Toluene diisocyanate (TDI) exposure produces rhinitis and nasal irritation, and increases the synthesis and release of substance P (SP) from airway sensory nerves. The mechanism leading to enhanced SP production following irritant inhalation remains unclear, but may involve actions of nerve growth factor (NGF). NGF binds trkA receptors located on sensory nerve terminals. Activation of trkA receptors initiates kinase-signaling cascades, which ultimately may increase SP. However, the effects of inhaled irritants on NGF release are not known. In this study, NGF levels in nasal lavages were examined following instillation of 10% TDI into both nasal cavities. NGF was significantly increased 2, 6, 12, and 24 h after TDI exposure compared with controls. The increase in NGF preceded the neuronal and mucosal increases in SP. Pretreatment with K252a, a nonselective tyrosine-kinase inhibitor, prevented the increase in SP-immunoreactivity in TG neurons and epithelial nerve fibers and the inflammatory response to TDI exposure. Because NGF binds to trkA tyrosine-kinase receptors, the NGF released during TDI exposure may mediate SP upregulation in airway sensory neurons, innervating the nasal cavity.

Military personnel deployed in the Middle East have emphasized concerns regarding high levels of dust generated from blowing desert sand and the movement of troops and equipment. Airborne particulate matter levels (PM(10); PM < 10 μm) in the region may exceed 1500 μg/m(3), significantly higher than the military exposure guideline (MEG) of 50 μg/m(3). Increases in PM(10) have been linked to a rise in incidences of asthma, obstructive pulmonary disease, lung cancer, and cardiovascular diseases. Male Sprague-Dawley rats received a single intratracheal (IT) instillation of 1, 5, or 10 mg of Middle East PM(10) collected at a military occupied site in Kuwait, silica (positive control), or titanium dioxide (TiO(2); negative control) suspended in 400 μl sterile saline, or saline alone (vehicle control). Twenty-four hours, 3 d, 7 d and 6 mo postexposure (n = 15/group), organs including lung were evaluated for histopathological changes and for particle contaminants. Bronchoalveolar fluid (BALF) was also analyzed for cellular and biochemical parameters, including cytokines and chemokines. Instillation of silica resulted in early, pronounced, sustained inflammation indicated by significant increases in levels of total protein and neutrophils, and activities of lactate dehydrogenase activity and β-glucuronidase activity. Lower magnitude and transient changes using the same markers were observed in animals exposed to TiO(2) and Middle East PM(10). The results suggest that for acute exposures, this Middle East PM(10) is a nuisance-type dust with relatively low toxicity. However, since average deployment of military personnel to the Middle East is 180 d with potential for multiple follow-on tours, chronic exposure studies are needed to fully understand the pulmonary effects associated with Middle East PM exposure.

The distribution of radio-labeled N-Acetyl-L-Cysteine (NAC) and its impact on glutathione (GSH) metabolism was studied in Sprague-Dawley rats following single and multiple dosing with NAC by oral gavage. Radioactivity associated with administration of (14)C-NAC distributed to most tissues examined within 1 hour of administration with peak radioactivity levels occurring within 1 hour to 4 hours and for a majority of the tissues examined, radioactivity remained elevated for up to 12 hours or more. Administration of a second dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the first increased liver, kidney, skin, thymus, spleen, eye, and serum radioactivity significantly beyond levels achieved following 1 dose. Administration of a third dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the second dose did not significantly increase tissue radioactivity further except in the skin. GSH concentrations were increased 20% in the skin and 50% in the liver after one dose of 1,200 mg/kg NAC whereas lung and kidney GSH were unaffected. Administration of a second and third dose of 1,200 mg/kg NAC at 4 hours and 8 hours after the first did not increase tissue GSH concentrations above background with the exception that skin GSH levels were elevated to levels similar to those obtained after a single dose of NAC. Glutathione-S-transferase (GST) activity was increased 150% in the kidney and 10% in the liver, decreased 60% in the skin, and had no effect on lung GST activity following a single dose of 1,200 mg/kg NAC. Administration of a second dose of 1,200 mg/kg NAC 4 hours after the first decreased skin GST activity a further 20% whereas kidney GST activity remained elevated at levels similar to those obtained after 1 dose of NAC. Administration of a third dose of NAC 4 hours after the second dose increased liver GST activity significantly as compared to background but did not affect skin, kidney, or lung GST activity. Transient decreases in glutathione reductase (GR) activity were measured in the skin and kidney in association with repeat administration of 1,200 mg/kg NAC. Glutathione peroxidase (GxP) activity was increased in the skin, kidney, and liver suggesting that oxidative stress was occurring in these tissues in response to repeat dosing with NAC. Overall, the results of this study present the possibility that NAC could provide some benefit in preventing or reducing toxicity related to exposure to chemical irritants (particularly sulfur mustard) in some tissues by increasing tissue NAC and/or cysteine levels, GSH concentrations, and GST activity. However, follow-on studies in animals are needed to confirm that oral administration of single and multiple doses of NAC can significantly reduce skin, eye, and lung toxicity associated with sulfur mustard exposure. The finding that GxP activity is elevated, albeit transiently, following repeat administration of NAC suggests that repeat administration of NAC may induce oxidative stress in some tissues and further studies are needed to confirm this finding.

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