Toxicity and occupational exposure assessment for Fischer-Tropsch synthetic paraffinic kerosene.

Fischer-Tropsch (FT) Synthetic Paraffinic Kerosene (SPK) jet fuel is a synthetic organic mixture intended to augment petroleum-derived JP-8 jet fuel use by the U.S. armed forces. The FT SPK testing program goal was to develop a comparative toxicity database with petroleum-derived jet fuels that may be used to calculate an occupational exposure limit (OEL). Toxicity investigations included the dermal irritation test (FT vs. JP-8 vs. 50:50 blend), 2 in vitro genotoxicity tests, acute inhalation study, short-term (2-week) inhalation range finder study with measurement of bone marrow micronuclei, 90-day inhalation toxicity, and sensory irritation assay. Dermal irritation was slight to moderate. All genotoxicity studies were negative. An acute inhalation study with F344 rats exposed at 2000 mg/m3 for 4 hr resulted in no abnormal clinical observations. Based on a 2-week range-finder, F344 rats were exposed for 6 hr per day, 5 days per week, for 90 days to an aerosol-vapor mixture of FT SPK jet fuel (0, 200, 700 or 2000 mg/m3). Effects on the nasal cavities were minimal (700 mg/m3) to mild (2000 mg/m3); only high exposure produced multifocal inflammatory cell infiltration in rat lungs (both genders). The RD50 (50% respiratory rate depression) value for the sensory irritation assay, calculated to be 10,939 mg/m3, indicated the FT SPK fuel is less irritating than JP-8. Based upon the proposed use as a 50:50 blend with JP-8, a FT SPK jet fuel OEL is recommended at 200 mg/m3 vapor and 5 mg/m3 aerosol, in concurrence with the current JP-8 OEL.

Embedded fragments from U.S. military personnel--chemical analysis and potential health implications.

BACKGROUND: The majority of modern war wounds are characterized by high-energy blast injuries containing a wide range of retained foreign materials of a metallic or composite nature. Health effects of retained fragments range from local or systemic toxicities to foreign body reactions or malignancies, and dependent on the chemical composition and corrosiveness of the fragments in vivo. Information obtained by chemical analysis of excised fragments can be used to guide clinical decisions regarding the need for fragment removal, to develop therapeutic interventions, and to better anticipate future medical problems from retained fragment related injuries. In response to this need, a new U.S Department of Defense (DoD) directive has been issued requiring characterization of all removed fragments to provide a database of fragment types occurring in combat injuries. OBJECTIVES: The objective of this study is to determine the chemical composition of retained embedded fragments removed from injured military personnel, and to relate results to histological findings in tissue adjacent to fragment material. METHODS: We describe an approach for the chemical analysis and characterization of retained fragments and adjacent tissues, and include case examples describing fragments containing depleted uranium (DU), tungsten (W), lead (Pb), and non-metal foreign bodies composed of natural and composite materials. Fragments obtained from four patients with penetrating blast wounds to the limbs were studied employing a wide range of chemical and microscopy techniques. Available adjacent tissues from three of the cases were histologically, microscopically, and chemically examined. The physical and compositional properties of the removed foreign material surfaces were examined with energy dispersive x-ray fluorescence spectrometry (EDXRF), scanning electron microscopy (SEM), laser ablation inductively-coupled plasma mass-spectrometry (LA-ICP-MS), and confocal laser Raman microspectroscopy (CLRM). Quantitative chemical analysis of both fragments and available tissues was conducted employing ICP-MS. RESULTS: Over 800 fragments have been characterized and included as part of the Joint Pathology Center Embedded Fragment Registry. Most fragments were obtained from penetrating wounds sustained to the extremities, particularly soft tissue injuries. The majority of the fragments were primarily composed of a single metal such as iron, copper, or aluminum with traces of antimony, titanium, uranium, and lead. One case demonstrated tungsten in both the fragment and the connected tissue, together with lead. Capsular tissue and fragments from a case from the 1991 Kuwait conflict showed evidence of uranium that was further characterized by uranium isotopic ratios analysis to contain depleted uranium. CONCLUSIONS: The present study provides a systematic approach for obtaining a full chemical characterization of retained embedded fragments. Given the vast number of combat casualties with retained fragments, it is expected that fragment analysis will have significant implications for the optimal short and long-term care of wounded service members.

Biological responses in rats exposed to cigarette smoke and Middle East sand (dust).

Respiratory symptoms are frequently reported in personnel deployed to the Middle East. This project characterized the respiratory toxicity of inhaled Iraqi sand (IS). Adult rats underwent a 6-wk inhalation to air or mainstream cigarette smoke (MSCS) (3 h/d, 5 d/wk) that included exposure to IS or crystalline silica (1 mg/m(3), 19 h/d, 7 d/wk) or air during the last 2 weeks. Assessments included motor activity, whole-body plethysmography, cytological and biochemical analysis of bronchoalveolar lavage fluid, lung metal burden, nasal and lung pathology, and changes in lung protein and gene expression. A number of metals including nickel, manganese, vanadium, and chromium were detected in IS. Elevated lung parenchyma aluminum, silica, barium, manganese, and vanadium concentrations were seen in IS-exposed rats, suggesting that several metals present in IS are bioavailable. Rats exposed to IS only developed mild inflammation in the anterior nose and lung. Silica inhalation was associated with some pulmonary responses that were not seen in IS-exposed rats, such as mild laryngeal and tracheal inflammation, mild tracheal epithelial hyperplasia, and elevated lung silica concentrations. MSCS inhalation with or without co-exposure to either IS or silica resulted in changes consistent with pulmonary inflammation and stress response. Rats exposed to MSCS and silica had more widespread airway lesions when compared with rats exposed to MSCS only. Silica-exposed rats had more robust pulmonary gene expression and proteomic responses than that seen in IS-exposed rat. Our studies show that the respiratory toxicity of IS is qualitatively similar to or less than that seen following short-term silica exposure.

Pharmacokinetics of radiolabeled tungsten ((188)W) in male Sprague-Dawley rats following acute sodium tungstate inhalation.

Aerosol cloud formation may occur when certain tungsten munitions strike hard targets, placing military personnel at increased risk of exposure. Although the pharmacokinetics of various forms of tungsten have been studied in animals following intravenous and oral administration, tungsten disposition following inhalation remains incompletely characterized. The objective of this study was to evaluate the pharmacokinetics of inhaled tungstate (WO(4)) in rats. Male, 16-wk-old, CD rats (n = 7 rats/time point) underwent a single, 90-min, nose-only exposure to an aerosol (mass median aerodynamic diameter [MMAD] 1.50 mum ) containing 256 mg W/m(3) as radiolabeled sodium tungstate (Na(2)(188)WO(4)). (188)W tissue concentrations were determined at 0, 1, 3, 7, and 21 days postexposure by gamma spectrometry. The thyroid and urine had the highest (188)W levels postexposure, and urinary excretion was the primary route of (188)W elimination. The pharmacokinetics of tungsten in most tissues was best described with a two-compartment pharmacokinetic model with initial phase half-lives of approximately 4 to 6 h and a longer terminal phase with half-lives of approximately 6 to 67 days. The kidney, adrenal, spleen, femur, lymph nodes, and brain continued to accumulate small amounts of tungsten as reflected by tissue:blood activity ratios that increased throughout the 21-day period. At day 21 all tissues except the thyroid, urine, lung, femur, and spleen had only trace levels of (188)W. Data from this study can be used for development and refinement of pharmacokinetic models for tungsten inhalation exposure in environmental and occupational settings.

Acute sodium tungstate inhalation is associated with minimal olfactory transport of tungsten (188W) to the rat brain.

Olfactory transport of represents an important mechanism for direct delivery of certain metals to the central nervous system (CNS). The objective of this study was to determine whether inhaled tungsten (W) undergoes olfactory uptake and transport to the rat brain. Male, 16-week-old, Sprague-Dawley rats underwent a single, 90-min, nose-only exposure to a Na(2)(188)WO(4) aerosol (256 mg W/m(3)). Rats had the right nostril plugged to prevent nasal deposition of (188)W on the occluded side. The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 3, 7, and 21 days post-exposure. Gamma spectrometry (n=7 rats/time point) was used to compare the levels of (188)W found on the left and right sides of the nose and brain and blood to determine the contribution of olfactory uptake to brain (188)W levels. Respiratory and olfactory epithelial samples from the side with the occluded nostril had significantly lower end-of-exposure (188)W levels confirming the occlusion procedure. Olfactory bulb, olfactory tract/tubercle, striatum, cerebellum, rest of brain (188)W levels paralleled blood (188)W concentrations at approximately 2-3% of measured blood levels. Brain (188)W concentrations were highest immediately following exposure, and returned to near background concentrations within 3 days. A statistically significant difference in olfactory bulb (188)W concentration was seen at 3 days post-exposure. At this time, (188)W concentrations in the olfactory bulb from the side ipsilateral to the unoccluded nostril were approximately 4-fold higher than those seen in the contralateral olfactory bulb. Our data suggest that the concentration of (188)W in the olfactory bulb remained low throughout the experiment, i.e., approximately 1-3% of the amount of tungsten seen in the olfactory epithelium suggesting that olfactory transport plays a minimal role in delivering tungsten to the rat brain.

Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism.

IL-4 prevents the death of naive B lymphocytes through the up-regulation of antiapoptotic proteins such as Bcl-x(L). Despite studies implicating glucose utilization in growth factor-dependent survival of hemopoietic cells, the role of glucose energy metabolism in maintaining B cell viability by IL-4 is unknown. We show that IL-4 triggers glucose uptake, Glut1 expression, and glycolysis in splenic B cells; this is accompanied by increased cellular ATP. Glycolysis inhibition results in apoptosis, even in the presence of IL-4. IL-4-induced glycolysis occurs normally in B cells deficient in insulin receptor substrate-2 or the p85alpha subunit of PI3K and is not affected by pretreatment with PI3K or MAPK pathway inhibitors. Stat6-deficient B cells exhibit impaired IL-4-induced glycolysis. Cell-permeable, constitutively active Stat6 is effective in restoring IL-4-induced glycolysis in Stat6-deficient B cells. Therefore, besides controlling antiapoptotic proteins, IL-4 mediates B cell survival by regulating glucose energy metabolism via a Stat6-dependent pathway.

Glucose sensors made of novel carbon nanotube-gold nanoparticle composites.

Carbon nanotube and metal particle composites have been exploited to fabricate high performance electrochemical devices. However, the physical and chemical procedures to synthesize the composites are labor intensive and inefficient. Our study reveals an one-step wet chemistry method to accomplish fast and controllable production of gold nanoparticle (AuNP) and carbon naotube (CNT) composites. Such a process is sensitive to the surface charge. Especially, when functionalized with carboxyl groups, the CNTs carried negative charges and showed low level association with negatively charged AuNPs. Thermal treatment was employed to decompose the carboxyl groups and render each CNT a charge-free surface thereby achieving a high level AuNP-CNT association. The fabricated glucose sensors demonstrated dependence of their sensitivities to the amount of AuNPs on the CNTs. The enhancement of sensitivity can be attributed to an accelerated electron transfer rate from glucose oxidase Gox to the electrode. The Michaelis-Menten kinetics also indicated improved performance in the glucose sensor made of AuNP-CNTs. Therefore, our research revealed a novel approach to produce metallic nanoparticle and CNT composite for fabricating high performance electrochemical sensors.

Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth.

The bioenergetic response of B lymphocytes is subject to rapid changes following antigen encounter in order to provide ATP and anabolic precursors necessary to support growth. However, the pathways involved in glucose acquisition and metabolism are unknown. We find that B lymphocytes rapidly increase glucose uptake and glycolysis following B-cell antigen receptor (BCR) crosslinking. Inhibition of glycolysis blocks BCR-mediated growth. Prior to S-phase entry, glucose metabolism shifts from primarily glycolytic to include the pentose phosphate pathway. BCR-induced glucose utilization is dependent upon phosphatidylinositol 3-kinase (PI-3K) activity as evidenced by inhibition of glucose uptake and glycolysis with LY294002 treatment of normal B cells and impaired glucose utilization in B cells deficient in the PI-3K regulatory subunit p85alpha. Activation of Akt is sufficient to increase glucose utilization in B cells. We find that glucose utilization is inhibited by coengagement of the BCR and FcgammaRIIB, suggesting that limiting glucose metabolism may represent an important mechanism underlying FcgammaRIIB-mediated growth arrest. Taken together, these findings demonstrate that both growth-promoting BCR signaling and growth-inhibitory FcgammaRIIB signaling modulate glucose energy metabolism. Manipulation of these pathways may prove to be useful in the treatment of lymphoproliferative disorders, wherein clonal expansion of B lymphocytes plays a role.