron capture enhancement of fast neutron therapy (BNCEFNT) is discussed.

Modelling DNA damage induced by different energy photons and tritium beta-particles.

PURPOSE: To model the production of single- and double-strand breaks (ssb and dsb) in DNA by ionizing radiations. To compare the predicted effectiveness of different energy photon radiations and tritium beta-particles. MATERIALS AND METHODS: Modelling is carried out by Monte Carlo and includes consideration of direct energy depositions in DNA molecules, the production of species, their diffusion and interactions with each other and DNA. Computer-generated electron tracks in liquid water are used to model energy deposition and to derive the initial positions of chemical species. Atomistic representation of the DNA in B form with a first hydration shell is used. Photon radiations in the energy range 70keV-1MeV and tritium beta-particles are considered. RESULTS: A tentative increase for dsb yield has been predicted for 70 keV photons and tritium compared with 137Cs. This increase is more pronounced for complex dsb. Double-strand breaks are much more prone compared with ssb to combine with additional strand breaks and base damage, which contributes to break complexity. At least half of DNA breaks are hydroxyl radical mediated. CONCLUSIONS: The developed model makes predictions compatible with features of available experimental data. Break complexity has to be addressed in biophysical modelling when the relative effectiveness of radiations in DNA damage is studied. Obtained data strongly argue against the dominance of direct radiation action in DNA damage in the cellular environment predicted by some theoretical studies.

Microdosimetric investigation of a fast neutron radiobiology facility utilising the d(4)-9Be reaction.

For fast neutron therapy and radiobiology beams, knowledge of the primary neutron spectrum is the most fundamental requirement for the definition of radiation quality. However, microdosimetric measurements in the form of single-event spectra not only complement the primary neutron spectrum as a statement of radiation quality but also provide a sensitive method of detecting changes in the radiation field in situations where it is no longer possible to have precise knowledge of the primary neutron spectrum, for example after collimator changes and in positions where the radiation field consists of a large scattered component. For the various collimator arrangements employed at the Gray Laboratory facility small perturbations of the radiation field are observed which can be related to a softening of the primary neutron spectrum with increasing field size of the collimator. Gamma fraction determinations are in very good agreement with measurements employing the dual chamber technique and also show small changes with collimator field size giving rise to gamma components ranging from 0.09 to 0.12, the higher values being measured for the larger field sizes. Quality changes represented by the shape of the measured event-size spectra and the derived microdosimetric parameters were greatest for off axis and phantom measurements. With increasing depth in water, yD was found to decrease from 47.3 keV micron-1 at 5 cm to 35.6 keV micron-1 at 15 cm depth, and the gamma fraction was found to increase from 0.23 to 0.40. Although there is no generally accepted and agreed method of relating microdosimetric information to biological effectiveness, the dual radiation theory in its original form (Kellerer and Rossi 1972) has been shown to be a very useful model for the assessment of the biological effectiveness of fast neutrons (Kellerer et al 1976). The microdosimetric parameter which is used in the dual radiation model is the dose mean specific energy corrected for saturation zeta* which, for a 2 micron simulated diameter, is related to the dose mean lineal energy corrected for saturation y* by zeta* = y* keV micron-1 X 0.51 X 10(-2) Gy. Values of y* determined for each of the collimator arrangements used at the Gray Laboratory show a spread of some 6% (table 1) and, as the dose fraction between lineal energies 5 and 150 keV micron-1 (the recoil proton component) do not alter by more than 3%, radiobiological experiments performed with different collimator arrangements would show no observable differences.(ABSTRACT TRUNCATED AT 400 WORDS)

Optimization of the electric field distribution in a large volume tissue-equivalent proportional counter.

Large volume tissue-equivalent proportional counters are of interest in radiation protection metrology, as the sensitivity in terms of counts per unit absorbed dose in these devices increases as the square of the counter diameter. Conventional solutions to the problem of maintaining a uniform electric field within a counter result in sensitive volume to total volume ratios which are unacceptably low when counter dimensions of the order of 15 cm diameter are considered and when overall compactness is an important design criterion. This work describes the design and optimization of an arrangement of field discs set at different potentials which enable sensitive volume to total volume ratios to approach unity. The method has been used to construct a 12.7 cm diameter right-cylindrical tissue-equivalent proportional counter in which the sensitive volume accounts for over 95% of the total device volume and the gas gain uniformity is maintained to within 3% along the entire length of the anode wire.

The measurement of absorbed dose and dose-equivalent levels for in vivo neutron activation analysis.

A dual-chamber dosimetric method together with microdosimetric measurements have been employed to characterise the mixed neutron-gamma radiation field of a d-T neutron activation facility. Central axis and patient axis air kerma levels are reported together with patient midline dose levels determined from phantom measurements. The gamma-ray fraction of the total absorbed dose determined by the dual-chamber and microdosimetric method were found to be in agreement, within the estimated uncertainty limits. The free-air measurements indicate a uniform kerma profile across the patient couch with a midpoint kerma rate of about 0.2 mGy min-1 and a gamma-ray fraction of 14%. Phantom measurements yielded a patient midline total absorbed dose rate of about half this value and a gamma-ray fraction of 27%. A mean neutron quality factor of 9.3 derived from microdosimetric measurements was assigned to the neutron absorbed dose.

The application of microdosimetry in clinical bone densitometry using a dual-photon absorptiometer.

Experimental microdosimetric methods have been used to determine absorbed dose values for a scanning dual-photon absorptiometer. Absorbed doses within the scanned field have been obtained for three different scanning speeds. For the normal speed setting used clinically, measurements have also been carried out in a water-filled phantom in order to estimate typical patient entrance, exit and midline doses. The results agree well with values obtained using thermoluminescence dosimetry and support the claims of the manufacturers with regard to upper limits placed on patient dose levels. The microdosimetric method enables changes in radiation quality to be followed and comparisons to be made with other low-energy photon fields used in medical diagnosis.

Neutron fields inside containment of a CANDU600-PHWR power plant.

Neutron fields in six locations inside containment of a CANDU600-PHWR power plant were characterized using Bonner-sphere spectrometry. Unfolded fluence spectra were used to predict and understand the behavior of a rem meter (a moderator-type dose equivalent survey instrument). The suitability of employing commonly-used sources such as 241Am-Be for calibrating the rem meter was investigated by calculational means. Results of these calculations suggest that employing a calibration field more representative of the power-plant fields would likely provide more accurate dose equivalents.

Development of a low-energy monoenergetic neutron source for applications in low-dose radiobiological and radiochemical research.

The McMaster University 3 MV KN Van de Graff accelerator facility primarily dedicated to in vivo neutron activation measurements has been used to produce moderate dose rates of monoenergetic fast neutrons of energy ranging from 150 to 600 keV with a small energy spread of about 25 keV (1sigma width of Gaussian) by bombarding thin lithium targets with 2.00-2.40 MeV protons. The calculated dose rate of the monoenergetic neutrons produced using thin lithium targets as functions of beam energy, target thickness, lab angle relative to beam direction, and the solid angle subtended by the sample with the target has also been reported.

Investigating the TEPC radiation quality factor response for low energy accelerator based clinical applications.

The use of a tissue equivalent proportional counter (TEPC) filled with propane based tissue equivalent gas simulating a 2 microm diameter tissue sphere has been investigated to estimate the radiation quality factor of the neutron fields used in in vivo neutron activation measurements at the McMaster University 3 MV Van de Graaff accelerator. The counter response to estimate the effective quality factor based on the definitions of Q(L) provided in ICRP 26 and 60 as a function of neutron energy has been examined experimentally using monoenergetic and continuous neutron spectra in the energy range of 35 to 600 keV. In agreement with other studies, the counter failed to provide a flat R(Q) response and showed a sharp drop below 200 keV neutron energy. Development of an algorithm to evaluate the quality factors using measured dose-mean lineal energy, yD, and comparison of the algorithm with other reported algorithms and analytical methods developed for the improvement in TEPC dose equivalent response has been reported.

Classical microdosimetry in radiation protection dosimetry and monitoring.

Classical microdosimetry concerns the measurement and analysis of the spectrum of radiation energy deposition events in simulated microscopic tissue-equivalent sites. Over the past three decades, classical microdosimetry has been extensively applied for the direct measurement of dosimetric quantities, such as the ambient dose equivalent, and for the spectroscopic properties of tissue-equivalent proportional counters that have led to methods of mixed-field analysis and particle identification. This paper reviews some of the special applications of classical microdosimetry such as the determination of kerma coefficients, differential dosimetry and aviation dosimetry. Also reviewed are some of the technological innovations related to the application of microdosimetry in operational health physics and in particular the development of multi-element proportional counters and detectors based on gas microstrip technology.

Application of TEPC microdosimetry to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a bimodal radiation therapy used primarily for highly malignant gliomas. Tissue-equivalent proportional counter (TEPC) microdosimetry has proven an ideal dosimetry technique for BNCT, facilitating accurate separation of the photon and neutron absorbed dose components, assessment of radiation quality and measurement of the BNC dose. A miniature dual-TEPC system has been constructed to facilitate microdosimetry measurements with excellent spatial resolution in high-flux clinical neutron capture therapy beams. A 10B-loaded TEPC allows direct measurement of the secondary charged particle spectrum resulting from the BNC reaction. A matching TEPC fabricated from brain-tissue-equivalent plastic allows evaluation of secondary charged particle spectra from photon and neutron interactions in normal brain tissue. Microdosimetric measurements performed in clinical BNCT beams using these novel miniature TEPCs are presented, and the advantages of this technique for such applications are discussed.

Intercomparison of Monte Carlo radiation transport codes to model TEPC response in low-energy neutron and gamma-ray fields.

Tissue-equivalent proportional counters (TEPC) can potentially be used as a portable and personal dosemeter in mixed neutron and gamma-ray fields, but what hinders this use is their typically large physical size. To formulate compact TEPC designs, the use of a Monte Carlo transport code is necessary to predict the performance of compact designs in these fields. To perform this modelling, three candidate codes were assessed: MCNPX 2.7.E, FLUKA 2011.2 and PHITS 2.24. In each code, benchmark simulations were performed involving the irradiation of a 5-in. TEPC with monoenergetic neutron fields and a 4-in. wall-less TEPC with monoenergetic gamma-ray fields. The frequency and dose mean lineal energies and dose distributions calculated from each code were compared with experimentally determined data. For the neutron benchmark simulations, PHITS produces data closest to the experimental values and for the gamma-ray benchmark simulations, FLUKA yields data closest to the experimentally determined quantities.

Measurements of neutron energy spectra from 7Li(p,n)7Be reaction with Bonner sphere spectrometer, Nested Neutron Spectrometer and ROSPEC.

Neutron spectrometry measurements were carried out at the McMaster Accelerator Laboratory (MAL), which is equipped with a 3-MV Van de Graaff-type accelerator. Protons were accelerated onto a thick natural lithium target inducing the (7)Li(p,n)(7)Be threshold reaction. Depending on the proton energy, slightly different poly-energetic neutron fields were produced. Neutron spectra were measured at two incident proton energies: 2.15 and 2.24 MeV, which produced poly-energetic neutrons with maximum kinetic energies of 401 and 511 keV, respectively. Measurements were performed at a distance of 1.5 m from the target in the forward direction with three different instruments: Bonner sphere spectrometer, Nested Neutron Spectrometer and ROtational proton recoil SPECtrometer.