Ana Pejović-MilićBSc, MSc, PhD
t. 416-979-5000 x7952
Medical physics, trace elements analysis in humans, bone strontium, aluminum, manganese, and magnesium, nuclear analytical methods for medical applications, X-ray fluorescence (XRF), in vivo neutron activation analysis (IVNAA)
My research group, in collaboration with colleagues at McMaster University, carries out research in the general area of medical physics by developing non-invasive elemental techniques for medical applications, primarily for applications in the field of occupational and bone health or toxicology. In particular, we use a variety of nuclear techniques (i.e. neutron activation, x-ray fluorescence) to determine the amount of toxic trace elements stored in human bone. We are active in establishing both commercial and research collaborations, as well as are actively seeking new graduate students.
Toxic elements are commonly measured in blood and serum, or by a bone biopsy. It is widely accepted that blood and serum concentrations of elements provide information only about the recent exposure to the element, and therefore do not necessarily reflect chronic exposure of an individual. On the other hand, bone biopsy is painful, involves a risk to the patient and it may not be possible to repeat it several times.
The assessment of lifetime exposure from a medication, environment, or in the work place, to a toxic element therefore requires a different approach. Because many toxic/trace elements are well retained by bone tissue and may reside there for years to decades, a non-invasive, non-distractive and without-pain X-ray fluorescence (XRF) based or neutron activation based diagnostic technique is being developed to assess these elements.
Current research interests include:
Bone strontium X-ray fluorescence (XRF) system to measure strontium levels stored in human bone.
(in collaboration with McMaster University)
Dr. Pejović-Milić, followed by her graduate student, is the first in Canada to apply the X-ray fluorescence technique (XRF) to measure strontium (Sr) in bone. The developed in vivo bone strontium technique appears to be the only one currently available in the world. The key advantage of in vivo XRF is that it is non-invasive, painless, and delivers an insignificant radiation dose to the subject.
Sr health effects are dose dependent. High levels of dietary Sr have been correlated with skeletal abnormalities in animals and to rickets occurrence in children. High Sr bone concentration has been associated with osteomalacia. Animal studies have found that oral administration of strontium salts can redirect and improve the condition of osteoporotic bone. Prolonged administration of strontium to postmenopausal osteoporotic women resulted in a decoupling between bone resorption and formation that yielded a significant increase in lumbar spine bone mineral density of treated subjects. These findings point to a promising strontium based agent for the treatment of osteoporosis in humans that is currently undergoing human trials in Europe. Bone Sr XRF, a novel diagnostic tool, has the potential to help us understand the mechanism by which strontium exerts its detrimental or therapeutic effects.
Osteoporosis, as defined by the World Health Organization, is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility of fracture. It can affect the entire skeleton with most the common sites being the hip, wrist and vertebrae. Osteoporosis is also defined using the measurement of bone mineral density (BMD), where a value of BMD 2.5 SD or more below the young adult reference mean denotes the condition.
Dual Energy X-ray Absorptiometry (DEXA) is a well-established and clinically available diagnostic tool that is used to diagnose changes in the bone mineral density (BMD) or bone mineral content (BMC) in osteoporotic patients. A small Sr fraction incorporated in the bone, however, will be registered as calcium when BMD or BMC is measured by DEXA. The apparent values of BMD and BMC increase linearly with increasing substitution of Ca by Sr. This demonstrates that reliable DEXA determinations may be carried out in the presence of Sr only if the Sr content of the measured bone is known. Currently, a correction due to Sr exchange in bone can be made if bone biopsies are taken from a representative location. Thus, one of our research objectives is to investigate the application of an in vivo bone Sr XRF technique to correct the DEXA measurements non-invasively.
WHO study group on assessment of fracture risk and its application to screening for postmenopausal osteoporosis, WHO technical series, 843, (1994).
Bone aluminum In Vivo Neutron Activation Analysis to assess aluminum concentration in human bone.
(in collaboration with McMaster University)
The harmful biological effects of excessive aluminum (Al) load in humans have been an important area of research in recent decades. Al stored in bone can interfere with normal bone remodeling and can be expected to relate to osteoarthritis. The relationship between chronic Al exposure and the risk of Alzheimer's Disease remains controversial. The non-invasive technique of IVNAA has been under development for measurement of Al in the bones of the hand by our research team. Recently we have reported on the projected performance of an upgraded system (Pejović-Milić et al., 2005). This was to include a high current tandem accelerator based neutron source, an irradiation/shielding cavity and a 4π NaI(Tl) detector system with γ-ray spectral decomposition, located at the McMaster Accelerator Laboratory. We are continuing to develop this unique diagnostic tool in Canada, with the building of a new generation of hand phantoms that closely resemble spectra recently collected from the hand of a normal, non-exposed subject. Furthermore, a new protocol of bone Al measurement will be developed that will lead to the minimal detectable limit achieved in the context of measuring bone Al levels in both exposed and non-exposed subjects while keeping the radiation dose as low as possible. Human measurements are anticipated in the near future.
Bone manganese using in vivo neutron activation analysis technique to measure manganese stored in human bone.
(in collaboration with the Occupational Health Clinics for Ontario Workers (OHCOW) and McMaster University)
We are the first research team (led by Dr. Pejović-Milić) to achieve a human bone measurement in a project in which welders occupationally exposed to manganese (Mn) in Hamilton, Ontario have bone manganese measurements compared to levels found in subjects without any history of occupational exposure to manganese. With this novel technique we will be able to assess cumulative bone manganese, which in turn will be an objective technique for the diagnosis of manganese related diseases and the monitoring of time-integrated manganese exposure in occupationally exposed workers. If the pilot study (summer 2007) confirms the supposition that bone manganese levels do reflect differences in long-term exposure, then more extensive research will be developed.
Mn is one of the Earth-s most abundant metals and is essential to human life, in particular, to neurological and skeletal functions. Sources of Mn include diet, occupational exposure (Mn mines, iron/steel and ferro/silico-Mn production plants, welding, and dry-cell battery manufacturing), environmental exposure (MMT, a Mn compound in gasoline), and medical exposure (total parenteral nutrition and Mn-based contrast agents). Mn is readily absorbed when inhaled from dust and/or fumes. It is estimated that bone tissue holds ~ 40% of the total body Mn. Mn air levels are highest in occupational settings; the workers of such industries are at an increased risk of Mn intoxication. Longstanding, excessive exposure to manganese compounds may result in manganism, a Parkinson's-like disease syndrome. Exposure to Mn at low levels for a prolonged period of time can result in milder neurological symptoms than those seen in manganism, including memory deficit, loss of motor control and reduction in the refinement of certain bodily motions.
We have previously reported the feasibility study of measuring Mn concentrations in human bone with in vivo neutron activation analysis (Arnold et al., 2001). Measurements are non-invasive and hence, there is no discomfort to the patient. Since then, an irradiation/shielding cavity, consisting of moderator, gamma-ray filter, neutron reflector, and shield walls, has been built at McMaster Accelerator Laboratory for the clinical application of Mn IVNAA.
All recent technical improvements have led to a minimum detectable limit of the bone Mn IVNAA, which meets the estimated bone Mn level of 0.65 to 1 mg in the hand of healthy subjects, while delivering a significantly lower radiation dose than reported in the feasibility study.
In vivo assessment of magnesium levels in the human body using accelerator-based neutron activation analysis measurement of the hand.
(in collaboration with McMaster University)
Magnesium (Mg) is an essential element for many enzymetic reactions in the human body. Various human and animal studies suggest that the changes in Mg status are linked to diseases such as cardiac arrhythmia, coronary heart disease, hypertension, premenstrual syndrome, diabetes mellitus etc. Thus the 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, need 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 research presents a feasibility study of a non-invasive IVNAA technique using the 26Mg(n,γ)27Mn reaction to measure Mg levels in the human hand. This technique employs the McMaster University high beam current tandetron accelerator hand irradiation facility and an array of 8 NaI(Tl) detectors arranged in 4π geometry for delayed counting of 844 and 1014 keV gamma rays emitted when 27Mg decays in the irradiated hand. A measurement of Mg levels measured in volunteers' hands is underway to demonstrate the application of this technique for possible use in the clinical environment.
Multi-elemental analysis of tissues using wavelength dispersive X-ray fluorescence.
This research utilizes wavelength dispersive X-ray fluorescence (WDXRF) spectrometry, which is available in Canada only at the Department of Physics at Ryerson University and is one of the methods for trace element analysis in a small size sample.
This project focuses on the development of the WDXRF system for multi-elemental analysis of various trace and minor elements (i.e. Sr, Zn, Pb) in human and animal tissues or other samples. The impetus for this study is the development of a system capable of using a small sample size and for the quantification of various elements within the samples. The present work requirement is for the system development and the workings of a novel data analysis algorithm for X-ray spectra. Archaeological dating has become dominated by the use of various trace element markers, such as the various concentrations of strontium in tooth enamel or for the elemental analysis of archeological remains, i.e. fossils or mummified remains. The use of this system will also allow for the pharmacokinetic study of, for example, Sr-based osteoporosis drugs and their interaction with other elements in the etiology of osteoporosis.
S. H. Byun, A. Pejović-Milić, S. McMaster, W. Matysiak, Aslam, Z. Liu, L. Watters, W. V. Prestwich, F. E. McNeill and D. R. Chettle (2007), Dosimetric characterization of the irradiation cavity for accelerator-based in vivo neutron activation analysis, Physics in Medicine and Biology, Vol. 52, pp. 1693‐1703.
M. Zamburlini, A. Pejović-Milić, D. R. Chettle, C Webber, J Gyorffy (2007), In-vivo study of an x-ray fluorescence system to detect bone strontium non-invasively, Physics in Medicine and Biology, Vol. 52, pp. 2107‐2122.
M. Zamburlini, S. H. Byun, A. Pejović-Milić, W. V. Prestwich, D. R. Chettle (2007), Evaluation of MCNP5 and EGS4 for the simulation of in-vivo strontium XRF measurements, X-Ray Spectrometry, Vol. 36 (2), pp. 76‐81.
A. Pejović-Milić, S. H. Byun, D. R. Chettle, F. E. McNeill and W. V. Prestwich (2006), Development of an Irradiation/Shielding Cavity for In Vivo Neutron Activation Analysis of Manganese in Human Bone, Journal of Radioanalytical and Nuclear Chemistry, Vol. 269 (2), pp. 417‐420.
S. H. Byun, A. Pejović-Milić, W. V. Prestwich, D. R. Chettle and F. E. McNeill (2006), Improvement of in vivo neutron activation analysis of Mn using a 4π NaI(Tl) detector array, Journal of Radioanalytical and Nuclear Chemistry, Vol. 269 (3), pp. 615-618.
M. Zamburlini, A. Pejović-Milić and D. R. Chettle (2006), Evaluation of Geometries Appropriate for I-125 in vivo bone strontium X-ray Fluorescence Measurement, Journal of Radioanalytical and Nuclear Chemistry, Vol. 269 (3), pp. 625-629.
Popović M., Chettle D. R., McNeill F. E. and Pejović-Milić A (2006), In Vivo Detection of Cadmium in Human Bone using X-Ray Fluorescence, Journal of Radioanalytical and Nuclear Chemistry, Vol 269, No. 3.
Ana Pejović-Milić and Bill Whelan (2006), Medical and Biological Physics on the Rise, Physics in Canada, September 2006 issue.
A. Pejović-Milić, S. H. Byun, D. C. Comsa, F. E. McNeill, W. V. Prestwich, and D. R. Chettle (2005), in vivo Measurement of Bone Aluminum: Recent Developments, Journal of Inorganic Biochemistry, Vol. 99 (9), pp. 1899-1903.
A. Pejović-Milić, I. M. Stronach, J. Gyorffy, C. E. Webber and D. R. Chettle (2004), Quantification of bone strontium levels in humans by in vivo X-ray fluorescence, Medical Physics, Vol. 31 (3), pp. 528-538.
A. Pejović-Milić, J. A. Brito, J. Gyorffy D. R. Chettle (2002), Ultrasound measurements of overlying soft tissue thickness at four skeletal sites suitable for in vivo X-ray fluorescence, Medical Physics, Vol. 29 (11), pp. 2687-2691.
M. L. Arnold, F. E. McNeill, I. M. Stronach, A. Waker, A. Pejović-Milić, D. R. Chettle (2001), An Accelerator Based System for in vivo Neutron Activation Analysis Measurements of Manganese in Human Hand Bones, Medical Physics, Vol. 29 (11), pp. 2718-2724.
A. Pejović-Milić, M. L. Arnold, F. E. McNeil and D. R. Chettle (2000), Monte Carlo design study for in vivo bone aluminum measurement using a low energy accelerator beam, Applied Radiation and Isotopes, Vol. 53, pp. 657-664.
S. N. Bateman, A. Pejović-Milić, I. M. Stronach, F. E. McNeill and D. R. Chettle (2000), Performance appraisals of digital spectroscopy systems for the measurement of bone lead, Applied Radiation and Isotopes, Vol. 53, pp. 647-650.
- Canadian Foundation for Innovation/Ontario Innovation Trust (CFI/OIT)
- Natural Science and Engineering Research Council of Canada - Discovery Grant
- Natural Science and Engineering Research Council of Canada - Equipment Grants
- Natural Science and Engineering Research Council of Canada - Major Facilities Access Grant
- Workplace Safety and Insurance Board of Ontario (WSIB)
Graduate student (Completed): 1 M.Sc (transfer to PhD), 1 Postdoctoral Fellow
Graduate Student (In progress): 2 M.Sc, 1 PhD, 1 Postdoctoral Fellow
Undergraduate students (Completed): 5 research assistants, 2 co-op students
Current Highly Qualified Personnel
Aslam Ibrahim, PhD - post-doctoral fellow, McMaster University
Mariangela Zamburlini, PhD student, McMaster University
Kanakam Davis, MSc student, Ryerson University
Lesley Watters, Research Associate, Ryerson/McMaster University
Eric da Silva, MSc student, Ryerson University