The objective of this thesis was to investigate firefighters’ exposures to carcinogens and mutagens. This thesis aimed to (1) characterize firefighters’ exposures during emergency fire suppression, (2) examine the use of silicone wristbands as passive samplers to assess firefighters’ exposures, and (3) assess the ability of post-fire decontamination protocols to reduce firefighters’ exposures. Chapter 1 provides a general introduction and background information on the concepts covered in this thesis. In Chapter 2, I examined air and surface contamination with polycyclic aromatic hydrocarbons (PAHs) and metals, both at fire stations and following emergency fire suppression activities. I also investigated the ability of current laundering methods to remove surficial PAHs and metals from firefighters’ personal protective equipment. In Chapter 3, I assessed the ability of silicone wristband passive samplers to measure firefighters’ exposures to PAHs during live fire training. In Chapter 4, I assessed the ability of three post-fire dermal decontamination methods to remove surface contamination and reduce internal dose. In Chapter 5, conclusions and implications for each chapter are summarized. Future directions for the field are described. The overall conclusions for this thesis were: i. firefighters experience significant occupational exposures to carcinogens during emergency fire suppression and live fire training; ii. the ability of silicone wristbands to properly sample PAHs is altered in a fire environment and correction factors must be determined to improve their utility for exposure assessment; iii. current post-fire dermal decontamination methods, which are intended to reduce firefighters’ exposures, do not reduce their internal dose of PAHs.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2000. / Bibliography: leaves 114-122.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Umeå : Umeå universitet, 2008. / Härtill 4 uppsatser.

Exposure to combustion emissions poses a threat to human health due to the complex mixture of toxic compounds. Polycyclic aromatic hydrocarbons (PAHs) are one group of compounds found within this mixture, and have known carcinogenic and mutagenic properties. Rates of exposure to PAHs depend on a wide range of variables including, but not limited to, demographic, geographical location, dietary habits, smoking habits, and occupation. Understanding magnitude of exposure to these compounds in various groups is imperative to highlight at-risk populations and provide appropriate exposure reduction recommendations. Here, urinary biomarkers are used as a non-invasive, convenient way to assess an individual’s exposure to combustion emissions. Urinary measurements of metabolites of individual PAHs as well as compounds indicative of a physiological condition resulting from combustion emission exposure are used to infer exposure. Pairing urinary data with information from questionnaires collecting data on possible sources of combustion by-product exposure was used to determine situations of high exposures. This thesis investigated the influence of demographic, lifestyle, and occupational factors on urinary levels of PAH metabolites and/or urinary mutagenicity. More specifically, statistical methods were used to analyze population data compiled for the Canadian Health Measures Survey (CHMS). Smoking, age, and sex were identified as the variables most predictive of urinary PAH metabolite concentrations in Canadians. Together with the other demographic and lifestyle variables examined, 24-50% of the variation in the various PAH metabolites was explained. Furthermore, the results obtained illustrated that utilizing PAH metabolites other than the traditionally used 1-hydroxypyrene may be more suitable for certain exposure scenarios (e.g., fluorene metabolites for tobacco smoke exposure). Occupational exposures to combustion emission were investigated in firefighters as they experience above average risk of cancer, thus paired with their obvious involvement with combustion, are an ideal population to apply the use of urinary biomarkers to assess PAH and combustion exposure. The effect of participating in fire suppression activities (i.e., firefighting) on urinary levels of selected PAH metabolites and organic mutagens was examined. Levels of external PAH exposures were assessed using personal air monitoring and surface wipes of skin. Significant increases in urinary PAH metabolites and mutagenicity were seen after fire suppression events. Empirical relationships between urinary PAH metabolites and duration of fire event and skin concentrations of PAHs suggested that dermal contamination during live fire events is a major route of exposure. Overall, the results from both studies identified factors that may affect an individual’s concentrations of urinary biomarkers of combustion emission exposure. This may be used to identify at-risk populations and/or determine effective exposure reduction techniques to these hazardous compounds.

Mutagen-sensitive (mus) mutations in Drosophila melanogaster render developing flies hypersensitive to the lethal effects of DNA-damaging agents. In general, mus mutations identify DNA repair-related genes. In this study, 5 new second chromosome mus mutations (mus205B¹, mus208B¹, mus209B¹, mus210B¹ and mus211B¹), selected on the basis of sensitivity to methyl methanesulfonate (MMS), were characterized using a variety of genetic tests. One test measured the MMS-sensitivity of double mutant mus strains compared to their component single mutants. Mutant interactions were examined in 8 double mus and in 2 triple mus strains containing combinations of mus201D¹, mus205B¹, mus208B¹, mus210B¹ and mus211B¹ (or mus211B²). These analyses have revealed predominantly synergistic and epistatic responses to MMS. Taken together with the findings of previous genetic and biochemical studies of Drosophila mus strains, these results suggest that 3 major repair pathways may operate in flies to correct damage caused by MMS. Mutagen cross-sensitivity data and the results of the interaction studies suggest that mus mutations might serve as rapid and sensitive bioassays of somatic genotoxicity caused by mutagens and carcinogens. To explore this possibility, a simple mutagen test system was devised employing triple mutant mus strains. One strain (mus208B¹ mus210B¹ mus211B²) was tested for sensitivity to 14 mutagens/carcinogens and 2 non-carcinogens. Eleven of the mutagens/carcinogens were readily detected as genotoxic. Both non-carcinogens were non-genotoxic. These preliminary results demonstrate the feasibility (and some limitations) of the proposed somatic genotoxicity assay and emphasize the need for further test validation using a larger chemical data base. The temperature-sensitive lethal mutation mus209B¹ was subjected to extensive genetic analyses and to temperature shift experiments during development. This locus was found to encode a product(s) that (1) is essential for viability at virtually all pre-imaginal developmental stages (the latter half of pupation appears to be an exception), (2) is necessary for wildtype levels of resistance to the genotoxic effects of MMS and ionizing radiation, and (3) is required for female fertility. Confirmation of the pleiotropic nature of this mutation was obtained by meiotic and cytogenetic mapping studies and by complementation tests with a series of allelic mutations. The mus209B¹ phenotypes are similar to ones conferred by mutations in Drosophila and yeast that disrupt various aspects of chromosome metabolism. In this context, some possible roles for mus209B¹ are discussed. / Science, Faculty of / Zoology, Department of / Graduate

The SUC2 locus of Saccharomyces cerevisiae encodes two forms of invertase; a constitutively expressed cytoplasmic enzyme and a glucose-repressible secreted and glycosylated enzyme which is initially produced with an amino-terminal signal peptide. The coding sequence of the SUC2 locus has been placed under the control of the constitutive ADH1 promoter and transcription terminator in a centromere based yeast plasmid vector from which invertase is expressed in a Sue" strain of yeast. Oligonucleotide-directed mutagenesis has been used to create a PstI site in the gene at the point encoding the signal peptide cleavage site. An internal methionine codon, the translation start for the cytoplasmic invertase, has been replaced by a serine codon. Mutants in the signal peptide sequence have been produced by replacing the region of the gene upstream of the PstI site with synthetic oligonucleotide cassettes with mixtures of nucleotides at several positions. The mutants could be divided into three classes based on their ability to secrete invertase. The first class of mutants produced secreted invertase, but in reduced amount. There is no obvious correlation between mutation and phenotype. The second class, represented by mutant 4-55B, also exhibited a reduced level of invertase, but a significant fraction (30%) of the enzyme is intracellular. This mutant had a delay in signal peptide cleavage which retards passage of invertase through the secretory pathway. The third class was defective in secretion. Most were defective in translocation from the cytoplasm to the lumen of the endoplasmic reticulum (ER), and produced enzymatically active, non-glycosylated pre-invertase in the cytoplasm. This class of mutant invertases, when transcribed and translated in vitro, was not processed by canine pancreas signal recognition particle (SRP) and microsomes. Comparison of the sequences of the mutant signal peptides of this non-translocating class identifies amino acids at the extreme amino-terminus as the causative defect. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

<p> In order to compare the mode of action of mutagens which cause mass conversion of green Euglena to colorless forms lacking chloroplasts, mutants were selected either for resistance to U.V. light or for resistance to N-methyl-N-nitroso-p-toluenesulfonamide (MNTS). The U.V. resistant mutants selected showed strong resistance to U.V. but the slow growth of these mutants indicated that they probably carried multiple lesions. Some of the problems inherent in selection techniques were explored and discussed. A mutant selected for resistance to MNTS was found to have the ability to convert MNTS to an innocuous compound N-methyl-p-toluenesulfonamide. Experiments using the MNTS resistant strain provide information concerning the mode of action of MNTS and the related mutagen nitrosoguanidine.</p> / Thesis / Doctor of Philosophy (PhD)

In the present study DNA damage was measured in peripheral blood lymphocytes from polyposis coli and colorectal cancer patients, treated with different dietary and environmental compounds and compared with lymphocytes from healthy individuals. In addition, confounding factors such as age, gender, alcohol intake and smoking habits were taken into consideration. The assays used in this study included the Comet assay, the Micronucleus assay, the Micronucleus-FISH assay and the sister chromatid exchange assay. The food mutagens, PhIP and IQ, as well as titanium dioxide nanoparticles (TiO2 NPs) induced a dose dependent increase in the DNA damage and chromosomal abnormalities in all tested groups regardless of confounding factors. Prior to experiments physicochemical characterisation of nanoparticles was conducted. In the presence of the flavonoids, quercetin and rutin that were acting in an antioxidant manner, the DNA damage resulting from the highest doses of food mutagens was significantly reduced. Thus, dietary supplementation with flavonoid-rich vegetables and fruits may prove very effective in protection against oxidative stress. The polyposis coli and colon cancer patients were more susceptible to food mutagens, PhIP and IQ, as well as TiO2 NPs, and in the majority of cases had a higher level of DNA damage in the Comet assay and higher cytogenetic damage in the Micronucleus assay. In the final project, twelve frequently encountered (NewGeneris) chemical compounds were evaluated to establish their damaging potential in lymphocytes and spermatozoa from healthy donors. The highest damage was produced by DNA reactive aldehydes, food mutagens and benzo[a]pyrene when assessed with the neutral and alkaline Comet assay with and without metabolic activation.

Thesis (M. Sc.) (Hons.) -- University of Western Sydney, Hawkesbury, 1997. / Thesis submitted for the degree of Master of Science (Honours), School of Horticulture, University of Western Sydney, Hawkesbury, 1997. In Chapter 1, figures 1.1 and 1.2 are not reproduced in the text. Bibliography : leaves 112-135.