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.

The public reportina burden for this collection of information is estimated to average 1 hour per response, including the lime for reviewing instnjotlons. ^^.^/^^'"a existing data sou^^^^^ gathering and malnteining the data needed, and completing and reviewing the collection of lnfom,ation Serjd comments regarding this Ijurden estimate or any other asped of ^|^*='™ <>' infonnation including suggestions for reducing this burden to Washington Headquarteis Services. Directorate for infomiation , 1215 Jefferson Dav^s High™y;suite 12IH Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for falling to comply with a collection of Information if it does not display a currently valid 0MB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT TJ-PE Final REPORT DATE (DD-MM-YYYY) 07-13-2004 TITLE AND SUBTITLE Impact SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION/AVAILABILITY STATEMENTApproved for public release; distribution is unlimited. SUPPLEMENTARY NOTES 242 ABSTRACT (Maximum 200 words)A number of studies have demonstrated a protective effect associated with N-acetyl-L-cysteine (NAC) against toxic chemical exposure. However, the impact of long-term oral dosing on tissue pathology has not been detennlned. In this study, we assessed the impact of long-term oral NAC administration on organ histopathology and tissue glutathione (GSH) and total glutathione-Stransferase (GST) activity levels in Sprague-Dawley (SD) rats. Groups of 20 SD rats (10 male, 10 female), 8 weeks of age, were dosed daily by oral gavage with deionized H2O (negative controls) or NAC solution at a rate of 600 or 1,200 mg/kg/d for 30 days. Animals were euthanized 6 hours after treatment on study Day 30. There were no significant differences in final body weights or weekly average weight gain between treatment groups. Serum alanine aminotransferase (ALT) activities were significantly elevated (p^O.05) in NAC-treated animals compared to controls when measured on study Day 30. Histopathologic evaluation of the liver, stomach, small intestine, liver, kidneys, spleen, thymus, and lungs revealed no lesions associated with NAC administration. When measured on study Day 30, total GST activity for kidney and skin from NAC-treated animals were increased 39-131% as compared to controls. Tissue GSH concentrations from NAC-treated animals were increased 24-81% as compared with negative controls. -H=wthePsfadies-afe-Fieede€l-te-d6teFmiB6-i^4he-observed4ocreaseJn-tissue GSH concentration and GST activity provide a degree of chemoprotection against dernial and systemic chemical toxicants. SUBJECT TERMS Disclaimer:This work was supported by the U.S. Navy Office of Naval Research Work Unit #60263. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. This article is approved for pubhc release, di...

In 2001, the Naval Health Research Center Toxicology Detachment was funded by the U.S. Army Medical Research Acquisition Activity (USAMRAA) to conduct a study of the effects of surgically implanted depleted uranium (DU) pellets on adult rat reproductive success and development across two successive generations. This article presents some of the findings for the group of offspring from adult rats mated at 30 d post surgical implantation of DU pellets. Adult male and female Sprague-Dawley rats (P1 generation) were surgically implanted with 0, 4, 8, or 12 DU pellets (1 x 2 mm). The P1 generation was then cross-mated at 30 d post surgical implantation. Urine collected from P1 animals at 27 d post surgical implantation showed that DU was excreted in the urine of DU-implanted animals in a dose-dependent manner. DU surgical implantation did not have a negative impact on P1 reproductive success, survival, or body weight gain through post surgical implantation d 90. There were no statistically significant differences in F1 birth weight, survival, and litter size at postnatal day (PND) 0, 5, and 20. No gross physical abnormalities identified in the offspring were attributable to neonatal DU exposure. A series of neurodevelopment and immune function assessments were also conducted on F1 offspring. No group differences were observed that were related to parental DU exposure. Studies are ongoing on the impact of leaving DU embedded in soft tissue for 120 d on rat reproduction and subsequent offspring survival and development.

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