Freshwater teleost fish often experience natural and anthropogenic conditions that result in fluctuating energy availability, therefore the ability to acquire, transform and use energy is essential for the survival of these fish. Polychlorinated biphenyls (PCB's) are recognized as physiological sources of stress to fish as they incite defense mechanisms that are generally costly in terms of metabolic resources. Over time, such responses may decrease individual performance and possibly fitness by changes in foraging, migration and escape behaviors, and the population in terms of reproductive capacity due to the alterations in energy allocation following an exposure. The main goal of this study was to determine if a sublethal exposure to PCB-126 affects the energy budget of the fish and can therefore be responsible for functional deficiencies associated with their locomotion. Fish were injected low (100 mug/kg) and high (400 mug/kg) concentrations of PCB-126 and swimming performance parameters including critical swimming speed, metabolic rate and recovery ratios were evaluated. EROD activity was also measured in the liver as an indication of PCB-126 intoxication while blood and white muscle tissue metabolites were analyzed to quantify the physiological disturbance levels associated with this exposure. A significant decrease was observed in the swimming performance of rainbow trout for the low and high PCB-126 treatments as well as an impaired recovery with increasing level of PCB exposure following exhaustive exercise. This study also showed the occurrence of physiological disturbance by a reduction in the hepatosomatic and spleen somatic indices and elevation of plasma cortisol and glucose levels, as well as white muscle reductions in glucose and glycogen indicating higher metabolic costs during recovery and muscle restoration for PCB-exposed fish. Overall, this research provides insights into the sublethal effects of toxic organic compounds on fish.

The term "biomarker" refers to an indicator employed to monitor the interactions between a xenobiotic and an individual, provide information of an individual's biologic state, or refer to an individual's susceptibility to a xenobiotic, condition or disease. They are currently employed to assess exposure to, or effects from, environmental toxicants. It is important to have biomarkers that can accurately and precisely assess complex mixture exposures, since environmental exposures to single substances rarely occur outside the laboratory setting, and complex exposures are often associated with specific occupational or environmental settings. This project employed microarray technology and subsequent bioinformatic analyses to identify candidate biomarkers of in vitro exposure to coal tar extract. Murine pulmonary epithelial cells were exposed to coal tar extract and gene expression was assessed using microarrays. The results showed that expression of genes involved in steroidogenesis, cytokine-cytokine interaction, angiogenesis, as well as several genes that code for secreted proteins, were altered by coal tar exposure. The entire work constitutes the initial stages of a project that will ultimately identify gene expression and secretome profiles that are specific to coal tar exposure.

Cyanobacteria produce toxic compounds with the hepatotoxic microcystins being the most commonly encountered in freshwater. Microcystins are produced by several cyanobacterial genera and show large spatial and temporal variation in aquatic ecosystems as both toxigenic and non-toxigenic strains may co-exist and reach bloom levels. The regulation of microcystin production, the ecological or physiological role(s) of microcystins, and the factors that specifically promote toxic cyanobacterial blooms are not yet well understood. The first part of this thesis tested the role of light intensity in regulating the production and composition of microcystin congeners using laboratory culture experiments. The second part, using field observations and a lake enclosure experiment, examined the effects of physical, chemical and biological variables on microcystin concentrations and the growth of toxigenic cyanobacteria in a shallow, mesotrophic lake. Throughout, chemical and molecular based methods were utilized along with traditional culture and limnological methods in order to measure microcystin production and the presence of toxigenic cyanobacteria. Light intensity had a significant effect on microcystin concentrations and congener composition. However, there were no clear advantages of either toxigenic or non-toxigenic strains in terms of their ability to grow, compete for light resources, or dominate in a mixed-culture setting. The response of each strain of Microcystis aeruginosa was unique such that generalizations could not be made between toxigenic and non-toxigenic strains in terms of their competitive ability in nature; microcystin production did not appear to impair the competitive ability of toxigenic strains. In field studies of a shallow mesotrophic lake over two years, the number of microcystin gene copy numbers (mcyD) did not correlate well with microcystin concentrations. Both within the lake and across a nutrient gradient established in in situ enclosures, the best predictor of the presence of toxigenic strains was the actual biomass of potentially toxigenic genera (mainly Anabaena and Microcystis ), rather than any particular chemical or physical variable such as light. However, both environmental and biological variables were significant in predicting actual microcystin concentrations. The combination of molecular, chemical, and taxonomic data appears necessary to understand and predict toxic cyanobacterial blooms.

Mercury (Hg) is a persistent contaminant present naturally in our environment but, as a result of anthropogenic activity, has now accumulated in lake sediments at concentrations 2.2 times greater than those found in pre-industrial sediments (pre-1850) (Chapter 2). However, present spatial patterns of mercury accumulation do not match patterns in natural mercury accumulation (Chapter 4). Once spatially uniform across south-central Ontario, mercury concentrations in present-day lake sediment display strong spatial correlation. Further, the broad scale spatial patterns (>500 km) which correlate with mean annual precipitation (MAP) found to significantly predict pre-industrial sediment Hg, has now been replaced with finer scale spatial patterns (<120km). Rather than one significant spatial scale explaining sediment Hg, as during the pre-industrial era (p = 0.01), present sediment Hg are predicted by more than one spatial scale (p < 0.001, p < 0.001) both of which are highly correlated with lake pH. While MAP and lake pH explain much variance in mercury accumulation, their significance is spatially dependent. In addition to differences in spatial trends, models which suggest that pre-industrial sediment Hg was in steady state with watershed accumulation do not apply to present day Hg accumulation (Chapter 2). Instead, Hg enrichment in lake sediment decreased as a function of drainage ratio (R2 = 0.458, p = 0.0001), suggesting that Hg export from watersheds may be lagging behind atmospheric Hg deposition. The enrichment of Hg since the pre-industrial era is also influenced by the amount of open water (r = 0.91, p = 0.035), mining activity (r = 0.94, p = 0.019) and organic deposits within surficial geology (r = -0.91, p = 0.034) which lead to local hot and cold spots (Chapter 4). There is a close link between the present-day sediment Hg concentrations and that in dorsal muscle of smallmouth bass (Micropterus dolomieul) (r = 0.92, p = 0.0002) (Chapter 3). However, the discrepancies that do exist between these two components are determined by landcover, longitude, and dissolved organic carbon. An examination of methylmercury in two catchments revealed that the concentration of methylmercury in stream water from ten watersheds is predicted from a time sensitive (lagged regression) interaction among sulfate (tpartial = 9.60, p < 0.001), dissolved organic carbon (tpartial = 7.06, p < 0.001), and temperature (tpartial = 4.44, p < 0.001) (Appendix A). The error of which decreases exponentially with increasing wetland size (R2 = 0.838, p = 0.0105). The difference between methylmercury inflow and outflow (MeHgNet) within these two catchments (a dystrophic and an oligotrophic lake) was seasonally dependent (Chapter 5). However, seasonal accumulation and loss of methylmercury was significantly larger in magnitude within the dystrophic lake. Further, a net production of methylmercury was found in the dystrophic lake alone (1.9 +/- 0.3 mg·d -1). This study examines Hg contamination in a relatively pristine, remote environment which like other regions, has been challenged by contaminants originating from far distances.

Antagonists have been crucial in the characterization of nicotine's pharmacology. Initial evidence for the existence of central nicotinic receptors was based on the fact that nicotine produced a number of behavioral effects that were antagonized by ganglionic blockers that crossed the blood-brain barrier, such as mecamylamine and pempidine. Although the mechanism of action of these compounds has been studied extensively in the periphery, little is known about their mechanisms of action in the brain. These compounds are thought to be noncompetitive antagonists due to the fact that they do not compete for agonist binding to brain homogenate in vitro. However, pharmacological evidence in support of noncompetitive antagonism is lacking. Dose-response curves for nicotine were determined in the presence of various doses of pempidine for depression of spontaneous activity and antinociception in mice. Pempidine was found to shift the dose-response curves for these effects of nicotine in a manner consistent with noncompetitive antagonism. A number of mecamylamine analogs were investigated for antagonism of these central effects of nicotine as well. These studies revealed that the N-, 2-, and 3-methyls were crucial for optimal efficacy and potency and suggests that these compounds possess a specific mechanism of action, possibly involving a receptor. Furthermore, the structure-activity relationships for the mecamylamine analogs were found to be different than that previously reported for the agonists, suggesting that they do not act at the same site. The binding of [3H]-L-nicotine and [3H]-pempidine was studied in vitro to mouse brain homogenate and in situ to rat brain slices. The in situ binding of [3H]-L-nicotine to rat brain slices was quantitated autoradiographically to discrete brain areas in the presence and absence of 1, 10 and 100 µM nicotine and pempidine. Pempidine did not effectively displace [3H]-L-nicotine binding. The studies with [3H]-pempidine failed to demonstrate saturable binding. The evaluation of the antagonism of nicotine by mecamylamine and pempidine presented in this thesis supports a noncompetitive action of these compounds in the brain. The shift in the dose-response curves for nicotine, the structure-activity relationship for mecamylamine analogs and the binding studies are consistent with this hypothesis. The noncompetitive nature of these compounds suggests that they do not compete for the binding site of the agonist, and that endogenous nicotinic antagonists may exist in the brain.

Arecoline and nicotine are two psychoactive cholinergic alkaloids. Arecoline is primarily a muscarinic agonist while nicotine, at low doses, is a nicotinic agonist. The experiments in this dissertation investigated two major areas: (1) the role of different factors in the development of tolerance to the behavioral effects of arecoline and nicotine, and (2) the possible mechanism and site of action of the discriminative stimulus (DS) effects of arecoline and nicotine. The role of dispositional and physiological factors comfiared to behavioral factors in the development of tolerance to the effects of arecoline and nicotine on operant behavior was assessed in Experiments I and II, respectively. In part one of Experiment I, rats were trained to respond (M1 a variable-interval 15 second (VI-15) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days Of arecoline administration prior to the session, the dose-effect relationship for total responses was not shifted. However, the dose-effect relationship for total reinforcements was shifted to the right. In part two of Experiment I, rats were trained to respond on a fixed-ratio 20 (FR-ZG) schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the seSsion and a second group received arecoline injections after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship in the pre-session group compared to the post-session group. These data demonstrate the importance cflf behavioral factors in the development of tolerance to arecoline. In Experiment II, rats were trained to respond on a VI-15 second schedule of milk reinforcement. Dose-effect relationships were determined prior to and during chronic nicotine (2.28 mg/kg/day) administration. One group of rats received daily injections Of nicotine prior to the session, another group received nicotine injections after the session. After 36 days of chronic treatment, similar degrees of tolerance were observed in both groups, however the group receiving post-session nicotine developed tolerance at a faster rate. The data suggested that 21 complex interaction of nicotine and the experimental environment affected the rate of tolerance development. Experiment III characterized the DS effect of arecoline. Using a two-lever operant paradigm, rats were trained to discriminate arecoline from saline on a VI-12 second schedule of milk reinforcement. Rats could learn to discriminate 1.74 mg/kg arecoline from saline, but not 0.58 mg/kg from saline. Agonist and antagonist studies demonStrated that the DS effect of arecoline is mediated through central muscarinic receptors. In Experiment IV, the ability of physostigmine to interact fiith the DS effect of nicotine (1.14 mg/kg) and arecoline (1.74 mg/kg) was assessed. Physostigmine (0.125 mg/kg) pretreatment shifted the dose-effect relationship for arecoline to the left but did not affect that of nicotine. Physostigmine (0.25 mg/kg) almost completely generalized to the DS effect of arecoline but not to the DS effect of nicotine. These data suggest an interaction of endogenous acetylcholine with muscarinic receptors but not with nicotinic receptors. In Experiment V, the ability hf arecoline and nicotine injected directly into the dorsal hippocampus (DH) and mesencephalic reticular formation (MRF) to generalize to the DS effect of peripherally administered arecoline (1.74 mg/kg) and nicotine (1.14 mg/kg) was assessed; Nicotine injected into these sites generalized in a dose-related manner to nicotine. The MRF was slightly more sensitive than the DH. Arecoline injected into either site did not generalize to the DS effect of, peripherally administered arecoline. However, a decrease in response rates was observed.

The access of drugs to variofis sites of action in the body is impeded by a succession of membranes. Likewise, the removal of a drug or foreign substance from the body is similarly dependent on the ability of the substance under consideration to permeate biological barriers. A con-committant problem generally arises concerning the overall time course of drug action: that of drug storage through binding or similar processes. Schanker (196h) however, has stated that "Although the mechanisms of localization and those of membrane transfer are in many respects different problems, there are some instances in which they are inseparable parts of the same problem." Examples include phenomena whereby the binding of a substance to the cell membrane is required for transport (Rosenberg and Wilbrandt, 1955; Peters; 1960; Lacko and Burger, 1961; Schwartz and Matsui, 1967; Stein, 1967). From a functional standpoint, body membranes may be classified in three major categories (Schanker, 1962b); membranes several cell layers thick such as skin, those one cell layer thick such as the brush border epithelium of the intestine, and membranes less than one cell in thickness such as the cell membrane itself or the membranes of organelles (e.g. mitochondria). Thus, except for the barriers associated with subcellular structures, the cell membrane 6 (or plasma membrane as it is often called) may be considered the fundamental unit of body membranes in general.

Occupational exposures to hand-arm vibration and dust have been shown to have deleterious human health effects. Exposure to vibration from pneumatic tools can result in Hand-arm Vibration Syndrome (HAVS), which is a collection of vascular, sensorineural, and musculoskeletal disorders. Exposure to dust can result in a variety of adverse respiratory symptoms. The use of a low-frequency, high-magnitude sand rammer tool during mold-making processes at a foundry could result in significant exposure to these hazards, thus it is important to mitigate the associated risks in order to ensure worker safety. The goal of this study was to evaluate whether different pneumatic pressure levels and sand rammer types have an effect on reducing hand-arm vibration and dust exposures at a foundry. Vibration and dust measurements were obtained at three different pneumatic pressure levels (90 psi, 80 psi, 70 psi) and for three different sand rammer types (LM, SM, T). The primary concern of the study was reducing hand-arm vibration exposure. Measurements were taken in compliance with ISO 5349-1 resulting in frequency-weighted, root-mean-square (rms) acceleration values (m/s2). Significant differences in mean rms acceleration were observed across all pneumatic pressure levels and sand rammer types. At 90 psi the mean rms acceleration value was 25.53 m/s2, decreasing to 19.58 m/s2 at 80 psi, and further decreasing to 18.38 m/s2 at 70 psi. The mean rms acceleration values were 19.63 m/s2 for sand rammer LM, 21.46 m/s2 for SM, and 19.95 m/s2 for T. The results of this study indicate that reducing pneumatic pressure levels can reduce vibration exposure in the workplace when using low-frequency, high-magnitude tools. The results also indicate that the use of different sand rammer types produces differences in vibration exposure when tested across all pneumatic pressure levels. Dust measurements were taken concurrently with vibration measurements. The number of dust particles was counted for each pneumatic pressure level and sand rammer type. Overall, the mean particle count for the dust measurements was the highest at 90 psi (41,681) followed by 70 psi (33,514), and 80 psi (26,047). Sand rammer SM had the highest mean dust particle count at 35,732, followed by T at 34,460, and LM at 31, 382. The results indicate that lowering pneumatic pressure levels could potentially reduce dust exposure in the workplace when using a percussive tool such as a sand rammer. However, variability in the sampling conditions related to dust measurements weaken the association.

The mainstream breast cancer movement, as represented by pink ribbons and foundations like Komen and Avon, has been very influential in shaping the research agenda toward a cure and promoting education and early detection. In the 1990s, a "green" sub-movement emerged that focused instead on the link between environment, cancer, and health. This study examined how pink and green breast cancer organizations differ in terms of organizational policies, characteristics, internal structure, model programs, tactics, advocacies, and diversity; which of those factors explain why individual breast cancer organizations prefer green or pink advocacy; and whether the goals of pink and green organizations are converging or diverging. The qualitative study included fifty-four in-depth, semi-structured interviews with different stakeholders in the breast cancer movement. This research builds on the work of Brown (2009), who argues that breast cancer is an embodied health movement, and this dissertation demonstrates that attributes of organizations such as strategy, mission, and branding have led to a greater convergence between the pink and green wings of the movement, and green can no longer be understood as a sub-movement.

Hormesis is a nonlinear dose-response characterized by biological responses at low doses that are opposite to those observed at higher doses. Studies and review articles on hormesis are being published at an increasing rate by researchers from diverse disciplines and debate has emerged over the role hormesis in risk assessment. As a result, a survey was conducted to assess toxicologists and risk assessors knowledge and attitudes about the hormesis dose response. Study goals were to: (1) ascertain attitudes towards hormesis and other dose-response models, (2) identify whether acceptance or rejection of hormesis is based on knowledge of hormesis, predisposing values, or demographic characteristics, and (3) evaluate potential for response bias. The survey consisted of 44 questions pre-tested by 25 toxicologists and risk assessors. The survey was distributed via email to the membership of the Society of Toxicology and the Society for Risk Analysis, 9,500 potential respondents. The overall response rate was 17% (n= 1,463) with a completion rate over 87%. Major findings were that 50% of respondents indicated sufficient data exist to support the view hormesis occurs across a wide range of species and endpoints, 59% indicated evaluating potential benefits due to hormesis should be included in risk assessments, and 65% are in favor of modifying hazard assessment protocols to identify the presence of hormesis. Respondent characteristics such as: years of experience, society membership, education, residence, employment (excluding government and pharmaceutical companies), and political, economic or social views had little influence on opinion. One of the largest positive influences was experience with hormesis based on actual research; 79% of subjects who reported observing hormesis commonly in their studies agreed hormesis is broadly generalizable. The influence of non-response bias was evaluated through several internal and external measures. Despite a lower than hoped for response rate, but because of robust external validity measures, it is concluded that respondents’ opinions are likely a reasonable representation of the societies of which they are members. Because this is a baseline survey, a follow-up survey is in order. Future survey design should separately evaluate the science of dose-response from the regulatory approach to risk assessment.