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We have previously reported the design of a portable 109 Cd x-ray fluorescence (XRF) system to measure iron levels in the skin of patients with either iron overload disease, such as thalassemia, or iron deficiency disease, such as anemia. In phantom studies, the system was found to have a detection limit of 1.35 μ g Fe per g of tissue for a dose of 1.1 mSv. However, the system must provide accurate as well as precise measurements of iron levels in the skin in order to be suitable for human studies. The accuracy of the system has been explored using several methods. First, the iron concentrations of ten pigskin samples were assessed using both the portable XRF system and ICP-MS, and the results were compared. Overall, it was found that XRF and ICP-MS reported average values for iron in skin that were comparable to within uncertainties. The mean difference between the two methodologies was not significant, 2.5 ± 4.6 μ g Fe per g. On this basis, the system could be considered accurate. However, ICP-MS measurements reported a wider range of values than XRF, with two individual samples having ICP-MS results that were significantly elevated (p < 0.05) compared to XRF. Synchrotron μ XRF maps of iron levels in pigskin were acquired on the BioXAS beam line of the Canadian Light Source. The μ XRF maps indicated two important features in the distribution of iron in pigskin. First, there were small areas of high iron concentration in the pigskin samples, that were predominantly located in the dermis and hypodermis at depths greater than 0.5 mm. Monte Carlo modelling using the EGS 5 code determined that if these iron 'hot spots' were located towards the back of the skin at depths greater than 0.5 mm, they would not be observed by XRF, but would be measured by ICP-MS. These results support a hypothesis that iron levels in the two samples that reported significantly elevated ICP-MS results compared to XRF may have had small blood vessels at the back of the skin. Second, the synchrotron μ XRF maps also showed a narrow (approximately 100μm thick) layer of elevated iron at the surface of the skin. Monte Carlo models determined that, as expected, the XRF system was most sensitive to these skin layers. However, the simulations found that the XRF system, when calibrated against homogenous water-based phantoms, was found to accurately measure average iron levels in the skin of normal pigs despite the greater sensitivity to the surface layer. The Monte Carlo results further indicated that with highly elevated skin surface iron levels, the XRF system would not provide a good estimate of average skin iron levels. The XRF estimate could, with correction factors, provide a good estimate of the iron levels in the surface layers of skin. There is limited data on iron distribution in skin, especially under conditions of disease. If iron levels are elevated at the skin surface by diseases including thalassemia and hemochromatosis, this XRF device may prove to be an accurate clinical tool. However, further data are required on skin iron distributions in healthy and iron overload disease before this system can be verified to provide accurate measurements., (Creative Commons Attribution license.)

This article describes the development of a system for in vivo measurements of lead body burden in mice using 109 Cd K x-ray fluorescence (XRF). This K XRF system could facilitate early-stage studies on interventions that ameliorate or reverse organ tissue damage from lead poisoning by reducing animal numbers through a cross-sectional study approach. A novel mouse phantom was developed based on a mouse atlas and 3D-printed using PLA plastic with plaster of Paris 'bone' inserts. PLA plastic was found to be a good surrogate for soft tissue in XRF measurements and the phantoms were found to be good models of mice. As expected, lead detection limits varied with mouse size, mouse orientation, and mouse position with respect to the source and detector. The work suggests that detection limits of 10 to 20 μ g Pb per g bone mineral may be possible for a 2 to 3 hour XRF measurement in a single animal, an adequate limit for some pre-clinical studies. The 109 Cd K XRF mouse measurement system was also modeled using the Monte Carlo code MCNP. The combination of experiment and modeling found that contrary to expectation, accurate measurements of lead levels in mice required calibration using mouse-specific calibration standards due to the coherent scatter peak normalization failing when small animals are measured. MCNP modeling determined that this was because the coherent scatter signal from soft tissue, which until now has been assumed negligible, becomes significant when compared to the coherent scatter signal in bone in small animals. This may have implications for some human measurements. This work suggests that 109 Cd K x-ray fluorescence measurements of lead body burden are precise enough to make the system feasible for small animals if appropriately calibrated. Further work to validate the technology's measurement accuracy and performance in vivo will be required., (Creative Commons Attribution license.)

Iron is an essential element vital for growth and development. The severe effects on the body due to iron deficiency or overload have prompted sustained research into accurate in vivo iron measurement techniques for the past several decades. X-ray fluorescence (XRF) analysis of iron in the body has been investigated in this work because of the non-invasive nature of the technique. A system has been designed using a silicon drift detector to measure the low-energy iron K α x-rays excited in the samples by the silver x-rays from 109 Cd of energy 22 keV and 25 keV. The source is contained within a tantalum shielding cap designed to reduce the spectral background. The system was calibrated against 3D printed polylactic acid (PLA) phantoms filled with solutions of iron at various concentrations. The iron x-ray signals were normalized to a nickel x-ray signal which improved the system's reproducibility. The 3D phantoms and normalisation resulted in a linear calibration line (p < 0.001 and r 2  > 0.999). For a real-time measurement of 1800 s, the minimum detectable limit for the system was measured to be 1.35 ± 0.35 ppm which is achieved with a low radiation dose of 1.1 mSv to the skin surface. This low detection limit and low dose mean the system is feasible for application to human measurements in both iron deficiency and overload disease. The system will proceed to post-mortem validation studies prior to in vivo system efficacy testing., (Creative Commons Attribution license.)

A small pilot study was conducted to test whether the technique of in vivo neutron activation analysis could measure bone aluminum levels in 15 miners who had been exposed to McIntyre Powder over 40 years prior. All miners were over 60 years of age, had worked in mines that used McIntyre Powder, and were sufficiently healthy to travel from northern to southern Ontario for the measurements. Individual aluminum levels were found to be significantly greater than zero with 95% confidence ( p  < 0.05) in 7 out of the 15 miners. The inverse variance weighted mean of the 15 participants was 21.77 ± 2.27µgAl/gCa. This was significantly higher ( p  < 0.001) than in a group of 15 non-occupationally exposed subjects of a comparable age from Southern Ontario who had been measured in a previous study. The inverse variance weighted mean bone aluminum content in the non-occupationally exposed group was 3.51 ± 0.85µgAl/gCa. Since the use of McIntyre Powder ceased in 1979, these subjects had not been exposed for more than 40 years. Calculations of potential levels at the cessation of exposure in the 1970s, using a biological half-life of aluminum in bone of 10 to 20 years predicted levels of bone aluminum comparable with studies performed in dialysis patients in the 1970s and 1980s. This pilot study has shown that the neutron activation analysis technique can determine differences in bone aluminum between McIntyre Powder exposed and non-exposed populations even though 40 years have passed since exposure ceased. The technique has potential application as a biomarker of exposure in cross-sectional studies of the health consequences of exposure to McIntyre Powder.

Biophoton emission leading to bystander effects (BEs) was shown in beta-irradiated cells; however, technical challenges precluded the analysis of the biophoton role in gamma-induced BEs. The present work was to design an experimental approach to determine if, what type, and how many biophotons could be produced in gamma-irradiated cells. Photon emission was measured in HCT116 p53 +/+ cells irradiated with a total dose of 22 mGy from a cesium-137 source at a dose rate of 45 mGy/min. A single-photon detection unit was used and shielded with lead to reduce counts from stray gammas reaching the detector. Higher quantities of photon emissions were observed when the cells in a tissue culture vessel were present and being irradiated compared to a cell-free vessel. Photon emissions were captured at either 340 nm (in the ultraviolet A [UVA] range) or 610 nm. At the same cell density, radiation exposure time, and radiation dose, HCT116 p53 +/+ cells emitted 2.5 times more UVA biophotons than 610-nm biophotons. For the first time, gamma radiation was shown to induce biophoton emissions from biological cells. As cellular emissions of UVA biophotons following beta radiation lead to BEs, the involvement of cellular emissions of the same type of UVA biophotons in gamma radiation-induced BEs is highly likely., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Today, patients undergoing dialysis are at low risk for aluminum-induced dementia. Workers are unlikely to experience cadmium-induced emphysema and the public's exposure to lead is an order of magnitude lower than in 1970. The research field of in vivo elemental analysis has played a role in these occupational and environmental health improvements by allowing the effects of people's chronic exposure to elements to be studied using non-invasive, painless, and relatively low-cost technology. From the early 1960s to the present day, researchers have developed radiation-based systems to measure the elemental content of organs at risk or storage organs. This reduces the need for (sometimes painful) biopsy and the risk of infection. Research and development has been undertaken on forty-nine in vivo measurement system designs. Twenty-nine different in vivo elemental analysis systems, measuring 22 different elements, have been successfully taken from design and testing through to human measurement. The majority of these systems employ either neutron activation analysis or x-ray fluorescence analysis as the basis of the measurement. In this review, we discuss eight of the successful systems, explaining the rationale behind their development, the methodology, the health data that has resulted from application of these tools, and provide our opinion on potential future technical developments of these systems. We close by discussing four technologies that may lead to new directions and advances in the whole field.

Objective: To report additional gadolinium bone and urine data that can contribute to gaps in knowledge with respect to gadolinium uptake and retention in the body., Approach: In vivo measurements of gadolinium retention in the tibia bone were performed on individuals self-identified as exhibiting symptoms of gadolinium toxicity as a result of receiving GBCA, as well as on control individuals. Gadolinium urine measurements for controls, symptomatic exposed, and non-symptomatic exposed were conducted through Mayo Medical Laboratories., Main Results: Gadolinium bone concentration in the exposed group is significantly higher than the control group (p < 0.01), with a significant difference between symptomatic and non-symptomatic (p < 0.01), using a one-tailed t test on variance-weighted means. Gadolinium urine levels in both control subjects and non-symptomatic exposed subjects are significantly lower than symptomatic exposed subjects (p ≤ 0.05). A linear regression analysis for gadolinium urine levels and GBCA dose resulted in a positive linear relationship (R 2 = 0.91, p < 0.01). Gadolinium levels in urine and gadolinium concentration in bone were found to have a non-significant relationship (R 2 = 0.11, p = 0.3)., Significance: Significant differences in gadolinium levels in bone and urine are observed between individuals experiencing symptoms of gadolinium toxicity and for those who are not exhibiting symptoms. No correlation was observed between gadolinium in bone and gadolinium excreted in urine, suggesting that the retention of gadolinium in the body is complicated, involving multiple long-term storage sites.

Objective: This article briefly reviews the main measurement techniques for the non-invasive detection of residual gadolinium (Gd) in those exposed to gadolinium-based contrast agents (GBCAs). Approach and Main results: The current status of in vivo Gd measurement is discussed and is put into the context of concerns within the radiology community. The main techniques are based on applied atomic/nuclear medicine utilizing the characteristic atomic and nuclear spectroscopic signature of Gd. The main emission energies are in the 40-200 keV region and require spectroscopic detectors with good energy resolution. The two main techniques, prompt gamma neutron activation analysis and x-ray fluorescence, provide adequate detection limits for in vivo measurement, whilst delivering a low effective radiation dose on the order of a few µSv., Significance: Gadolinium is being detected in measureable quantities in people with healthy renal function who have received FDA approved GBCAs. The applied atomic/nuclear medicine techniques discussed in this review will be useful in determining the significance of this retention, and will help on advising future administration protocols.

Radiation-induced biophotons are an electromagnetic form of bystander signalling. In human cells, biophoton signalling is capable of eliciting effects in non-irradiated bystander cells. However, the mechanisms by which the biophotons interact and act upon the bystander cells are not clearly understood. Mitochondrial energy production and ROS are known to be involved but the precise interactions are not known. To address this question, we have investigated the effect of biophoton emission upon the function of the complexes of oxidative phosphorylation (OXPHOS). The exposure of bystander HCT116 p53 +/+ cells to biophoton signals emitted from β-irradiated HCT116 p53 +/+ cells induced significant modifications in the activity of Complex I (NADH dehydrogenase or NADH:ubiquinone oxidoreductase) such that the activity was severely diminished compared to non-irradiated controls. The enzymatic assay showed that the efficiency of NADH oxidation to NAD+ was severely compromised. It is suspected that this impairment may be linked to the photoabsorption of biophotons in the blue wavelength range (492-455 nm). The photobiomodulation to Complex I was suspected to contribute greatly to the inefficiency of ATP synthase function since it resulted in a lower quantity of H + ions to be available for use in the process of chemiosmosis. Other reactions of the ETC were not significantly impacted. Overall, these results provide evidence for a link between biophoton emission and biomodulation of the mitochondrial ATP synthesis process. However, there are many aspects of biological modulation by radiation-induced biophotons which will require further elucidation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose To perform a preliminary evaluation of a noninvasive measurement system to assess gadolinium deposition in bone and to investigate the relationship between the administration of gadolinium-based contrast agents (GBCAs) and gadolinium retention in bone. Materials and Methods In vivo measurement of gadolinium retention in tibia bones was performed in 11 exposed subjects who previously received GBCAs (six exposed subjects were from a study performed 5 years previously involving injection of GBCAs in healthy volunteers; five exposed subjects had self-reported GBCA exposure), and 11 sex- and age-matched control subjects without a history of GBCA exposure. Each subject underwent one measurement of gadolinium retention in the tibia with x-ray fluorescence in a laboratory at McMaster University. A one-tailed t test was performed to compare gadolinium concentration in the exposed group with that in the control group. The relationship between the dose of GBCA administered and the gadolinium concentration measured in bone was analyzed with linear regression. Results Gadolinium concentration in bone was significantly higher in exposed subjects (mean, 1.19 μg Gd/g bone mineral ± 0.73 [standard deviation]) than in control subjects (mean, -1.06 μg Gd/g bone mineral ± 0.71) (P = .01). There was also a positive correlation between the dose of GBCA administered and the gadolinium concentration measured in bone (R 2 = 0.41); gadolinium concentration in bone increased by 0.39 μg Gd/g bone mineral ± 0.14 per 1 mL of GBCA administered. Gadolinium was detected in bone up to 5 years after one GBCA administration. Conclusion This x-ray fluorescence system is capable of measuring gadolinium deposition in bone noninvasively in vivo. Gadolinium can be retained in bone after one dose of GBCA in healthy subjects. © RSNA, 2017 Online supplemental material is available for this article.

Objective and Approach: A study, conducted in Toronto, Canada, between 2009 and 2011, measured the bone lead concentrations of volunteers aged 1-82 years using in vivo x-ray fluorescence (XRF) technology., Main Results: Bone lead levels were lower compared to Ontario in vivo XRF studies from the early 1990s. In adults, the slope of tibia lead content versus age was reduced by 36-56%, i.e. bone lead levels for a given age group were approximately half compared to the same age group 17 years prior. Further, bone lead levels of individuals fell over that time period. In 2010, an average person aged 57 years had a bone lead level approximately 1/3 less than their bone lead level age 40 years in 1993. Using this data, the half-lives of lead in the tibia were estimated as 7-26 years. Tibia lead levels were found to be low in children. The reduction in bone tibia content in children was not significant (p  =  0.07), but using data from additional north eastern US studies, there is evidence that childhood tibia stores are lower than in the 1990s., Significance: In vivo XRF analysis shows that there has been a reduction in the level of lead in bone in Canada over the last two decades. Public health measures have been very successful in reducing ongoing exposure to lead and in reducing bone lead stores.

Objective: Recent evidence of gadolinium (Gd) deposition in bones of healthy individuals who have previously received Gd-based contrast agents (GBCAs) for MRI has led to a demand for in vivo measurement techniques. The technique of x-ray fluorescence provides a low risk and painless method to assess Gd deposition in bone, and has the potential to be a useful clinical tool. However, interpatient variability creates a challenge while performing in vivo measurements., Approach: We explored the use of coherent normalization, which involves normalizing the Gd K x-rays to the coherent scattered γ-ray from the excitation source, for bone Gd measurements through a series of phantom-based experiments and Monte Carlo simulations., Main Results: We found coherent normalization is able to correct for variation in overlying tissue thickness over a wide range (0-12.2 mm). The Gd signal to coherent signal ratio is independent of tissue thickness for both experiments and Monte Carlo simulations., Significance: Coherent normalization has been demonstrated to be used in practice with normal healthy adults to improve in vivo bone Gd measurements.

The Figure-Of-Merit (FOM) performance, a combination of detection limit and dose, is compared between two generations of handheld X-Ray Fluorescence (XRF) spectrometers for the feasibility of in vivo XRF measurement of arsenic (As) in skin. The Olympus InnovX Delta model analyzer (40 kVp using either 37 or 17μA) was found to show improvements in Minimum Detection Limit (MDL) using arsenic As-doped skin calibration phantoms with bulk tissue backing, when compared to the first generation InnovX Alpha model (40kVp, 20μA) in 120s measurements. Differences between two different definitions of MDL are discussed. On the Delta system, an MDL of (0.462±0.002) μg/g As was found in phantoms, with a nylon backing behind to mimic bulk tissue behind skin. The equivalent and effective doses were found to be (10±2) mSv and ~7×10 -3 μSv respectively for the Alpha and (15±4) mSv and ~8×10 -3 μSv respectively for the Delta system in 120s exposures. Combining MDL and effective dose, a lower (better) FOM was found for the Delta, (1.7±0.4) ppm mSv 1/2 , compared to (4.4±0.5) ppm mSv 1/2 for the Alpha model system. The Delta analyzer demonstrates improved overall system performance for a rapid 2-min measurement in As skin phantoms, such that it can be considered for use in populations exposed to arsenic., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: The objective of our study was to explore a possible molecular mechanism by which ultraviolet (UV) biophotons could elicit bystander responses in reporter cells and resolve the problem of seemingly mutually exclusive mechanisms of a physical UV signal & a soluble factor-mediated bystander signal., Methods: The human colon carcinoma cell line, HCT116 p53 +/+, was directly irradiated with 0.5 Gy tritium beta particles to induce ultraviolet biophoton emission. Bystander cells were not directly irradiated but were exposed to the emitted UV biophotons. Medium was subsequently harvested from UV-exposed bystander cells. The exosomes extracted from this medium were incubated with reporter cell populations. These reporter cells were then assayed for clonogenic survival and mitochondrial membrane potential with and without prior treatment of the exosomes with RNase., Results: Clonogenic cell survival was significantly reduced in reporter cells incubated with exosomes extracted from cells exposed to secondarily-emitted UV. These exosomes also induced significant mitochondrial membrane depolarization in receiving reporter cells. Conversely, exosomes extracted from non-UV-exposed cells did not produce bystander effects in reporter cells. The treatment of exosomes with RNase prior to their incubation with reporter cells effectively abolished bystander effects in reporter cells and this suggests a role for RNA in mediating the bystander response elicited by UV biophotons and their produced exosomes., Conclusion: This study supports a role for exosomes released from UV biophoton-exposed bystander cells in eliciting bystander responses and also indicates a reconciliation between the UV-mediated bystander effect and the bystander effect which has been suggested in the literature to be mediated by soluble factors.

Objective: To study the age and sex influence on bone and blood lead concentrations in a cohort of the general population living in Toronto., Approach: A 109 Cd K x-ray fluorescence (KXRF) measurement system was used from 2009 to 2011 in a study that measured the bone lead (Pb) concentration of 263 environmentally exposed individuals residing in Toronto, Ontario, Canada. Tibia (cortical bone) and calcaneus (trabecular bone) lead contents were measured in 134 males and 129 females between 1 and 82 years of age. Whole blood Pb concentration was measured by TIMS (thermal ionization mass spectrometer). Tibia (Ti) and calcaneus (Cal) Pb were examined versus the age of participants, taking into account uncertainties in bone Pb measurement values., Main Results: No significant sex differences were observed in any of the age categories. Participants older than 50 years of age demonstrated the highest concentrations of Pb in their blood, tibia, and calcaneus bones., Significance: In most of the previous publications, uncertainty was not considered in the regression model of bone Pb and age. However, in this paper, we adjusted the bone Pb values for the uncertainty level. This had a significant influence in regression models of bone Pb and thus we recommend that uncertainty be considered in future studies.

The safety of using Gd in MRI contrast agents has recently been questioned, due to recent evidence of the retention of Gd in individuals with healthy renal function. Bone has proven to be a storage site for Gd, as unusually high concentrations have been measured in femoral heads of patients undergoing hip replacement surgery, as well as in autopsy samples. All previous measurements of Gd in bone have been invasive and required the bone to be removed from the body. X-ray fluorescence (XRF) offers a non-invasive and non-destructive method for carrying out in vivo measurements of Gd in humans. An updated XRF system provides improved detection limits in a short measurement time of 30-min. A new four-detector system and higher activity Cd-109 excitation source of 5GBq results in minimum detection limits (MDLs) of 1.64-1.72μgGd/g plaster for an average overlaying tissue thickness of the tibia. These levels are well within the range of previous in vitro Gd measurements. Additional validation through comparison with ICP-MS measurements has confirmed the ability of the XRF system for detecting Gd further, proving it is a feasible system to carry out human measurements., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In this study, we investigated the potential influence of p53 on ultraviolet (UV) signal generation and response of bystander cells to the UV signals generated by beta-irradiated cells. Five cell lines of various p53 status (HaCaT, mutated; SW48, wild-type; HT29, mutated; HCT116 +/+ , wild-type; HCT116 -/- , null) were irradiated with beta particles from tritium. Signal generation (photon emission at 340 ± 5 nm) was quantified from irradiated cells using a photomultiplier tube. Bystander response (clonogenic survival) was assessed by placing reporter cell flasks directly superior to irradiated signal-emitting cells. All cell lines emitted significant quantities of UV after tritium exposure. The magnitudes of HaCaT and HT29 photon emission at 340 nm were similar to each other while they were significantly different from the stronger signals emitted from SW48, HCT116 +/+ and HCT116 -/- cells. In regard to the bystander responses, HaCaT, HCT116 +/+ and SW48 cells demonstrated significant reductions in survival as a result of exposure to emission signals. HCT116 -/- and HT29 cells did not exhibit any changes in survival and thus were considered to be lacking the mechanisms or functions required to elicit a response. The survival response was found not to correlate with the observed signal strength for all experimental permutations; this may be attributed to varying emission spectra from cell line to cell line or differences in response sensitivity. Overall, these results suggest that the UV-mediated bystander response is influenced by the p53 status of the cell line. Wild-type p53 cells (HCT116 +/+ and SW48) demonstrated significant responses to UV signals whereas the p53-null cell line (HCT116 -/- ) lacked any response. The two mutated p53 cell lines exhibited contrasting responses, which may be explained by unique modulation of functions by different point mutations. The reduced response (cell death) exhibited by p53-mutated cells compared to p53 wild-type cells suggests a possible role of the assessed p53 mutations in radiation-induced cancer susceptibility and reduced efficacy of radiation-directed therapy.

The practice of investigating pathological abnormalities in the breasts of females who are asymptomatic is primarily employed using X-ray mammography. The importance of breast screening is reflected in the mortality-based benefits observed among females who are found to possess invasive breast carcinoma prior to the manifestation of clinical symptoms. It is estimated that population-based screening constitutes a 17% reduction in the breast cancer mortality rate among females affected by invasive breast carcinoma. In spite of the significant utility that screening confers in those affected by invasive cancer, limitations associated with screening manifest as potential harms affecting individuals who are free of invasive disease. Disease-free and benign tumour-bearing individuals who are subjected to diagnostic work-up following a screening examination constitute a population of cases referred to as false positives (FPs). This article discusses factors contributing to the FP rate in mammography and extends the discussion to an assessment of the consequences associated with FP reporting. We conclude that the mammography FP rate in North America is in excess based upon the observation of overtreatment of in situ lesions and the disproportionate distribution of detriment and benefit among the population of individuals recalled for diagnostic work-up subsequent to screening. To address the excessive incidence of FPs in mammography, we investigate solutions that may be employed to remediate the current status of the FP rate. Subsequently, it can be suggested that improvements in the breast-screening protocol, medical litigation risk, image interpretation software and the implementation of image acquisition modalities that overcome superimposition effects are promising solutions.

Gadolinium (Gd) based contrast agents have been commonly used over the past three decades to improve contrast in magnetic resonance imaging. These complexes, originally thought to be stable and clear from the body shortly after administration, have been shown to dissociate to a small extent and deposit in organs such as bone. A safe and non-invasive method for measuring Gd in bone is necessary for further exploring Gd retention in the body following the administration of a contrast agent. A feasibility study using a K x-ray fluorescence (K-XRF) system to measure Gd in human tibias was investigated. Bone phantoms mimicking human tibia were created with Gd concentrations ranging from 0 to 120ppm. The minimum detection limit (MDL) was calculated from 20-hour and 7-hour phantom measurements with a source activity of 0.11GBq. All MDL values were scaled to a more realistic measurement time of 30-minutes with a stronger source. Scaling arguments were based on activity ratio, measurement time, and system dead time. The MDL for a 1GBq source was estimated to be 3.60-3.64ppm, for an average range of tissue thicknesses overlaying a human tibia. For a stronger source of 5GBq and a four detector cloverleaf system, the MDL was estimated to be 1.49-1.52ppm. Determined and predicted MDLs are within the range of previous in-vitro Gd measurement data. The K-XRF system shows promising results for detecting Gd in bone and should be seriously considered for in-vivo measurements., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In recent years, in vivo measurement systems of arsenic in skin by K-shell x-ray fluorescence (XRF) have been developed, including one which was applied in a pilot study of human subjects. Improved tube-based approaches suggest the method can be further exploited for in vivo studies. Recently, it has been suggested that selenium deficiency is correlated with arsenic toxicity. A non-invasive measurement of both elements could therefore be of potential interest. The main aim of this current study was to evaluate and compare the performance of an upgraded portable XRF system and an advanced version of the benchtop XRF system for both selenium and arsenic. This evaluation was performed in terms of arsenic and selenium Kα detection limits for a 4W gold anode Olympus InnovX Delta portable analyzer (40 kVp) in polyester resin skin-mimicking phantoms. Unlike the polychromatic source earlier reported in the literature, the benchtop tube-based technique involves monochromatic excitation (25 W silver anode, manufactured by x-ray optics, XOS) and a higher throughput detector type. Use of a single exciting energy allows for a lower in vivo dose delivered and superior signal-noise ratio. For the portable XRF method, arsenic and selenium minimum detection limits (MDLs) of 0.59  ±  0.03 ppm and 0.75  ±  0.02 ppm respectively were found for 1 min measurement times. The MDLs for arsenic and selenium using the benchtop system were found to be 0.35  ±  0.01 ppm and 0.670  ±  0.004 ppm respectively for 30 min measurement times. In terms of a figure of merit (FOM), allowing for dose as well as MDL, the benchtop system was found to be superior for arsenic and the two systems were equivalent, within error, for selenium. We shall discuss the performance and possible improvements of each system, their ease of use and potential for field application.

The Canadian population is currently subject to low, chronic lead exposure and an understanding of its effects is of great significance to the population's health. Such low exposure is difficult to measure directly; approximation by physiologically based modeling may provide a preferable approach to population analysis. The O'Flaherty model of lead kinetics is based on an age-dependent approach to human growth and development and devotes special attention to bone turnover rates. Because lead is a bone-seeking element, the model was deemed ideal for such an analysis. Sample from 263 individuals of various ages from the Greater Toronto Area were selected to evaluate the applicability of the current version of the O'Flaherty model to populations with low lead exposure. For each individual, the input value of lead exposure was calibrated to match the output value of cortical bone lead to the individual's measured tibia lead concentration; the outputs for trabecular bone, blood, and plasma lead concentrations obtained from these calibrations were then compared with the subjects' measured calcaneus, blood, and serum lead concentrations, respectively. This indicated a need for revision of the model parameters; those for lead binding in blood and lead clearance from blood to bone were adjusted and new outputs were obtained in the same fashion as before. Model predictions of trabecular lead concentration did not agree with measurements in the calcaneus. The outputs for blood and plasma lead concentrations were highly scattered and, on an individual level, inconsistent with corresponding measurements; however, the general trends of the outputs matched those of the measurements reasonably well, which indicates that the revised blood lead binding and lead clearance parameters may be useful in future studies. Overall, the analysis showed that with the revisions to the model discussed here, the model should be a useful tool in the analysis of human lead kinetics and body burden in populations characterized by low, chronic exposure to lead from the general environment.

The luminescence intensity of 340±5 nm photons emitted from HaCaT (human keratinocyte) cells was investigated using a single-photon-counting system during cellular exposure to (90)Y β-particles. Multiple factors were assessed to determine their influence upon the quantity and pattern of photon emission from β-irradiated cells. Exposure of 1 x 10(4) cells/5 mL to 703 μCi resulted in maximum UVA photoemission at 44.8 x 10(3)±2.5 x 10(3) counts per second (cps) from live HaCaT cells (background: 1-5 cps); a 16-fold increase above cell-free controls. Significant biophoton emission was achieved only upon stimulation and was also dependent upon presence of cells. UVA luminescence was measured for (90)Y activities 14 to 703 μCi where a positive relationship between photoemission and (90)Y activity was observed. Irradiation of live HaCaT cells plated at various densities produced a distinct pattern of emission whereby luminescence increased up to a maximum at 1 x 10(4) cells/5 mL and thereafter decreased. However, this result was not observed in the dead cell population. Both live and dead HaCaT cells were irradiated and were found to demonstrate different rates of photon emission at low β activities (⩽400 μCi). Dead cells exhibited greater photon emission rates than live cells which may be attributable to metabolic processes taking place to modulate the photoemissive effect. The results indicate that photon emission from HaCaT cells is perturbed by external stimulation, is dependent upon the activity of radiation delivered, the density of irradiated cells, and cell viability. It is postulated that biophoton emission may be modulated by a biological or metabolic process.

Routine tissue sample preparation using chemical fixatives is known to preserve the morphology of the tissue being studied. A competitive method, cryofixation followed by freeze drying, involves no chemical agents and maintains the biological function of the tissue. The possible effects of both sample preparation techniques in terms of the distribution of bio-metals (calcium (Ca), copper (Cu) zinc (Zn), and iron (Fe) specifically) in human skin tissue samples was investigated. Micro synchrotron radiation x-ray fluorescence (μSRXRF) was used to map bio-metal distribution in epidermal and dermal layers of human skin samples from various locations of the body that have been prepared using both techniques. For Ca, Cu and Zn, there were statistically significant differences between the epidermis and dermis using the freeze drying technique (p = 0.02, p < 0.01, and p < 0.01, respectively). Also using the formalin fixed, paraffin embedded technique the levels of Ca, Cu and Zn, were significantly different between the epidermis and dermis layers (p = 0.03, p < 0.01, and p < 0.01, respectively). However, the difference in levels of Fe between the epidermis and dermis was unclear and further analysis was required. The epidermis was further divided into two sub-layers, one mainly composed of the stratum corneum and the other deeper layer, the stratum basale. It was found that the difference between the distribution of Fe in the two epidermal layers using the freeze drying technique resulted in a statistically significant difference (p = 0.012). This same region also showed a difference in Fe using the formalin fixed, paraffin embedded technique (p < 0.01). The formalin fixed, paraffin embedded technique also showed a difference between the deeper epidermal layer and the dermis (p < 0.01). It can be concluded that studies involving Ca, Cu and Zn might show similar results using both sample preparation techniques, however studies involving Fe would need more special attention.

Previous research has shown that beta radiation can induce ultraviolet (UV) photon emission in human keratinocyte cells. Spectral analysis using a filter-based method in the ultraviolet range demonstrated that the strongest externally measureable photon emission was induced by beta radiation in the UVA range. In the current study, the potential biological implications of this UV photon emission from beta-irradiated cells were investigated. HaCaT human keratinocyte cells were irradiated with tritium ((3)H) and the photon emission induced was concurrently measured at the strongest externally measurable wavelength, 340 ± 5 nm, using a combination filter-photomultiplier tube system. Unirradiated reporter HaCaT cell cultures were also placed directly above (3)H-irradiated cells so that they would receive the induced secondary photons emitted from beta-irradiated cells, and the clonogenic survival in reporter cells was then assessed. Maximum photon emission (1207.04 ± 107.65 counts per second) was observed during irradiation of 2,000 cells/cm(2) with (3)H and the maximum reporter cell death (23.2 ± 0.9% reduction in survival) was observed under the same conditions. The measured photon emission from beta-irradiated cells and reporter cell death were strongly correlated (r = 0.977, P < 0.01). Placement of a polyethylene terephthalate filter, designed to eliminate >90% of UV wavelengths below 390 nm, between the directly irradiated and reporter cell layers was effective in nearly abolishing both 340 nm photon detection and reporter cell death in treated groups. Concurrent treatment of reporter cells with lomefloxacin during exposure to the secondary photons resulted in significantly increased cell killing, indicating a potential synergistic effect, while melanin treatment resulted in decreased reporter cell killing regardless of irradiation. These results suggest that secondary photons in the UV spectral range induced by beta irradiation play a role in inducing a response in neighboring non-beta-irradiated reporter cells.

Non-invasive in vivo neutron activation analysis (NAA) was used to measure the fluorine concentration in 35 people in Hamilton, Ontario, Canada. Measurement and precision data of this second generation NAA system were determined in 2013, and the results were compared with the performance of a first generation system used in a pilot study of 33 participants from the Hamilton area in 2008. Improvements in precision in line with those predicted by phantom studies were observed, but the use of fewer technicians during measurement seemed adversely to affect performance. We compared the levels of fluorine observed in people between the two studies and found them to be comparable. The average fluorine concentration in bone was found to be 3  ±  0.3 mg and 3.5  ±  0.4 mg F/g Ca for 2013 and 2008 measurements respectively. Ten people were measured in both studies; the observed average change in bone fluorine in this subgroup was consistent with that predicted by the observation of the relationship between bone fluorine and age in the wider group. In addition, we observed differences in the relationship between bone fluorine level and age between men and women, which may be attributable either to sex or gender differences. The rate of increase in fluorine content for men was found to be 0.096  ±  0.022 mg F/g Ca per year while the rate of increase for women was found to be slightly less than half that of men, 0.041  ±  0.017 mg F/g Ca per year. A discontinuity in the rate of increase in fluorine content with age was observed in women at around age 50. Bone fluorine content was significantly lower ([Formula: see text]) in women age 50 to 59 than in women age 40 to 49, which we suggest may be attributable to bone metabolism changes associated with menopause. We also observed increased fluorine levels in tea drinkers as compared to non-tea drinkers, suggesting tea may be a significant source of exposure in Canada. The rate of increase in fluorine content of the tea drinkers and the non-tea drinkers were found to be 0.127 (± 0.029) and 0.050 (± 0.009) mg F/g Ca per year respectively. Finally, we also obtained twelve bone samples from cadavers' skulls. Neutron activation analysis was used to determine the fluorine levels in these ex vivo samples. The rate of increase of fluorine content versus age for in vivo and ex vivo measurements were found to be 0.078  ±  0.014 and 0.078  ±  0.050 mg F/g Ca per year respectively. Excellent agreement was found between the fluorine levels determined in vivo and ex vivo using the two separate systems, providing confidence in the fluorine concentration data being measured in vivo.

The feasibility of using a (109)Cd γ-ray induced K x-ray fluorescence (K-XRF) system for the in vivo detection of gadolinium (Gd) in bone has been investigated. The K-XRF bone measurement system employs an array of four detectors, and is normally used for the non-invasive study of bone lead levels. The system was used to measure bone simulating phantoms doped with varying levels of gadolinium and fixed amounts of sodium (Na), chlorine (Cl) and calcium (Ca). The detection limits for bare bone phantoms, using a source of activity 0.17 GBq, were determined to be 3.9 ppm and 6.5 ppm (µg Gd per gram phantom) for the Kα1 and Kα2 Gd x-ray peaks, respectively. This leads to an overall detection limit of 3.3 ppm (µg Gd per gram phantom). Layers of plastic were used to simulate overlying soft tissue and this permitted prediction of a detection limit, using the current strength of our radioisotope source, of 6.1 ppm to 8.6 ppm (µg Gd per gram phantom) for fingers with 2-4 mm of overlying tissue. With a new source of activity 5 GBq, we predict that this system could achieve a detection limit of 4-5.6 µg Gd g(-1) Ca. This is within the range of levels (2-30 µg Gd g(-1) Ca) previously found in the bone of patients receiving Gd based contrast imaging agents. The technique is promising and warrants further investigation.

A (109)Cd K X-ray fluorescence (KXRF) measurement system consisting of four detectors in clover-leaf geometry is a non-invasive, low-radiation-dose method of measuring bone lead concentration. Its high precision in estimating the bone lead content makes it a promising tool for the determination of the low levels of lead currently found in the general population. After developing the clover-leaf geometry system, the system was used for the first time in a major survey in 2008 to measure the lead levels of 497 smelter employees (an occupationally exposed group with high lead levels). Since the delivered effective dose of the bone lead system in clover-leaf geometry is small (on the order of nSv), the technique can be used to measure the bone lead of sensitive populations such as the elderly and children. This detector system was used from 2009 to 2011, in a pilot study that measured the bone lead concentration of 263 environmentally exposed individuals (termed the EG group) residing in Toronto, Ontario, Canada. In this paper, the factors that influence uncertainties in lead content in tibia (cortical bone) and calcaneus (trabecular bone) are discussed based on gender, age, and body mass index (BMI) by using analysis of variance (ANOVA) and multiple linear regression models. Results from the two study groups (the EG group versus the occupationally exposed smelter employees) are compared where appropriate (i.e. for males older than 20). Results from univariate analyses showed that females have higher tibia uncertainty compared to males. We observed significant differences for both calcaneus and tibia uncertainty measures (p < 0.0005) among different age groups, where the uncertainties were highest in the lowest age group (<11 years). Lastly, and perhaps most significantly, we found that the product of source activity and measurement time influenced the precision of measurements greatly, and that this factor alone could account for the higher uncertainties observed for the male cohort of the EG group versus the smelter employees.

Gadolinium (Gd) based contrast agents are routinely used as part of many magnetic resonance imaging (MRI) procedures. The widespread use of these agents and concerns about Gd toxicity, motivated us to develop a monitoring procedure that could non-invasively measure quantitatively potential retention of toxic free Gd in tissues after use of the agent. We have been developing a method to measure Gd painlessly and non-invasively by prompt gamma neutron activation analysis. In this paper we present the results of a pilot study where we show that we can measure Gd, quantitatively in vivo, in the lower leg muscle of 10 participants. A series of three neutron leg scans were performed. The effective radiation dose for a single neutron leg scan was very low, 0.6 µSv, so multiple scans were possible. Calibration phantom and in vivo detection limits were determined to be identical: 0.58 ppm. Gd was not detectable in muscle prior to exposure to the contrast agent Gadovist(®). Gd was detected, at greater than 99% confidence, in 9 participants within 1 h of contrast administration and in 1 participant approximately 3.3 h post-contrast administration. The measured concentrations of Gd ranged from 2.0 to 17.3 ppm (6.9 to 56 uncertainties different from zero). No detectable Gd was measured in any participant in the third neutron scan (conducted 0.7 to 5.9 d post-contrast). The results of this study validate our new measurement technology. This technique could be used as a non-invasive monitoring procedure for exposure and retention of Gd from Gd-based chelates used in MRI.

The overwhelming proportion of the mass of lead (Pb) is stored in bone and the residence time of Pb in bone is much longer than that in other tissues. Hence, in a metabolic model that we used to solve the differential equations governing the transfer of lead between body compartments, three main compartments are involved: blood (as a transfer compartment), cortical bone (tibia), and trabecular bone (calcaneus). There is a bidirectional connection between blood and the other two compartments. A grid search chi-squared minimization method was used to estimate the initial values of lead transfer rate values from tibia (λTB) and calcaneus (λCB) to blood of 209 smelter employees whose bone lead measurements are available from 1994, 1999, and 2008, and their blood lead level from 1967 onwards (depending on exposure history from once per month to once per year), and then the initial values of kinematic parameters were used to develop multivariate models in order to express λTB and λCB as a function of employment time, age, body lead contents and their interaction. We observed a significant decrease in the transfer rate of lead from bone to blood with increasing body lead contents. The model was tested by calculating the bone lead concentration in 1999 and 2008, and by comparing those values with the measured ones. A good agreement was found between the calculated and measured tibia/calcaneus lead values. Also, we found that the transfer rate of lead from tibia to blood can be expressed solely as a function of cumulative blood lead index.

We previously published a method for the in vivo measurement of bone fluoride using neutron activation analysis (NAA) and demonstrated the utility of the technique in a pilot study of environmentally exposed people. The method involved activation of the hand in an irradiation cavity at the McMaster University Accelerator Laboratory and acquisition of the resultant γ-ray signals in a '4π' NaI(Tl) detector array of nine detectors. In this paper we describe a series of improvements to the method. This was investigated via measurement of hand simulating phantoms doped with varying levels of fluorine and fixed amounts of sodium, chlorine and calcium. Four improvements to the technique were tested since our first publication. The previously published detection limit for phantom measurements using this system was 0.66 mg F/g Ca. The accelerator irradiation and detection facilities were relocated to a new section of the laboratory and one more detector was added to the detection system. This was found to reduce the detection limit (possibly because of better detection shielding and additional detector) to 0.59 mg F/g Ca, a factor of 1.12. A new set of phantoms was developed and in this work we show that they improved the minimum detectable limit for fluoride in phantoms irradiated using neutrons produced by 2.15 MeV protons on lithium by a factor of 1.55. We compared the detection limits previously obtained using a summed signal from the nine detectors with the detection limit obtained by acquiring the spectra in anticoincidence mode for reduction of the disturbing signal from chlorine in bone. This was found to improve the ratio of the detection of fluorine to chlorine (an interfering signal) by a factor of 2.8 and the resultant minimum detection limit was found to be reduced by a factor of 1.2. We studied the effects of changing the timing of γ-ray acquisition. Our previously published data used a series of three 10 s acquisitions followed by a 300 s count. Changing the acquisition to a series of six 5 s acquisitions was found to further improve the detection limit by a factor of 1.4. We also present data showing that if the neutron dose is delivered to the phantom in a shorter time period, i.e. the dose rate is increased and irradiation shortened then the detection limit can be reduced by a further factor of 1.35.The overall improvement in detection limit by employing all of these changes was found to be a factor of 3.9. The technique now has an in phantom detection limit of 0.17 mg F/g Ca compared to a previous detection limit of 0.66 mg F/g Ca. The system can now be tested on human volunteers to see if individuals with diagnosed fluorosis can be distinguished from the general Canadian population using this technique.

Arsenic (As) distribution in nail clippings from three healthy human subjects was investigated using the microbeam experimental setup of the hard x-ray micro-analysis (HXMA) beamline from the Canadian Light Source (CLS) synchrotron. A pair of toenail and fingernail clippings was collected from each of three subjects (one contributed two fingernail clippings). The fingernail and toenail clippings were embedded in polyester resin and cut in cross-sectional slices with an average thickness of 270 µm. Nine nail clipping cross sections were analyzed from the three subjects. The same method was used to produce five cross sections of nail phantom clippings with concentrations of As ranging from 0 to 20 µg g−1, in increments of 5 µg g−1. These samples were used to produce a calibration line for the As Kα peak. The energy of the x-ray beam was set at 13 keV for optimal excitation of As and the beam size was 28 × 10 µm2. Each sample was analyzed using a point-by-point scanning technique in a 45° beam-sample and 90° beam-detector geometry. The dwelling time was set at 30 s for the human nail clippings and 20 s for the nail phantom clippings, using a step size of 50 µm in both the horizontal and vertical directions for all samples. As concentration for each point was calculated based on the calibration line parameters and the fitted amplitude of the observed As Kα peak. As concentration maps were produced for each nail clipping cross section. The maps show that small regions (<0.1 mm2) with higher As concentrations (>1 µg g−1) are located predominantly in the ventral and dorsal layers of the nail. The results are in agreement with findings reported in a recent study and can be linked to nail histology and keratin structure.

In vivo monitoring of trace and biometals in skin is normally quantified using phantoms that assume a constant elemental distribution within the skin. Layered calibration skin phantoms could potentially improve the reliability of in vivo calibration skin phantoms by better representing the actual in vivo distribution. This work investigates the micro-distribution of iron, calcium and zinc in prepared human skin samples taken from a number of locations on the body. Slices (orientation running from the skin surface into the dermis) were extracted from 18 formalin-fixed necropsy samples and scanned using the micro-XRF setup at the VESPERS beamline (Canadian Light Source). Elemental surface maps were produced using a 6×6 μm(2) beam in steps of 10 μm. Microscope images of histology slides were obtained for comparison. Statistically significant differences (p<0.01) were noted between the epidermal and dermal layers of skin for the elements examined (Ca, Fe and Zn), demonstrating the ability to clearly distinguish elemental content in each layer. Iron was consistently noted at the epidermal/dermal boundary. These results would indicate that when using phantoms to quantify elemental levels measured in the skin, note should be taken of the appropriate depth distribution., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Fluorine is an element that can be either beneficial or harmful, depending on the total amount accumulated in the teeth or bones. In our laboratory, we have developed a non-invasive technique for the in vivo measurement of fluoride in bone using neutron activation analysis and performed the first pilot human study. Fluoride in humans is quantified by comparing the γ-ray signal from a person to the γ-ray signal obtained from appropriate anthropomorphic calibration phantoms. An identified problem with existing fluoride phantoms is contamination with aluminum. Aluminum creates an interfering γ-ray signal which, although it can be subtracted out, increases the uncertainty in the measurement and worsens the detection limit. This paper outlines a series of studies undertaken to develop a better calibration phantom for fluorine measurement, which does not have aluminum contamination.

In this study, we aimed to establish the emission of UV photons when HPV-G cells and associated materials (such as the cell substrate and cell growth media) are exposed to low LET radiation. The potential role of UV photons in the secondary triggering of biological processes led us to hypothesize that the emission and absorption of photons at this wavelength explain some radiation induced "bystander effects" that have previously been thought to be chemically mediated. Cells were plated in Petri-dishes of two different sizes, having different thicknesses of polystyrene (PS) substrate, and were exposed to β-radiation from (90)Y produced by the McMaster Nuclear Reactor. UV measurements were performed using a single photon counting system employing an interference-type filter for selection of a narrow wavelength range, 340±5 nm, of photons. Exposure of the cell substrates (which were made of polystyrene) determined that UV photons were being emitted as a consequence of β particle irradiation of the Petri-dishes. For a tightly collimated β-particle beam exposure, we observed 167 photons in the detector per unit μCi in the shielded source for a 1.76 mm thick substrate and 158 photons/μCi for a 0.878 mm thick substrate. A unit μCi source activity was equivalent to an exposure to the substrate of 18 β-particles/cm(2) in this case. The presence of cells and medium in a Petri-dish was found to significantly increase (up to a maximum of 250%) the measured number of photons in a narrow band of wavelengths of 340±5 nm (i.e. UVA) as compared to the signal from an empty control Petri-dish. When coloured growth medium was added to the cells, it reduced the measured count rate, while the addition of transparent medium in equal volume increased the count rate, compared to cells alone. We attribute this to the fact that emission, scattering and absorption of light by cells and media are all variables in the experiment. Under collimated irradiation conditions, it was observed that increasing cell density in medium of fixed volume resulted in a decrease in the observed light output. This followed a roughly exponential decline. We suggest that this may be due to increased scattering at the cell boundary and absorption of the UV in the cells. We conclude that we have measured UVA emitted by cells, cell medium and cell substrates as a consequence of their irradiation by low LET β-particle radiation. We suggest that these secondary UV photons could lead to effects in non-targetted cells. Some effects that had previously been attributed to a chemically mediated "bystander effect" may in fact be due to secondary UV emission. Some radiation bystander effect studies may require re-interpretation as this phenomenon of UV emission is further investigated.

494 smelter employees from New Brunswick participated in a bone lead survey conducted by McMaster University in 2008, using the four element "clover-leaf" geometry germanium detector system. The employees were measured at two different bone sites, tibia and calcaneus, each measurement lasting 30 minutes. Scattered photons, including Pb X-rays, were collected by the germanium detectors located behind the ¹⁰⁹Cd source. A strong positive correlation was observed between tibia and calcaneus lead concentrations. Having been provided with blood lead levels, a cumulative blood lead index (CBLI) was generated. The employees were classified into four groups based on their date of hire, and their CBLI levels were compared to their tibia and calcaneus lead concentrations in the different groups. The slopes of bone Pb versus CBLI varied amongst groups, with those hired earliest showing the steepest slopes. This could be taken to imply a non-linearity in the uptake of Pb by bone from blood. In this paper, the association of the bone lead concentrations versus CBLI has been expressed by a polynomial function for the whole group of employees.

Humans can be exposed to fluorine (F) through their diet, occupation, environment and oral dental care products. Fluorine, at proper dosages, is believed to have positive effects by reducing the incidence of dental caries, but fluorine toxicity can occur when people are exposed to excessive quantities of fluorine. In this paper we present the results of a small pilot in vivo study on 33 participants living in Southwestern Ontario, Canada. The mean age of participants was 45 ± 18 years with a range of 20-87 years. The observed calcium normalized hand-bone-fluorine concentrations in this small pilot study ranged from 1.1 to 8.8 mg F/g Ca. Every person measured in this study had levels of fluorine in bone above the detection limit of the system. The average fluorine concentration in bone was found to be 3.5 ± 0.4 mg F/g Ca. No difference was observed in average concentration for men and women. In addition, a significant correlation (r(2) = 0.55, p < 0.001) was observed between hand-bone-fluorine content and age. The amount of fluorine was found to increase at a rate of 0.084 ± 0.014 mg F/g Ca per year. There was no significant difference observed in this small group of subjects between the accumulation rates in men and women. To the best of our knowledge, this is the first time data from in vivo measurement of fluorine content in humans by neutron activation analysis have been presented. The data determined by this technique were found to be consistent with results from ex vivo studies from other countries. We suggest that the data demonstrate that this low risk non-invasive diagnostic technique will permit the routine assessment of bone-fluorine content with potential application in the study of clinical bone-related diseases. This small study demonstrated that people in Southern Ontario are exposed to fluoride in measureable quantities, and that fluoride can be seen to accumulate in bone with age. However, all volunteers were found to have levels below those expected with clinical fluorosis, and only one older subject was found to have levels comparable with preclinical exposure.

Fluorine (F) plays an important role in dental health and bone formation. Many studies have shown that excess fluoride (F(-)) can result in dental or skeletal fluorosis, while other studies have indicated that a proper dosage of fluoride may have a protective effect on bone fracture incidence. Fluorine is stored almost completely in the skeleton making bone an ideal site for measurement to assess long-term exposure. This paper outlines a feasibility study of a technique to measure bone-fluorine non-invasively in the human hand using in vivo neutron activation analysis (IVNAA) via the (19)F(n,γ)(20)F reaction. Irradiations were performed using the Tandetron accelerator at McMaster University. Eight NaI(Tl) detectors arranged in a 4π geometry were employed for delayed counting of the emitted 1.63 MeV gamma ray. The short 11 s half-life of (20)F presents a difficult and unique practical challenge in terms of patient irradiation and subsequent detection. We have employed two simultaneous timing methods to determine the fluorine sensitivity by eliminating the interference of the 1.64 MeV gamma ray from the (37)Cl(n,γ)(38)Cl reaction. The timing method consisted of three counting periods: an initial 30 s (sum of three 10 s periods) count period for F, followed by a 120 s decay period, and a subsequent 300 s count period to obtain information pertaining to Ca and Cl. The phantom minimum detectable limit (M(DL)) determined by this method was 0.96 mg F/g Ca. The M(DL) was improved by dividing the initial timing period into three equal segments (10 s each) and combining the results using inverse variance weighting. This resulted in a phantom M(DL) of 0.66 mg F/g Ca. These detection limits are comparable to ex vivo results for various bones in the adult skeleton reported in the literature. Dosimetry was performed for these irradiation conditions. The equivalent dose for each phantom measurement was determined to be 30 mSv. The effective dose was however low, 35 µSv, which is comparable to other clinical diagnostic tools. The M(DL), relatively low radiation dose and non-invasiveness indicate the suitability of this method for routine in vivo analysis of bone-fluorine content. This prompted us to perform a trial study in human subjects. A preliminary human study on 34 participants was completed, with 33 of the 34 measurements proving to be successful. The in vivo M(DL) based on the improved timing method was determined to be 0.69 mg F/g Ca for the 33 successful human measurements. In our opinion, this technique has been demonstrated to be a suitable method for in vivo assessment of fluorine bone-burden.

Purpose: Neutron irradiations at the McMaster Tandetron Accelerator were performed to study direct and bystander effects of neutrons in a live organism., Methods: The neutrons were produced through (7)Li(p,n)(7)Be reaction. Although the gamma contamination of the neutron beam cannot be completely eliminated, it was designed to be as low as possible and remain below a threshold already established for bystander effects. Microdosimetric methods using a tissue-equivalent proportional counter have been used to measure the neutron and gamma doses for the cell irradiation. Previous data for a cell line exposed in vitro suggested that neutrons did not produce bystander effects at doses below 300 mGy. The current experiments sought to confirm this using a live whole organism (zebrafish) where tissue samples harvested 2 h after exposure were examined for direct evidence of apoptosis and tested for secretion of bystander factors using an established bioassay. Fish were either exposed directly to the beam or were allowed to swim with or in water previously occupied by irradiated fish., Results: Using the zebrafish model it was found that there was significant direct cell death seen both by apoptosis scores and clonogenic assay when the neutron dose was approximately 100 mGy. An equivalent dose of gamma rays produced a more toxic effect. It was further found that neutrons did not induce a bystander effect in fish receiving signals from irradiated fish., Conclusion: The results confirm in vitro experiments which suggest neutrons do not induce bystander signaling. In fact they may suppress gamma induced signaling suggesting a possible intriguing new and as yet unclear mechanism.

The feasibility of using the McMaster University in vivo prompt gamma neutron activation analysis system for the detection of gadolinium has been investigated. Phantoms have been developed for the kidney, liver, and the leg muscle. The initial detection limits are determined to be 7.2 ± 0.3 ppm for the kidney, 3.0 ± 0.1 ppm for the liver, and 2.33 ± 0.08 ppm for the lower leg muscle. A few system optimizations have been tested and show significant detection limit reduction from these initial values. The technique is promising and shows feasibility for in vivo studies of gadolinium retention., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Manganese (Mn) is a nutrient essential for regulating neurological and skeletal functions in the human body, but it is also toxic when humans are excessively exposed to Mn. Blood (or serum/plasma) and other body fluids reflect only the most recent exposure and rapidly return to within normal ranges, even when there has been a temporary excursion in response to exposure. In this context, we have been developing a non-invasive measurement of Mn stored in bone, using in vivo neutron activation analysis. Following feasibility studies, a first pilot study, using neutron activation analysis to measure Mn in the bones of the hand of ten healthy male human subjects, was conducted with the approval of the concerned research ethics boards. The participants of this study had no known history of exposure to Mn. Two volunteers were excluded from this study due to technical problems with their measurements. The inverse variance weighted mean value of Mn/Ca for the participants of this study is 0.12+/-0.68 microg Mn/g Ca which is comparable within uncertainties with the estimated range of 0.16-0.78 microg Mn/g Ca and mean value of 0.63+/-0.30 microg Mn/g Ca derived from cadaver data. It is recommended to investigate the use of the diagnostic technique for in vivo measurements of workers exposed occupationally to excessive amounts of Mn who could develop many-fold increased levels of Mn in bones as demonstrated through various animal studies. The technique needs further development to improve the precision of in vivo measurements in the non-exposed population.

Manganese is both an essential element to human health and also toxic when humans are exposed to excessive levels, particularly by means of inhalation. Biological monitoring of manganese exposure is problematic. It is subject to homeostasis; levels in blood (or serum/plasma) reflect only the most recent exposure and rapidly return to within normal ranges, even when there has been a temporary excursion in response to exposure. In this context, we have been developing a non-invasive technique for measurement of manganese stored in bone, using in vivo neutron activation analysis. Following preliminary feasibility studies, the technique has been enhanced by two significant infrastructure advances. A specially designed irradiation facility serves to maximize the activation of manganese with respect to the dose of ionizing radiation. Secondly, an array of eight NaI(Tl) crystals provides a detection system with very close to 4 pi geometry. This feasibility study, using neutron activation analysis to measure manganese in the bones of the hand, takes two features into account. Firstly, there is considerable magnesium present in the bone and this produces a spectral interference with the manganese. The 26 Mg(n,gamma)27 Mg reaction produces gamma -rays of 0.843 MeV from the decay of 27 Mg, which interfere with the 0.847 MeV gamma -rays from the decay of 56 Mn,produced by the 55 Mn(n,gamma)56 Mn reaction. Secondly, this work provides estimates of the levels of manganese to be expected in referent subjects. A revised estimate has been made from the most recent literature to explore the potential of the technique as 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. This report presents the enhancements to the neutron activation system, by which manganese can be measured, which resulted in a detection limit in the hand of human subjects of 1.6 microg/g Ca. It also provides a revised estimate of expected referent levels of manganese in bone, now estimated to be 0.63 microg/g Ca and highlights the extent to which technical improvements will be required to further extend the application of the technique for in vivo measurements in non-exposed human subjects.

Magnesium (Mg) is an element essential for many enzymatic reactions in the human body. Various human and animal studies suggest that changes in Mg status are linked to diseases such as cardiac arrhythmia, coronary heart disease, hypertension, premenstrual syndrome, and diabetes mellitus. Thus, knowledge of Mg levels in the human body is needed. A direct measurement of human blood serum, which contains only 0.3% of the total body Mg, is generally used to infer information about the status of Mg in the body. However, in many clinical situations, Mg stored in large levels, for example in bones, muscles, and soft tissues, needs to be monitored either to evaluate the efficacy of a treatment or to study the progression of diseases associated with the deficiency of total body Mg. This work presents a feasibility study of a noninvasive, in vivo neutron activation analysis (IVNAA) technique using the 26Mg (n, gamma) 27Mg reaction to measure Mg levels in human hands. The technique employs the McMaster University high beam current Tandetron accelerator hand irradiation facility and an array of eight NaI (T1) detectors arranged in a 4 pi geometry for delayed counting of the 0.844 and 1.014 MeV gamma rays emitted when 27Mg decays in the irradiated hand. Mg determination in humans using IVNAA of hands has been demonstrated to be feasible, with effective doses as low as one-quarter of those delivered in chest x rays. The overall experimental uncertainty in the measurements is estimated to be approximately 5% (1 sigma). The results are found to be in the range of the in vitro measurements reported for other cortical bones collected from different sites of the human skeleton, which confirms that this technique mainly provides a measure of the amount of Mg in hand bones. The average concentration of Mg determined in human hands is 10.96 +/- 1.25 (+/- 1 SD) mg Mg/g Ca. The coefficient of variation (11%) observed in this study is comparable with or lower than several studies using in vitro measurements reported in the literature and therefore allows for a quantitative intersubject comparison, even if to a limited extent. The features of the developed technique such as its simplicity, rapidity, accuracy, robustness, noninvasive nature, and very effective use of radiation doses, present the technique as a viable diagnostic tool available for trial in a clinical environment.

Although radiation-induced bystander effects are frequently observed biological phenomena, the mechanism for these effects has not been fully determined. The target-hit theory and related concepts from microdosimetry provide a convenient formalism to help identify the nature of the targets responsible for initiating the emission of diffusible factors in medium transfer experiments. We used the microdosimetric models proposed by Stewart et al. (Radiat. Res. 165, 460-469, 2006) to analyze the results of published medium transfer experiments for gamma-ray doses in the range of 0.04 mGy to 5 Gy. The analysis suggests that the effective size of the target responsible for initiating signal emission in HPV-G human keratinocyte donor cells is approximately 2 microm.

Bone lead concentrations measured in vivo by x-ray fluorescence (XRF) are subjected to left censoring due to limited precision of the technique at very low concentrations. In the analysis of bone lead measurements, inverse variance weighting (IVW) of measurements is commonly used to estimate the mean of a data set and its standard error. Student's t-test is used to compare the IVW means of two sets, testing the hypothesis that the two sets are from the same population. This analysis was undertaken to assess the adequacy of IVW in the analysis of bone lead measurements or to confirm the results of IVW using an independent approach. The rationale is provided for the use of methods of survival data analysis in the study of XRF bone lead measurements. The procedure is provided for bone lead data analysis using the Kaplan-Meier and Nelson-Aalen estimators. The methodology is also outlined for the rank tests that are used to determine whether two censored sets are from the same population. The methods are applied on six data sets acquired in epidemiological studies. The estimated parameters and test statistics were compared with the results of the IVW approach. It is concluded that the proposed methods of statistical analysis can provide valid inference about bone lead concentrations, but the computed parameters do not differ substantially from those derived by the more widely used method of IVW.

A neutron irradiation cavity for in vivo activation analysis has been characterized to estimate its dosimetric specifications. The cavity is defined to confine irradiation to the hand and modifies the neutron spectrum produced by a low energy accelerator neutron source to optimize activation per dose. Neutron and gamma-ray dose rates were measured with the microdosimetric technique using a tissue-equivalent proportional counter at the hand irradiation site and inside the hand access hole. For the outside of the cavity, a spherical neutron dose equivalent meter and a Farmer dosemeter were employed instead due to the low intensity of the radiation field. The maximum dose equivalent rate at the outside of the cavity was 2.94 microSv/100 microA min, which is lower by a factor of 1/2260 than the dose rate at the hand irradiation position. The local dose contributions from a hand, an arm and the rest of a body to the effective dose rate were estimated to be 1.73, 0.782 and 2.94 microSv/100 microA min, respectively. For the standard irradiation protocol of the in vivo hand activation, 300 microA min, an effective dose of 16.3 microSv would be delivered.

Using a 50 W x-ray tube as the fluorescing source, an x-ray fluorescence system was designed to measure arsenic in superficial layers of tissue-simulating phantoms. The detection limit for arsenic in the phantoms at a setting of 35 kV and with 200 microm of a Mo filter was 0.40 +/- 0.06 microg As g(-1). This measurement results in an effective dose of 0.6 microSv.

The existence of radiation-induced bystander effects mediated by diffusible factors is now accepted, but the mechanisms and precise behavior at low doses remain unclear. We exposed cells to gamma-ray doses in the range 0.04 mGy-5 Gy, harvested the culture medium, and transferred it to unirradiated reporter cells. Calcium fluxes and clonogenic survival were measured in the recipients. We show evidence for a dose threshold around 2 mGy for the human skin cell line used with a suggestion of increased survival below that dose. Similar experiments using direct gamma irradiation showed no reduction in survival until the dose exceeded 7 mGy. Preliminary data for neutrons where the gamma-ray dose was kept below the bystander threshold do not show a significant bystander effect in the dose range 1-33 mGy. A lack of a bystander response with neutrons occurred at around 1 Gy, where significant cell killing from direct irradiation was observed. The result may have implications for understanding the role of bystander effects at low doses.

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.

Long term lead metabolism in the human body has never been fully understood due to the lack of human data in this area. The technological improvement of bone lead measurement systems has made bone lead data of substantial populations available. In this study, a set of X-ray fluorescence bone lead data was used to test Leggett's lead metabolism model (R. W. Leggett, Environ. Health Perspect., 1993a, 101, 598-616), especially the model of metabolism in bone. The data set includes the bone lead concentration of 539 occupationally exposed workers, of whom 327 were measured twice in five years. The bone lead concentrations of both cortical bone (tibia) and trabecular bone (calcaneus) were obtained by Cd-109 gamma-ray induced XRF measurement. The histories of blood lead concentration for these workers were used to regulate the input file of the model. The results show that the bone lead concentrations predicted by Leggett's model greatly underestimate the measured values, especially for older workers. This data set was then organized into five age groups. A new simplified model was applied to estimate the lead transfer rates between blood and lead compartments for these age groups. The original transfer rates and the new transfer rates are compared, and the differences are discussed. When the transfer rates derived from measured bone lead data were put into the input file of the model to replace the existing parameters, the predicted values were much closer to the measured values for both cortical bone and trabecular bone.