Pharmacology, Toxicology and Environmental Health Commons^™

Deterministic Intracellular Modeling, Jacqueline B. Young

Theses and Dissertations

The United States Air Force is interested in the potential side effects at the cellular level from exposure to mission-essential chemicals. Presently, Air Force toxicology studies are conducted to help shed light in identifying potential hazards to workers. However, it takes a considerable amount of money, resources, and time to obtain and analyze experimental results from toxicology studies. The necessity for innovative methods that enable researchers to more effectively generate and analyze data is apparent.

Toxicity Of Tolyltriazole To Bacillus Microorganisms, Christopher J. Leonard

Theses and Dissertations

The safety of air travel in cold weather depends upon the use of aircraft deicing fluids (ADAF). The environmental and toxic effects of the ADAF component tolyltriazole are not well understood. Tolyltriazole is a potential human carcinogen and has exhibited microbial toxicity in Microtox test. This research used two methods to investigate the toxicity of tolyltriazole on bacillus shaped microorganisms. The first method compared the dissolved oxygen uptake of microcosms exposed to varying concentrations of tolyltriazole. When exposed to 1000 ppm tolyltriazole, all isolated species showed inhibition in respiration. There was no evidence that tolyltriazole at

A Pharmacokinetic Study Of The Effects Of Stress On Chemical Exposure, Sierra H. Suhajda

Theses and Dissertations

Following the Gulf War there were many concerns raised about human exposure to the combination of chemicals and stress. Stress causes several changes in basic functions of a human body, from breathing and blood flow changes to hormonal and enzyme changes, and increased permeability of the blood-brain barrier. Each of these changes can strongly influence chemical uptake, distribution, and accumulation in the body. The purpose of this thesis was to model and predict the changes that will occur when stress is combined with chemical exposure. Physiologically-based pharmacokinetic (PBPK) modeling is one tool that can be used to visualize, predict, and …

Chromate Dissociation From Primer Paint In Simulated Lung Fluid, Tiffany J. R. Morgan

Theses and Dissertations

OSHA has proposed a new strontium chromate exposure standard that would potentially cause Air Force paint facilities to be in violation of the proposed standard if adopted. This proposed reduction make the continued use of chromate containing primer paints very difficult. There is currently no acceptable replacements for chromate containing primer paints on AF aircraft. This study suggests that paint particles with chromate bound in primer paint may be unavailable for bodily absorption if inhaled and a reduced standard for painting applications may be unnecessary. Primer paint overspray was collected into simulated lung fluid (SLF) and allowed 6 hr, 24 …

Modeling Chemical Absorption Through Membranes, Jeffrey M. Hemmes

Theses and Dissertations

Understanding the processes involved in dermal penetration of chemicals and drugs is important to both toxicologists and pharmacologists. Researchers developing new drugs are interested in enhancing the penetration of chemicals through the skin, while environmental professionals are interested in limiting such penetration. For both types of applications, predictive biologically-based mathematical models can be very useful in understanding the processes involved, particularly when such models are based on physiological and biochemical parameters which can be measured experimentally. In this thesis we study two existing physiologically-based pharmacokinetic (PBPK) models that predict concentrations of neat and aqueous dibromomethane (DBM) absorbed into and through …

The Roles Of Several Kinases In Mice Tolerant To Delta-9-Tetrahydrocannabinol, Matthew C. Lee

Theses and Dissertations

It has been suggested that the CB1 G-protein-coupled receptor is internalized following agonist binding and activation of the second messenger pathways. The process of desensitization and resensitization is intimately involved with receptor internalization. Phosphorylation alters tolerance to cannabinoids thus contributing to tolerance. It is proposed that phosphorylation enhances the down-regulation of the CB1 receptor. These findings led us to look at which kinase(s) may be involved in cannabinoid tolerance. We therefore hypothesize that by preventing phosphorylation of the CB1 receptor, we may reverse tolerance. We evaluated our hypothesis by testing the role of several kinases in tolerance: protein kinase A …

Metabolic Inhibition Of A Toluene-Enriched Microbial Population Due To Lead (Pb2+): Verification Of A Free Metal Ion Toxicity Model, Patrick J. S. Marbas

Theses and Dissertations

A dissolved oxygen probe and an ion specific electrode were used to study the lead-induced metabolic inhibition in a toluene-enriched microbial population. Predicted toxicity values were compared to the actual toxicity responses using a free metal ion toxicity model (TM) which linked metabolic inhibition with lead activity. Experimentally derived values for the model parameters (lead activity and a lead distribution coefficient) were used in the TM. It was postulated that cellular metabolism is disrupted by the conformational changes to the cell's plasma membrane produced by lead ion adsorption. The predicted toxicity values were higher than the actual toxicity response. This …

Heavy Metal Toxicity In Bioremediation: Microbial Cultures And Microscopy, Jason B. Goodbody

Theses and Dissertations

This research employed a variety of microscopy and spread plating techniques to observe the effects of heavy metal treatments on a toluene-selected bacterial population. Microbial colonies were cultured on spread plates and the resulting numbers were compared to respiration data. The mechanisms of reproduction were demonstrated to be more sensitive to metal treatments than were the mechanisms of respiration. Phase contrast, Gram stain, fluorescent microscopy, were used to compare and document a wide variety of bacteria resulting from different metal treatments as well as from environmental changes within the source bioreactor. The removal of sensitive bacteria and the selection of …

Modified Model For Transient Response Of Mrna Synthesis To Magnetic Field Exposure, Timothy W. Crosnoe

Theses and Dissertations

It is a well-known fact that high frequency, or radio frequency, radiation can be directly harmful to biological tissue. The radiation frequencies to which humans are most exposed, however, are the extremely low frequencies, or ELFs. To date there has been no definitive measure for predicting the ability of low frequency electromagnetic radiation to cause adverse biological effects. Two specific measures, average magnetic field and kinetic index, have been used in studies to determine if they are useful predictors of adverse effects, specifically leukemia. Unfortunately, both have shown only marginal results. This thesis analyzed and improved the kinetic index measure …

Bioremediation: Factors Influencing Metal Ion Toxicity In A Toluene Selected Bacterial Population, Scott D. Hansen

Theses and Dissertations

This research was a general phenomenalistic overview of the effects of metals on the respiration rates of a toluene selected microbe culture. The metals studied were copper, zinc, cobalt, manganese and iron. Relative inhibition, Cu>Fe>Zn=Co>Mn, corresponded to hydrogen phosphate binding strengths. Inhibition was found to be pH dependent; it increased with increasing pH and was shown to correlate to an increased adsorption of metal onto the cell. Zn, Cu, and Co toxicities were shown to decrease with increasing magnesium concentrations. This decrease was linked to increased magnesium adsorption and decreased metal adsorption. The magnitude of effect was …

An Analysis Of 1994 Air Force Toxic Release Inventory Reporting, Brian A. Pollock

Theses and Dissertations

The purpose of this research is to analyze the Air Force's 1994 Toxic Release Inventory data. Statistical tests were used to meet the following research objectives: (1) review the CY 94 data to determine which chemicals were most often reported and which bases and major commands had the most releases in terms of the number of chemicals reported and the amount of chemicals reported and (2) investigate factors which could influence the reporting status of a facility. An analysis of the TRI data showed that dichloromethane was the chemical released in the largest amount while methyl ethyl ketone was the …

Effects Of Ammonium Perchlorate On The Thyroid Hormone Levels Of The Sprague-Dawley Rat, James H. King Jr.

Theses and Dissertations

The purpose of this research was to determine the threshold dose for ammonium perchlorate (AP) in the Sprague-Dawley rat. No dose response data exist for AP and the EPA has studied literature on the subject of perchlorates to determine a provisional reference dose. The Perchiorate Group, a consortium of DoD and industry representatives, believes this provisional reference dose is too conservative. This experiment was executed to provide dose response data on which to base a more accurate reference dose. The study consisted of eight groups of 12 Sprague-Dawley rats, six male and six female, which were exposed to incremental doses …

Determining Types Of Health Effects To Persian Gulf Veterans Due To Exposure To Occupational Hazards, Rebecca A. Nelson

Theses and Dissertations

Persian Gulf Veterans' Illnesses (PGVI) consists of multiple illnesses with overlapping symptoms and causes. This research examined health effects literature concerning several occupational chemicals, to identify significant adverse health trends and assess research quality, completeness, and relevance. After compiling this knowledge base, the research focus was narrowed to Chronic Fatigue Syndrome (CFS), solvents, and pyridostigmine bromide (PB). The existing data was analyzed and compared to PGVI health data using the nonparametric statistical method of contingency table analysis to prove or disprove a link between the substance and PGVI. The results of the contingency table analysis were used to make inferences …

Physiologically-Based Pharmacokinetic Modeling Of Skin Absorption Using Dermal Subcompartments, Richard L. Bookout Jr.

Theses and Dissertations

Dermal penetration of chemicals and drugs is important to both toxicologists and pharmacologists. Drug developers try to enhance and environmental professionals try to limit penetration of chemicals through the skin. Both can use predictive biologically-based mathematical models to assist in understanding the processes involved. When these models are based on physiological and biochemical parameters which can be measured in the laboratory, they can be extremely useful. Appropriately validated models based on first principles can be predictive of human exposures when the processes involved are adequately understood. In this thesis we develop four new physiologically-based pharmacokinetic (PBPK) models to predict blood …

A Retrospective Quantitative Assessment Of Trichloroethylene Exposure Of Workers At Aircraft Maintenance Facilities At Hill Air Force Base Through The Use Of Modeling, Anthony O. Copeland

Theses and Dissertations

Monte Carlo simulation and source-receptor modeling are used to estimate the TCE exposures encountered by select workers at aircraft maintenance facilities at Hill Air Force Base between 1955 and 1979. An epidemiological study of this group, a retrospective cohort study of 14,457 workers who were employed at the base for a minimum of one year between 1952 and 1956, was headed by Dr. R. Spirtas of the National Cancer Institute to evaluate mortality associated with occupational exposure. One of the major conclusions of the study was that TCE 'probably does not pose a strong carcinogenic risk for man.' In the …

Development Of A Comprehensive Base-Level Environmental Training Program For Total Environmental Compliance, William M. Barrett Jr

Theses and Dissertations

The leadership of the Air Force has established a goal of total environmental compliance because it is the right and necessary thing to do. Commitment to this goal can be accomplished through strong leadership, however, achieving this goal can only be accomplished through effective training. The lack of consistent guidance for developing and executing comprehensive base- level environmental training programs has forced bases to develop these training programs by whatever means available to them. This has resulted in a broad variation in the thoroughness of base-level training programs throughout the Air Force. This research effort investigates the relationship between the …

A Comparative Pharmacokinetic Study Of The Role Of Gender And Developmental Differences In Occupational And Environmental Exposure To Benzene, Elizabeth A. Brown

Theses and Dissertations

The purpose of this study is two-fold. First, it shows that physiological differences between men and women result in gender-specific exposures with respect to benzene. Second, it assesses the potential for a lactating woman's occupational and personal benzene exposure to impact a nursing infant's exposure, highlighting the possibility of subjecting an infant to the effects of industrial chemicals via breast feeding. This study employs physiologically based pharmacokinetic (PBPK) modeling to investigate the influence of physiological parameters and to evaluate the ability of inhaled benzene to transfer from mother to infant through breastmilk. The models are run through scenarios that simulate …

Development Of Field Guidance For Assessing Feasibility Of Intrinsic Bioremediation To Restore Petroleum-Contaminated Soils, John T. Enyeart

Theses and Dissertations

This research evaluated the process of intrinsic bioremediation, also called natural attenuation, and the parameters that affected it. The goal of this study was to use these intrinsic bioremediation parameters to develop a valid prediction of the cleanup duration using this restoration technology. This analysis was limited to a JP-4 release and focused on the remediation of the BTEX constituents to a cleanup level of 10 ppm total BTEX. The review of intrinsic bioremediation found that the BTEX hydrocarbons can aerobically and anaerobically biodegrade. Of the many factors that affect intrinsic bioremediation, those that most influenced its occurrence were the …

A Risk Assessment Of The Health Liabilities From Exposure To Toxic Metals Found In The Composted Material Of Air Force Municipal Solid Waste, Timothy L. Merrymon

Theses and Dissertations

This thesis assesses the risk of the health liabilities from exposure to toxic metals found in the composted material of Air Force municipal solid waste (MSW). The goal is to determine the probability that the composted MSW could be a health hazard if it were used as a soil amendment. The research limited the assessment of the exposure risk to heavy metals found in raw MSW and its resulting compost. The thesis uses reviews of present literature to examine the food and soil ingestion exposure pathways. These pathways are assessed using the heavy metal concentrations found in MSW compost and …

A Refinement Of Risk Analysis Procedures For Trichloroethylene Through The Use Of Monte Carlo Method In Conjunction With Physiologically Based Pharmacokinetic Modeling, William J. Cronin Iv, Eric J. Oswald

Theses and Dissertations

This study refines risk analysis procedures for trichloroethylene (TCE) using a physiologically based pharmacokinetic (PBPK) model in conjunction with the Monte Carlo method. The Monte Carlo method is used to generate random sets of model parameters, based on the mean, variance, and distribution types. The procedure generates a range of exposure values for human excess lifetime cancer risk of lxl0 (exp-6), based on the upper and lower bounds and the mean of a 95% confidence interval. Risk ranges were produced for both ingestion and inhalation exposures. Results are presented in a graphical format to reduce reliance on qualitative discussions of …

A Comparative Test And Evaluation Of Lead-Based-Paint Test Kits, Lynn S. Hill

Theses and Dissertations

This research compares the performance of five chemical spot-test kits on lead-based paints. The kits are designed to give a qualitative assessment of lead in paint. The intent of the research effort was to develop a standard evaluation procedure for follow-on studies and assess the baseline performance of the kits. The test kits in this study use either sodium sulfide or sodium rhodizonate to react with the lead. The presence of lead is indicated by a color change. The kits were used to test prepared sample paint films at seven known lead concentrations ranging from 0.04 to 1.3% by weight. …

Physiologically Based Pharmacokinetic Modelling Of Percutaneously Absorbed Dibromomethane Utilizing Multiple Dermal Sub-Compartments, Christopher R. Mcdaniel

Theses and Dissertations

The goal of this study was to develop a physiologically based pharmacokinetic (PBPK) model that predicts mammalian blood concentrations of dibromomethane following exposure by dermal absorption more accurately than a previously developed Homogeneous Dermal Model. The Homogeneous Dermal Model contains a dermal compartment with no dermal sub-compartments. The 1:1 Dermal Model developed in this research contains a dermal compartment with a stratum corneum and a composite dermal sub-compartment of equal volume. This model yields predictions which are 21.4 percent more accurate than the original homogeneous model. In order to represent skin anatomy more accurately, the 1:10 Dermal Model variation was …

Pharmacological Manipulation Of Protein Kinase C Modulates The Growth And Lineage Commitment Of Enriched Human Myeloid Progenitor Cells Induced By Hematopoietic Growth Factors, Fei Li

Theses and Dissertations

The activity of protein kinase C (PK-C) has been implicated in regulating the growth and differentiation of both normal and neoplastic hematopoietic cells. We have examined the effects of the PK-C activators, phorbol 12,13- dibutyrate, mezerein, and bryostatin 1, on the proliferation and lineage commitment of enriched CD34+ human myeloid progenitor cells stimulated by lL-3, GM-CSF, stem cell factor and the lL-3/GM-CSF hybrid cytokine plXY321. Coadministration of these PK-C activators with plateau concentrations of rlL-3 or rGM-CSF induced 100-150% increase in the number of day 14 CFU-GM.with a selective stimulation on neutrophil and macrophage lineages while inhibiting eosinophilic growth. plXY321 …

Evidence That Nicotine Can Acutely Desensitize Central Nicotinic Cholinergic Receptors In Vivo, John Randolph James

Theses and Dissertations

Current concepts concerning nicotine's central nervous system (CNS) mechanism(s) of action suggest that this drug is producing its effects via an interaction at nicotiniccholinergic receptors (nAChRs) which open a membrane cation channel. Following initial opening of the channel, nicotine appears to induce a rapid desensitization of the nAChRs, closing the channel and resulting in a cessation of nicotine's effects. Research presented here will provide evidence of this secondary desensitization process in vivo by demonstrating nicotine's ability to induce acute tolerance in the discriminative stimulus (DS) paradigm. The ability of nicotine to elicit DS control of behavior was significantly reduced via …

Effects Of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin (Tcdd) On The In Vitro Antibody Response: Differential Effects On The B Lymphocyte Depending On The State Of In Vivo Activation And The Modulation By Serum-Derived Growth Factors, Dale L. Morris

Theses and Dissertations

Previous reports have indicated a dichotomy in the actions of TCDD on humoral immunity, both in vitro and in vitro, in which enhancements and suppression have been identified. The latter effect has been correlated with induction of liver P4501A1 enzyme activity, a response which is regulated by the Ah-gene locus. Additionally, the primary alteration in suppression of antibody responses is in the differentiation of the B cell. Therefore, the current investigation was undertaken to determine the relationship between these dual actions of TCDD on humoral immunity as related to its direct actions on B lymphocyte function. Specific emphasis was placed …

Evaluation Of The Antagonism Of Nicotine By Mecamylamine And Pempidine In The Brain, Thomas Jeffrey Martin

Theses and Dissertations

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, …

An Evaluation Of The Central Neurotoxic Effects Of Aroclor 1254, A Commercial Mixture Of Polychlorinated Biphenyls, In Mice, Diane L. Rosin

Theses and Dissertations

Polychlorinated biphenyls (PCBs) are industrial compounds whose ubiquitous environmental contamination has been known since the late 1960's. Incidents of human intoxication have been reported, most notably, the "Yusho" incident that affected over 1600 people in Japan in 1968. A broad spectrum of adverse effects are produced by PCBs, including some neurological symptoms. While examination of the toxic effects of PCBs has received much attention, there has been little work on the neurotoxicity of PCBs. The intent of the experiments presented in this thesis is to provide further information on the central neurotoxicity of PCBs in mice.

A commercial mixture of …

Psychopharmacological Analysis Of Central Muscarinic And Nicotinic Receptors, Leonard T. Meltzer

Theses and Dissertations

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 …

The Effects Of Streptozotocin-Induced Diabetes On Responses To Opiates And Other Centrally-Acting Pharmacologic Agents, Glenn Stuart Simon

Theses and Dissertations

Diabetes mellitus affects millions of people. Although diabetics can lead relatively normal lives, all treatments for the disease are symptomatic and not curative. The purpose of this investigation was to determine whether the sensitivity to opiates and other selected centrally-acting drugs in animals is altered by streptozotocin (STZ)-induced diabetes. A second objective was to determine which aspect of the diabetic syndrome primarily was responsible for the altered sensitivity. Other experiments were performed in an attempt to elucidate the mechanism whereby this altered sensitivity occurred.

STZ-induced diabetes or dextrose-induced transient hyperglycemia did not have a significant effect on the duration of …

The Responsiveness Of Murine Tumors To Maleic Vinyl Ether, Paal Christian Klykken

Theses and Dissertations

Studies were undertaken to characterize the immune status of mice bearing the Lewis lung carcinoma (LLC) and to maximize the cure rate of LLC and Madison l09 carcinoma (Ml09) bearing mice by employing the immunomodulator maleic vinyl ether (MVE) in combination with surgery or radiotherapy.

The pattern of immunodeficiency in mice bearing the LLC appeared to be in contrast to most studies. LLC mice with a minimal tumor burden were found to have a diminished ability to phagocytize sheep erythorcytes (SRBC) or elicit an antibody response to the same antigen. Vascular clearance and phagocytic uptake of ⁵¹Cr-labeled SRBC into …