This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

A research program was developed to investigate basic and applied aspects of toxicity, both lethal and sublethal, of hemoxidants, particularly nitrite, on fish, non-fish aquatic vertebrates, and crayfish. The major objectives of this research were to determine A) acute and sublethal toxicity of nitrite to selected aquatic organisms: 1. aquatic salamander larvae, Ambystoma texanum, 2. swamp crayfish, Procambarus simulans, 3. bluegill, Lepomis macrochirus, 4. bullfrog, tadpoles, Rana catesbiana, 5. channel catfish, Ictalurus punctatus, B) the influence of environmental chloride on acute and sublethal exposures to hemoxidants: 1. on acute nitrite toxicity to salamander larvae, crayfish, and bluegill, 2. on nitrite-induced methemoglobinemia in bullfrog tadpoles, Rana catesbian, C) the effect of environmental hydrogen ion concentrations (pH) on acute nitrite toxicity 1. to the crayfish, Procambarus simulans, 2. to the bluegill, Lepomis macrochirus, D) the effect of temperature in sublethal exposures to nitrite 1. methemoglobin formation in channel catfish exposed at different acclimation temperatures, 2. recovery from methemoglobinemia at different acclimation temperatures, E) the effect of the fish anesthetic TMS-222 on nitrite-induced methemoglobinemia in channel catfish 1. supression of nitrite-induced methemoglobinemia, 2. dose-response curve for TMS-222 induced methemoglobinemia, and F) if a methemoglobin reductase system is present in channel catfish.

A dapsona, fármaco de escolha no tratamento da hanseníase, na prevenção da malária e no da pneumonia pelo Pneumocystis carinii vem sendo associada a casos clinicamente freqüentes, caracterizadas por metemoglobinemia e anemia hemolítica. Essa hemotoxicidade está diretamente relacionada à N-hidroxilação sofrida pelo fármaco. Com o objetivo de se verificar a inibição da hemotoxicidade acarretada pelos produtos de biotransformação reativos, a arginina, fármaco antioxidante, precursor do óxido nítrico, foi administrado concomitantemente à dapsona em ratos Wistar, em estudo de doses únicas e múltiplas, por gavage: Grupo I: 40 mg/kg de dapsona. Grupos II, III, IV, V e VI; administração de 0.5%, 1.5%, 3%, 6% e 18% de arginina. Grupo VII, 0.5% de arginina antes de 40 mg/Kg de dapsona. Grupo VIII, 1.5% de arginina antes de 40 mg/Kg de dapsona, Grupo IX, 3,0% de arginina antes de 40 mg/kg de dapsona. Grupo X, 6,0% de arginina antes de 40 mg/kg de dapsona. Grupo XI, 18,0% de arginina antes de 40 mg/kg de dapsona. Os parâmetros hematológicos e bioquímicos serão correlacionados com a concentração plasmática de dapsona, determinada por CLAE, na exposição à dapsona em monoterapia e na associação com a com a arginina. O resultado mostrou que a interação com a arginina e dapsona não protegeu da hemotoxicidade da dapsona, principalmente a metemoglobinemia e anemia hemolítica. / The dapsone, medicine used in the treatment of Hansen\'s disease, in the malaria prevention and in pneumonia caused by Pneumocystis carinii is being associated to the clinically frequents cases, characterized by methemoglobinemia and hemolytic anemia. This hemotoxicity is directly related to the N-hidroxidation suffered by the medicine. With the target to verify the inhibition of the hemotoxicity occurred by the products of biotransformation reactive, the arginine, antioxidant, forerunner of the nitric oxide, will be dosed concurrently with dapsone in Wistar mice, with only one and multiple dose, per gavage: Group I: 40 mg/Kg of dapsone. Groups II, III, IV, V and VI: management the just one dose of 0,5%, 1,5%, 3,0%, 6,0% and 18,0% de arginine. Group VII: arginine 0,5% before of 40 mg/Kg dapsone. Group VIII: arginine 1,5% before of 40 mg/Kg dapsone. Group IX: arginine 3,0% before of 40 mg/Kg dapsone, Group X: arginine 6,0% before of 40 mg/Kg dapsone. Group XI: arginine 18,0% before of 40 mg/Kg dapsone The hematologyc and biochemical parameters are related to the plasmatic concentration of dapsone, determined by CLAE, in the exposition to the dapsone in monotherapic and in the association with arginine. The result showed that the interaction with arginine and dapsone did not protect the hemotoxicity of the dapsone, mainly the methemoglobinemia and hemolytic anemia.

A dapsona, fármaco de escolha no tratamento da hanseníase, na prevenção da malária e no da pneumonia pelo Pneumocystis carinii vem sendo associada a casos clinicamente freqüentes, caracterizadas por metemoglobinemia e anemia hemolítica. Essa hemotoxicidade está diretamente relacionada à N-hidroxilação sofrida pelo fármaco. Com o objetivo de se verificar a inibição da hemotoxicidade acarretada pelos produtos de biotransformação reativos, a arginina, fármaco antioxidante, precursor do óxido nítrico, foi administrado concomitantemente à dapsona em ratos Wistar, em estudo de doses únicas e múltiplas, por gavage: Grupo I: 40 mg/kg de dapsona. Grupos II, III, IV, V e VI; administração de 0.5%, 1.5%, 3%, 6% e 18% de arginina. Grupo VII, 0.5% de arginina antes de 40 mg/Kg de dapsona. Grupo VIII, 1.5% de arginina antes de 40 mg/Kg de dapsona, Grupo IX, 3,0% de arginina antes de 40 mg/kg de dapsona. Grupo X, 6,0% de arginina antes de 40 mg/kg de dapsona. Grupo XI, 18,0% de arginina antes de 40 mg/kg de dapsona. Os parâmetros hematológicos e bioquímicos serão correlacionados com a concentração plasmática de dapsona, determinada por CLAE, na exposição à dapsona em monoterapia e na associação com a com a arginina. O resultado mostrou que a interação com a arginina e dapsona não protegeu da hemotoxicidade da dapsona, principalmente a metemoglobinemia e anemia hemolítica. / The dapsone, medicine used in the treatment of Hansen\'s disease, in the malaria prevention and in pneumonia caused by Pneumocystis carinii is being associated to the clinically frequents cases, characterized by methemoglobinemia and hemolytic anemia. This hemotoxicity is directly related to the N-hidroxidation suffered by the medicine. With the target to verify the inhibition of the hemotoxicity occurred by the products of biotransformation reactive, the arginine, antioxidant, forerunner of the nitric oxide, will be dosed concurrently with dapsone in Wistar mice, with only one and multiple dose, per gavage: Group I: 40 mg/Kg of dapsone. Groups II, III, IV, V and VI: management the just one dose of 0,5%, 1,5%, 3,0%, 6,0% and 18,0% de arginine. Group VII: arginine 0,5% before of 40 mg/Kg dapsone. Group VIII: arginine 1,5% before of 40 mg/Kg dapsone. Group IX: arginine 3,0% before of 40 mg/Kg dapsone, Group X: arginine 6,0% before of 40 mg/Kg dapsone. Group XI: arginine 18,0% before of 40 mg/Kg dapsone The hematologyc and biochemical parameters are related to the plasmatic concentration of dapsone, determined by CLAE, in the exposition to the dapsone in monotherapic and in the association with arginine. The result showed that the interaction with arginine and dapsone did not protect the hemotoxicity of the dapsone, mainly the methemoglobinemia and hemolytic anemia.

2,4,6-Trinitrotoluene, TNT, is an explosive used in munitions production that is known to cause both aplastic and hemolytic anemia in exposed workers. Deaths have been reported secondary to both varieties of anemia. Studies have shown that TNT systemic absorption is significant by both the respiratory and dermal routes. A literature review revealed that the most recent review article on TNT exposure arguing for a TWA drop from the PEL to the TLV was in 1977 -- this article cited anemia issues in addition to other untoward effects of TNT. No studies encountered looked at hemoglobin change or anemia cases in respiratory protected workers, this present effort may be the first. TNT PEL (1.5mg/m^3), REL (0.5mg/m^3), and TLV (0.1 mg/m^3) 8 hr TWAs all with skin notations (based on animal models and TNT urine metabolite extrapolation in TNT workers suggesting important role of skin absorption). The earliest effects of systemic TNT poisoning involve hgb and hematocrit drop. The investigator hypothesized that respiratory protection alone is insufficient to protect TNT workers from the risk of anemia development and hemoglobin concentration drop. A retrospective observational study design was incorporated utilizing a records review of TNT vapor air concentration values and worker Hgb values for 8 sets of workers in respiratory protection at a demilitarization operation from October 2006 to April 2007 in order to observe whether or not respiratory protection provided adequate protection against anemia development and hemoglobin change; and to help characterize the probable role of TNT skin absorption on hemoglobin change and anemia risk. Worker baseline hgbs were compared with their exposure hgbs for statistically significant hgb concentration changes (two-tailed paired t-tests), and anemia cases were recorded. Mean hgb changes within each of the 8 groups of workers were then regressed on mean TNT air concentrations (10 hr TWAs) using air sampling levels that were performed closest in time to exposure hgbs. Statistically significant hgb concentration drops and anemia cases were apparent at values about the REL and PEL in respiratory protected workers. There were no anemia cases or statistically significant hgb drops at values about the TLV, however. For mean TNT air concentrations from 0.12/m 3 to 0.31/m 3 there was strong positive linear association with regard to magnitude of hgb change (r=0.996). The results appear to confirm the necessity of the skin notation for TNT. However, the TLV seems to be protective against the possibility of anemia risk principally by the dermal route in workers who are respiratory protected. A question does still remain, however, as to anemia risk in workers who are below the TLV who may not be using respiratory protection. The absence of a continued linear association between mean TNT air concentrations and mean hgb change above the 0.31 mg/m 3 TNT level most likely reflects a marrow response, as the TNT levels evident in the study are reported to be mainly associated with extravascular hemolysis with a minimal, or non-existent, aplastic component assumed. This study adds evidence to the argument that the TLV should be adopted as the new PEL.

Gadolinium-based contrast agents (GBCAs) are in widespread use to enhance magnetic resonance angiography images for evaluating vascular pathology. However, there are safety concerns and limitations regarding the use of GBCAs. It has been shown that the magnetic resonance imaging (MRI) signal intensity (T1-weighted images) in some of the brain's tissues is higher for patients who had multiple exposures to GBCAs compared to patients who had never had exposure to GBCAs. This implies that GBCAs are not sufficiently removed from body such that GBCAs may potentially have long-term effects on the human body. These potential safety concerns have led to an increased interest in alternative contrast agents. Methemoglobin (metHb) and oxygen-free hemoglobin (HHb) are two forms of hemoglobin with paramagnetic properties. It has been shown that the T1-weighted signal intensity of blood is changed during MRI scans for metHb and HHb, leading to enhanced contrast of MRI images. The ability of metHb and HHb to change the signal intensity has led to the idea that they can be used as effective contrast agents. MetHb can be made by exposing oxyhemoglobin (oxyHb) to nitric oxide (NO) and HHb can be made by removing the oxygen from hemoglobin using nitrogen (N2). In this study, a new gas delivery system was developed to make metHb and HHb. The new gas delivery system was developed to have greater experimental control compared to the PermSelect hollow-fiber module that was used in preliminary studies to make metHb. The same system can be used to make HHb. Initial experiments showed significant amounts of undesired nitrite (NO2-) formation during metHb formation due to the presence of contaminants in the NO gas source. To minimize this problem, flow of NO from the gas source was bubbled in a sodium hydroxide solution in order to reduce the NO2- concentration. Following metHb formation, continuous delivery of NO also led to the formation of ferrous nitrosyl hemoglobin (HbIINO). MRI studies showed that HbIINO can also increase the signal intensity of an MRI image. It is unknown as to whether metHb, HHb, or HbIINO would be a stronger and more appropriate contrast agent and to what extent the T1-weighted signal is affected by the concentration. This study evaluated T1-weighted images of blood samples over a range of metHb and HHb concentrations, as well as HbIINO concentrations. Comparison of T1 values showed that metHb is the strongest contrast agent and that HHb is a relatively weak contrast agent. This study showed for the first time that HbIINO can provide a contrast effect, although not as strong as metHb but stronger than HHb. With metHb providing a viable contrast between 10-20%, metHb has the potential to be a safe and effective contrast agent since it can be naturally converted back to hemoglobin.