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Sulfonamide- and sulfone-induced hypersensitivity reactions are thought to be mediated through bioactivation of parent drug molecule(s) to their respective reactive metabolite(s). In order to explain the cutaneous drug reactions caused by sulfonamides and sulfone, a mechanism can be proposed by which the bioactivation of these drugs in keratinocytes of the skin forms reactive hydroxylamine metabolites that can covalently bind to cellular proteins, which in turn act as antigens leading to the cascade of immune reactions resulting in a cutaneous drug reaction. In order to probe the proposed mechanism, we determined the enzymes responsible for the bioactivation of these parent drugs to their hydroxylamine metabolites in cultured human keratinocytes. It was found that flavin containing monooxygenases and peroxidases play an important role in the bioactivation of these drugs in keratinocytes. We also confirmed the presence of these enzymes in keratinocytes. Interestingly, though cytochrome P450s are important in the oxidation of parent arylamine xenobiotics to their hydroxylamine metabolites in the liver, they do not appear to play a significant role in the bioactivation of these drugs in keratinocytes. The hydroxylamine metabolites of sulfamethoxazole and dapsone can undergo autooxidation, generating reactive free radicals. Our studies showed that both of these metabolites elevate oxidative stress in keratinocytes by forming reactive oxygen species. Though the cytotoxicity induced by these metabolites is not correlated with the extent of oxidative stress, the generation of reactive oxygen species may be important finding as these species can act as danger signals that activate antigen presenting cells in the skin. As a possible explanation for the idiosyncratic nature of these reactions, folate deficiency was studied as a potential risk factor. However, the results of these studies suggested that deficiency of folic acid in keratinocytes does not predispose such cells to the toxicity associated with the parent drugs or their metabolites. Unexplored is the potential role of such deficiency on the immune response itself.

Atmospheric transport and dispersion modeling systems are often used in assessing human exposures to chemical hazards. Models validated through quantitative and qualitative evaluation can be applied to epidemiologic study. Here, we modeled the 2005 Graniteville, South Carolina, USA railcar release of chlorine using dense gas plume dispersion models including the Hazard Prediction and Assessment Capability (HPAC) and Areal Locations of Hazardous Atmospheres (ALOHA). The release volume (54,915 kg) and rate was estimated by an engineering analysis combining semi-quantitative observations and fundamental physical principles. The use of regional meteorological conditions was validated by statistically (correlation, mean bias, root mean square deviation) comparing 1,024 HPAC concentration and surface dosage point estimates generated by two source-location weather data sets. An improved HPAC model was then statistically (correlation, root mean square deviation) compared to the earlier HPAC model using up to 9,446 surface dosage sampling points paired in time and space. The older HPAC model consistently overpredicted compared to the newer, refined model. When compared to HPAC, the ALOHA model significantly overpredicted downwind, centerline concentrations (up to 55 times that of HPAC). The refined HPAC model was then evaluated against post-incident environmental indicators of exposure such as phytotoxicity, corrosion events, deposition benchmarks, casualty data and exposed animal health outcome. A further sub-analysis was performed by comparing observed dog health outcome-derived exposure estimations versus model-predicted exposure. This statistical sub-analysis showed good agreement between observed and estimated, particularly when a sub-cohort of indoor dogs was excluded to determine the impact of structural shielding. Although the model was favorably evaluated based on literature-established standards, further assessment should be performed before the model can be fully validated and applied in human epidemiologic study to estimate acute exposures. Language: English / 1 / Dev D. Jani

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Extraction, production, utilization and disposal of material resources have been undertaken continuously for much of human histories. Unavoidably, all of these activities have disturbed our environment, and subsequently have been harmful to humans and ecosystems in this and future generations. Due to time lag associated with both environment impact and the effects of measures taken to reduce this impact, existing approaches (i.e. monitoring and reacting) do not give sufficiently rapid feedback for effective environmental management. With regard to the complexity and concern related to environment-health chain effects, there is currently no environmental tool or approach that can provide comprehensive information and indicators covering all major environment and health themes, to enable decision makers to make informed judgements about regional policies and plans, relating to the sustainable use and disposal of material resources. Consequently, there is a need for developing a new approach by taking account of a multidisciplinary concept used in this thesis. Substance Flow Analysis (SFA) has been mainly applied in order to provide input information for Health Risk Assessment (HRA). The SFA approach provides the quantity of the substance that is transported (flows) and stored in the system (stock), and of which sub-system, flow, and process is the greatest concern. The HRA approach provides estimates of human health risk associated with site, activity and facility. An environmental fate and transport model is another key knowledge area incorporated into the HRA process. An integrating method of SFA, environmental fate and transport, and HRA is developed and illustrated by a case study of cadmium in Australia. This thesis shows that this new integration of existing stand-alone methods can provide holistic information and useful indicators covering all significant economic activities, environment, flows, and health risk assessment for selected substances. This enables better decision making on the use and disposal of substances at a range of levels in the economy, from corporations to regions and nations.

The dominant paradigms of the past decade involve the preservation of biodiversity through the use of landscape corridors and buffer zones, as well as the integration of economic growth through sustainable use. The International Biosphere Reserve (IBR) program, as defined in the Seville Strategy, encourages locations already involved in conservation to continue to protect biodiversity and foster harmonious relationships between humans and their environment through sustainable development. An excellent example of an IBR is the Mammoth Cave Area Biosphere Reserve (MCABR) in south-central Kentucky. In order to measure the significance of the implementation of the Seville Strategy in the MCABR, a methodology was developed which not only measures the implementation level of the Seville Strategy, but also the policies involved in the implementation procedure. Twenty-four indicators, designed by the authors of the Seville Strategy, were analyzed. These indicators were broken down into three categories, administrative, research, and educational indicators. The results of the analysis show that the implementation of the MCABR has had a significant impact on the biodiversity, environmental management, and sustainable development of the Mammoth Cave area. This methodology has the potential to successfully measure other IBR programs at the local, national, or international level.

The relatively recent interest in the U.S. in the development of atmospheric fluidized bed combustion (AFBC) has been preceded by two main factors. First of these is the ever present problem of acid rain and growing public support for cleaner burning fossil fuels. Second is the increasing demand on public landfills and subsequent need for burning of municipal solid waste. From these factors and their corresponding influences, Western Kentucky University has the impetus and has received the financial assistance necessary to build and develop a laboratory scale AFBC system. A brief history of the events leading to this development, as well as selected results from the last 12 months of this project are discussed.

The ability for wetlands to purify contaminated water is not a new concept. Natural wetlands have been cleansing water within our environment for ages. After studying the process of natural wetlands the same concept was applied to municipal waste. It is the success of constructed wetlands treating municipal waste that created the new idea for the application of a wetland system to treat wastewater from livestock facilities. Through proper design and management, constructed wetlands may be useful for reducing the nutrient concentration of waste (Rieck el al., 1996). Taking into consideration the higher nutrient loads of livestock waste, the same basic idea of constructed wetlands used for municipal waste is being utilized to protect public water sources from contamination of livestock wastes. In this study a constructed wetland (total recycle) built for the purification of swine waste was evaluated. In cooperation with Pig Improvement Company of Allen County, Kentucky, water samples were collected from the nine connected cells making up the wetlands created at The Dogwood Ridge Farm. After collection of the samples, they were analyzed at the Western Kentucky University Environmental Laboratory. Samples were tested for levels of the following parameters: • Ammonia Nitrogen • Nitrate Nitrogen • Total Phosphorus • Biological Oxygen Demand • Total Suspended Solids • Total Dissolved Solids • Fecal Coliform • Conductivity • Mineral Elements The data in this report accounts for seven sample dates throughout 1996. Samples were also collected for three additional months prior to the first sample date in which data is reported, although these dates are considered to be a part of the initial start up phase for the testing period. Sample dates within the start up phase are not included among the results. With greater concern directed towards higher water quality standards, there is the need to eliminate any activities resulting in non-point source pollution (NPS). Livestock waste is considered one of the leading causes of NPS pollution which has created this awareness for better waste management. As traditional waste treatment equipment is commonly too expensive for the average livestock producer, constructed wetlands are proving to be an affordable, environmentally friendly, and manageable solution for livestock waste treatment.