The measurement of lead isotope abundances with a gas source mass spectrometer has been limited to lead ores and minerals. This thesis describes a technique by means of which the sample size necessary for a precise gas source analysis has been decreased by more than two orders of magnitude. In this way, the range of minerals which may be studied by means of a gas source mass spectrometer has been greatly extended. No particular effort has been made to analyze very small samples. The technique which has been developed begins with the evaporation of lead from a mineral to form a mirror. The synthesis of tetramethyllead is completed by the reaction of free methyl radicals with the lead mirror followed by gas chromatographic purification. The free radical method has been applied to the study of lead isotope abundance variations in the mining district of Sudbury, Ontario. A satisfactory chronological history for this region has not been obtained from the many conventional age determinations that exist. The analysis of lead from various sulphides has yielded lead isotope ratios which are linearly related on a plot of Pb²⁰⁷/Pb²⁰⁴ vs. Pb²⁰⁶/Pb²⁰⁴ with a slope of 0.131 ± 0.003. The standard deviation of points from their best straight line is 0.37% of the average Pb²⁰⁷/Pb²⁰⁴ value. From these results it is concluded that the linear relationship is the result of just two geological events, which fact simplifies the possible interpretations. The maximum ages for these two events are 2150 ± 50 million years and 1280 ± 50 million years. Two interpretations of the results are suggested. The first gives ages of 1950 million years and 350 million years for the primary and secondary events. The two events in the second interpretation are considered to have occurred 1600 million years and 950 million years ago. The second interpretation is more easily defended on geological grounds. The simple relationship of lead isotope ratios which has been observed in the Sudbury district is particularly significant in view of the geological complexity of this region. Thus the technique developed may be expected to have wide application. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

On the basis of data published prior to 1960, two basic lead isotope models - the isochron model and the primary lead model - were postulated to fit those crustal leads that have had the simplest history. The present writer's analyses of samples from Southern Finland, and the results of other research workers, now indicate that the primary lead model more adequately describes these leads, and that primary "isochrons" are either very short, or else non-existent. Lead in conformable deposits and in ultrabasic sulfides were postulated by R.L. Stanton to be examples of primary lead. Analyses of samples from several massive lead-zinc conformable deposits have indicated that the leads of many of these deposits possess primary lead characteristics. The present thesis describes a technique devised to prepare tetramethyllead from the conformable chalcopyrite deposits and ultrabasic sulfides and describes some initial results. This is a free radical technique, involving the reaction of methyl radicals with a lead mirror evaporated out of a sulfide. It appears to be capable of preparing tetramethyllead from samples containing one to two orders of magnitude less lead than previously reported for such a technique. Unfortunately, the full extent of the method cannot be utilized with present gas source mass spectrometer facilities, and only fair precision (0.4%) is possible at 10 ppm. lead. Samples from the conformable chalcopyrite deposits of Mt. Isa were analysed. The lead isotope ratios were found to be significantly different from those of the massive lead-zinc deposits. The results, interpreted with other lead and sulfur isotope data, suggest that these deposits could be the result of metal-bearing solutions entering a partially enclosed bay. Initial results for two ultrabasic deposits suggest that the lead in the sulfides is not necessarily primary; for example, that in two Stillwater ultrabasic complex samples appears to be the result of three stages of development. Hence, both the present lead isotope analyses, and those reported earlier by Ostic (1963) indicate that Stanton's geological criteria, while good, are not completely adequate for identifying primary leads. It is here suggested that sulfur isotope analyses might indicate which of these samples have been contaminated by crustal leads. During the investigation of the gas source mass spectrometric analyses of small tetramethyllead samples, lead isotope fractionation was observed. This occured with molecular flow into the mass spectrometer. Lead isotope fractionation has not been reported previously, and has some interesting geophysical implications. A preliminary study suggests that such fractionation in nature is likely to be rare, except possibly in biological processes in the sea. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

This thesis is primarily concerned with the problems involved in making precise mass spectrometer ion current measurements. A survey of the literature of the past decade shows that until the new type of system discussed in Chapter 3 was presented by R.D. Russell and F. Kollar, remarkably few developments were made in improving the precision of ion current measurements for the isotopes of the heavier elements. This situation is probably partly due to a failure to apply the modern methods of analysis which are presently used in the design of feedback control systems. Chapters 1 and 2 deal with the main requirements of ion current measuring systems. It has been assumed in previous systems that the resistor, through which the ion current is passed, has an approximately constant value for all values of the current. A method has been developed to measure the degree of this non-linearity, and results are given for the Victoreen Hi-Meg resistor. The theory necessary for the measurement is developed in detail. The final chapter deals with a general study of mass spectrometer measuring systems. A comparison is made of the two general types of measuring systems now in use, with an attempt to determine their relative advantages and disadvantages. The new system noted above is also discussed with the objectives of determining its theoretical performance, and of illustrating the methods of analysis. An appendix has been included to show the usefulness of the analogue computer in the design of an ion current measuring system. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

A thin-lens beta-ray spectrometer using ring-focus collection was modified. These modifications consisted of; 1) a centering mechanism enabling the source-detector axis to be aligned with the magnetic axis; 2) an extension of the vacuum chamber placing the detector further from the magnet coils. The latter considerably decreased the magnetic shielding requirements for the detector. A misalignment of 0.25 mm. for parallel axes and of 0°09' for intersecting axes produced noticeably poorer performance. Using a gathering power of .70%, a resolving power of .94% was obtained for the 661.6 Kev. K-conversion peak of Cs ¹³⁷. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

An apparatus was constructed to measure T₁, the "spin-lattice relaxation time" and T₂, the "spin-spin relaxation time" in liquids at low fields using the "spin-echo" technique. An outline of some basic ideas in nuclear magnetic resonance discussing the meaning of T₁ and T₂ is presented. This includes a comparison of steady state and pulsed techniques. The theoretical aspects, qualitative and quantitative of this low field spin-echo experiment is dealt with, showing explicitly how T₁ and T₂ are measured. The apparatus used in this experiment is described, giving details of construction and operation. The experimental results obtained include measurements of T₁ and T₂ in a water sample at a field of one gauss. T₁ was also measured at a field of 7,000 gauss and was found to be the same as at one gauss. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

The performance of a modified thin lens spectrometer was investigated over the energy ranges provided by Pm¹⁴⁷ and Cs¹³⁷ radioactive sources. The resultant spectra and Kurie plots provided evidence of a satisfactory performance. / Science, Faculty of / Physics and Astronomy, Department of / Graduate

The ion beam transmission efficiency of the ion source is an important factor in determining the sensitivity of a mass spectrometer. Vauthier (1955) has shown for a simple source that the transmission efficiency is very low. The present thesis examines the transmission efficiency of a more complex source. The first part of the thesis deals with the ion optical properties of a multiple slit ion source. The region of ion withdrawal has been sketched by computing the ion trajectories passing through the exit slit. It was found that for the more complex source the region of ion withdrawal is also much smaller than the total ionization space. It is not practical to confine the ionization region to the small volume from which ions are withdrawn. The effect of a source magnetic field has been taken into account. The perturbation of the trajectory due to the field is small, and therefore the mass discrimination due to the source magnetic field is imperceptible for heavy ions unless the field is of the order of a few webers/m². The multiple slit ion source produces a divergent ion beam, only a small fraction of which penetrates the exit slit. Obviously a system producing a beam converging at the exit slit to a narrow parallel ribbon will be most efficient. In order to devise such a system a theory of the inverse problem of particle motion is developed in the second part of the thesis. A procedure was found to determine a potential distribution required to guide a group of particles along a set of prescribed paths. There are two important limitations to the choice of paths: (a) there are certain paths which are not complete; that is a particle following such a path is turned back at certain points which we call mirror points. (b) The particles which do not satisfy the initial conditions of uniform energy and direction may deviate considerably from their projected paths leading to what we have called an unstable situation. Fortunately the complete paths are stable, and the incomplete paths are unstable. Of the two types of convergent paths studied, namely, exponentially decreasing and damped oscillatory paths, the system of damped oscillatory paths is stable. / Science, Faculty of / Earth, Ocean and Atmospheric Sciences, Department of / Graduate

The number of transferrin based therapeutics progressing to clinical trials remains disappointingly small despite promising capabilities of transporting therapeutic payloads to cancer cells and across the blood brain barrier. This meager success record is largely due to the complexity and heterogeneity of all protein conjugation products that generates difficulties for their analytical characterization. Discussed in this work, transferrin is conjugated to lysozyme as a model therapeutic to deliver this bacteriostatic protein to target central nervous system infections. In this work ESI- and MALDI-MS were used to characterize the modification sites at lysine residues in hopes of characterizing heterogeneity within the conjugate. Identification and quantization of modification sites using MS on tryptic digested samples proved difficult with poor signal to noise ratios and missing peptide fragments. The use of an 18O labeling method that exchanges both C-terminal oxygen atoms with 18O provided more reliable results, but still proved difficult to observe all needed peptide fragments. MALDI-MS allowed for verification of ESI-MS results, but was found unhelpful with full characterization due to abundant overlapping of isotopic labeled peaks. Hoping to create an ideal 1:1 binding ratio between the two proteins, a site-specific modification method using kinetically controlled conditions was used and was confirmed that the method, although capable of producing 1:1 conjugated species, actually created different isomers with separate binding frequencies at each lysine. Online-IEC helped with the identification of isomers and started the initial work of correlating modification sites with bioactivity of the proteins. It was determined that lysozyme has a high chance of being modified at lysine 33 and 116, with a possibility of also being highly modified at lysine 97. More work is needed to complete the characterization, especially with transferrin, but the experimental approaches developed in this work prove to be promising. This work aims at delivering an optimized framework for analytical characterization of protein and antibody conjugates to guide the development of future biopharmaceuticals.

Tandem mass spectrometry (MSMS) has become a powerful tool for the analysis of biomolecules. To reveal molecular identity, experimental mass (m/z) data are either matched to appropriate databases or processed de-novo. Both approaches are essentially one-dimensional, because the m/z values of fragment ions play dominant role, while the intensities (the second dimension) are being neglected, despite their potential to corroborate or contradict the identification. Unlike the trivial case of m/z values, predicting the ion intensities has not been mastered yet beyond empirical observation and statistical treatment. This dissertation presents a fundamental, structure-based algorithm for the prediction of fragment ion intensities in MSMS spectra of peptides and metabolites. The algorithm builds on the central hypothesis that the fragment ion intensities reflect the relative abundances of respective protonated precursor isomers prior to fragmentation. The hypothesis is supported by extensive experimental evidence showing that in ion trap mass detectors, relative ion intensities do not depend on the energy or activation time of fragmentation when commonly used ranges of conditions are explored. The multi-step algorithm developed includes molecular mechanics Monte Carlo conformational space sampling, semi-empirical calculations, and Density Functional Theory (DFT) quantum chemistry computations for structure refinement and energy calculations. A Boltzmann distribution determined from energy values of pertinent precursors accurately corresponded with relative ion intensities in MSMS spectra of three model pentapeptides. Reproducibility of the algorithm was tested, and while substantial differences were revealed among the multiple Monte Carlo samplings started from the same initial structures, the inconsistency was mitigated in following semi-empirical and DFT steps. The algorithm was optimized for efficiency as well. Computational costs were lowered (by more than 50%) by narrowing the energy window in which the conformers were taken to the following steps in the algorithm and finally to the Boltzmann distribution. For metabolites, ion intensity orders for nine out of eleven molecules were predicted correctly. However, the accuracy of the prediction of relative ion intensities was not satisfactory. Nevertheless, predicting the most intensive ion alone could be invaluable for preliminary metabolite identification and selecting good candidate standards for ultimate identification based on matched properties of analyte and standard.

This thesis investigates the exposure of humans to organic combustion products. Combustion of natural and anthropogenic materials can lead to highly complex mixtures of gas-phase and particle-bound chemical compounds, whose composition and health effects have been studied extensively. Nevertheless, the analysis of other potentially toxic products remains a challenge due to lack of analytical standards and methodologies. The research that encompasses this thesis is a progression from the analysis of known combustion products to the identification of previously unknown products. Targeted analytical techniques, such as gas chromatography tandem mass spectrometry (GC-MS/MS), were utilized to evaluate firefighter exposure to wood smoke chemicals during training exercises. The results suggest that a subset of the firefighters were at higher risk of exposure which could be related to specific operational roles and the use of personal protective gear. Comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCGC-TOF) was used for the identification of novel wood smoke markers and the results indicate that firefighters are equally exposed to gas-phase and particle phase compounds.. Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry is a non-targeted technique that is complementary to GCGC. Together, these tools enabled the identification of a suite of halogenated PAHs (haloPAHs) in samples obtained from the Plastimet Inc. fire, one the largest industrial fires in North America. HaloPAHs are similar in structure to toxic polychlorinated dibenzo-p-dioxins (PCDDs), a notorious class iv of toxic chemicals, and they were detected at much higher concentrations. In addition, highly substituted and high molecular weight haloPAHs were detected for the first time in an environmental sample. Finally, negative ion atmospheric pressure chemical ionization (NI-APCI) was explored as an alternative ionization technique for the analysis of mixed bromo/chloro dioxins (PXDDs) in the ash sample. PXDDs, with 1550 possible congeners, are potentially more toxic than their chlorinated counterparts (PCDDs). NI-APCI derived structure diagnostic fragments enabled the differentiation of co-eluting PXDD isomers in the ash sample which has not been possible using traditional ionization techniques (EI/CI) associated with GC-MS. / Thesis / Doctor of Philosophy (PhD)