Distribution of radio-labeled N-Acetyl-L-Cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage.

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.

N-acetyl-L-Cysteine as prophylaxis against sulfur mustard.

Sulfur mustard (HD) is a blister agent targeting the eyes, respiratory system, skin, and possibly other organs. Extensive exposure can destroy the immune system by destruction of bone marrow cells. There is no antidote for HD or effective treatment other than rapid decontamination. Clinical trials have demonstrated activity for N-acetyl-L-cysteine (NAC) against a number of significant human pathologies involving free radicals, and animal and tissue studies have suggested efficacy for NAC as a chemoprotectant against many toxic chemicals. Among these are studies demonstrating that NAC significantly reduces the effects of HD and HD simulants, both in cultured cells and animals. Given the historical effectiveness of HD, the lack of any effective treatment, the demonstrated chemoprotective properties of NAC, its low toxicity, the lack of regulatory controls, and the data supporting efficacy against HD effects, we suggest daily oral administration of the maximum safe dose of NAC to personnel entering combat zones.

Impact of 30-day oral dosing with N-acetyl-L-cysteine on Sprague-Dawley rat physiology.

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 determined. In this study, the authors assessed the impact of long-term oral NAC administration on organ histopathology and tissue glutathione (GSH) and total glutathione-S-transferase (GST) activity levels in Sprague-Dawley (SD) rats. Groups of 20 SD rats (10 males, 10 females), 8 weeks of age, were dosed daily by oral gavage with deionized H2O (negative controls) or NAC solution at a rate of 600 or 1200 mg/kg/day for 30 days. Animals were euthanized 6 h 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 =.05) in NAC-treated animals compared to controls when measured on study day 30. Histopathologic evaluation of the 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% to 131% as compared to controls. Tissue GSH concentrations from NAC-treated animals were increased 24% to 81% as compared with negative controls. Further studies are needed to determine if the observed increase in tissue GSH concentration and GST activity provide a degree of chemoprotection against dermal and systemic chemical toxicants.

Analysis of rat testicular protein expression following 91-day exposure to JP-8 jet fuel vapor.

We analyzed protein expression in preparations from whole testis in adult male Sprague-Dawley rats exposed for 6 h/d for 91 consecutive days to jet propulsion fuel-8 (JP-8) in the vapor phase (0, 250, 500, or 1000 mg/m(3) +/- 10%), simulating a range of possible human occupational exposures. Whole body inhalation exposures were carefully controlled to eliminate aerosol phase, and subjects were sacrificed within 48 h postexposure. Organ fractions were solubilized and separated via large-scale, high resolution two-dimensional electrophoresis, and gel patterns scanned, digitized and processed for statistical analysis. Seventy-six different testis proteins were significantly increased or decreased in abundance in vapor-exposed groups, compared to controls, and dose-response profiles were often nonlinear. A number of the proteins were identified by peptide mass fingerprinting and related to histopathological or physiological deficits shown in previously published studies to occur with repeated exposure to hydrocarbon fuels or solvents. These results demonstrate a significant effect of JP-8 exposure on protein expression, particularly in protein expression in the rodent testis, and suggest that a 91 d exposure to jet fuel vapor induces changes of equal or greater magnitude to those reported previously for shorter duration JP-8 aerosol exposures.

Biological and health effects of exposure to kerosene-based jet fuels and performance additives.

Over 2 million military and civilian personnel per year (over 1 million in the United States) are occupationally exposed, respectively, to jet propulsion fuel-8 (JP-8), JP-8 +100 or JP-5, or to the civil aviation equivalents Jet A or Jet A-1. Approximately 60 billion gallon of these kerosene-based jet fuels are annually consumed worldwide (26 billion gallon in the United States), including over 5 billion gallon of JP-8 by the militaries of the United States and other NATO countries. JP-8, for example, represents the largest single chemical exposure in the U.S. military (2.53 billion gallon in 2000), while Jet A and A-1 are among the most common sources of nonmilitary occupational chemical exposure. Although more recent figures were not available, approximately 4.06 billion gallon of kerosene per se were consumed in the United States in 1990 (IARC, 1992). These exposures may occur repeatedly to raw fuel, vapor phase, aerosol phase, or fuel combustion exhaust by dermal absorption, pulmonary inhalation, or oral ingestion routes. Additionally, the public may be repeatedly exposed to lower levels of jet fuel vapor/aerosol or to fuel combustion products through atmospheric contamination, or to raw fuel constituents by contact with contaminated groundwater or soil. Kerosene-based hydrocarbon fuels are complex mixtures of up to 260+ aliphatic and aromatic hydrocarbon compounds (C(6) -C(17+); possibly 2000+ isomeric forms), including varying concentrations of potential toxicants such as benzene, n-hexane, toluene, xylenes, trimethylpentane, methoxyethanol, naphthalenes (including polycyclic aromatic hydrocarbons [PAHs], and certain other C(9)-C(12) fractions (i.e., n-propylbenzene, trimethylbenzene isomers). While hydrocarbon fuel exposures occur typically at concentrations below current permissible exposure limits (PELs) for the parent fuel or its constituent chemicals, it is unknown whether additive or synergistic interactions among hydrocarbon constituents, up to six performance additives, and other environmental exposure factors may result in unpredicted toxicity. While there is little epidemiological evidence for fuel-induced death, cancer, or other serious organic disease in fuel-exposed workers, large numbers of self-reported health complaints in this cohort appear to justify study of more subtle health consequences. A number of recently published studies reported acute or persisting biological or health effects from acute, subchronic, or chronic exposure of humans or animals to kerosene-based hydrocarbon fuels, to constituent chemicals of these fuels, or to fuel combustion products. This review provides an in-depth summary of human, animal, and in vitro studies of biological or health effects from exposure to JP-8, JP-8 +100, JP-5, Jet A, Jet A-1, or kerosene.