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PubMed1998

Inhibition of rat lung mixed-function oxidase activity following repeated low-level toluene inhalation: possible role of toluene metabolites.

Toluene is a commonly used solvent that has been shown to alter mixed-function oxidase (MFO) activity, in an organ- and isozyme-specific pattern, following intraperitoneal administration. The purpose of this study was to determine whether similar changes occurred following repeated, low-level inhalation exposure, and to investigate the role of toluene metabolites in these alterations. Exposure to 375 ppm toluene, 6 h/d for up to 5 d, resulted in significant inhibition of the activity of pulmonary arylhydrocarbon hydroxylase (AHH), cytochrome P-4502B1 (CYP2B1), and CYP4B1, but not CYP1A1. After exposure to lower toluene levels (125 ppm, 6 h/d, 3 d), the activities of lung AHH, CYP2B1, and CYP4B1 were also significantly decreased, but in a dose-related manner. MFO activity was not consistently altered in liver. Control pulmonary or liver microsomes were incubated with various concentrations (0.01-10 mM) of toluene or its metabolites and CYP2B1, CYP1A1, and/or CYP4B1 activities were subsequently determined. Benzaldehyde produced a significant dose-related inhibition in the activity of all three lung P-450s examined (IC50 10(-3) M). Toluene was found to be a more potent inhibitor of lung CYP2B1 and CYP1A1 (IC50, 10(-4) M) than benzaldehyde, but neither toluene nor benzyl alcohol was an effective inhibitor of lung CYP4B1. Toluene and its metabolites were weaker inhibitors of CYP1A1 than of CYP2B1. For CYP2B1 and CYP1A1, the order of inhibitory potency was toluene > benzaldehyde > benzyl alcohol and suggests that both the parent molecule and its metabolites may act in concert to inhibit catalytic activity of these cytochromes. The MFO inhibition seen after repeated low-level toluene inhalation exposure could result in altered metabolic profiles of other xenobiotics in an organ-specific fashion.

Administration, Inhalation↗
PubMed1991

Experimental lung injury induced by trimellitic anhydride inhalation on guinea pigs.

Trimellitic anhydride (TMA) causes lung injury by inhalation exposure in humans. In order to investigate more precisely the mechanism of lung injury by TMA, an experimental animal model of TMA-induced lung injury was established. Guinea pigs were intramuscularly injected with trimellitylated bovine serum albumin (TM BSA) with complete Freund's adjuvant (CFA). Appreciable amounts of antibodies against TM epitopes were detected in the sera of these animals. Guinea pigs that were passively sensitized with anti-TM antisera as well as the actively immunized animals developed hemorrhagic pneumonitis after TMA inhalation. It is well recognized that hyperimmune antisera of guinea pigs contain two subclasses of IgG antibodies, IgG1 and IgG2, which are known as homocytotropic and heterocytotropic antibodies, respectively. To determine the role of these antibodies in the airway injury with alveolar hemorrhages, they were isolated by gel filtration and by ion exchange column chromatography, and the guinea pigs that were sensitized with each of these antibodies were exposed to TMA inhalation. The extent of lung injury in these animals was quantitatively determined by the measurements of lung extravasation of Evans blue dye injected intravenously after TMA inhalation. Significant increases in the extravasation of dye were observed in both animal groups sensitized with IgG1 and IgG2 antibodies. In addition, results obtained with heat-treated antisera and IgG1 antibody did not significantly differ from those obtained with untreated samples. These results suggest that the lung injury resulting from TMA inhalation exposure can be induced with humoral antibodies, not only IgG1 but also IgG2, and that at least two types of allergic reactions are involved in the pathogenesis of lung injury.

Alveolitis, Extrinsic Allergic↗
PubMed2000

Inhibition of cytochrome P450 2E1 decreases, but does not eliminate, genotoxicity mediated by 1,3-butadiene.

1,3-Butadiene (BD), a rodent carcinogen, is metabolized to mutagenic and DNA-reactive epoxides. In vitro data suggest that this oxidation is mediated by cytochrome P450 2E1 (CYP2E1). In this study, we tested the hypothesis that oxidation of BD by CYP2E1 is required for genotoxicity to occur. Inhalation exposures were conducted with B6C3F1 mice using a closed-chamber technique, and the maximum rate of butadiene oxidation was estimated. The total amount of butadiene metabolized was then correlated with the frequency of micronuclei (MN). Three treatment groups were used: (1) mice with no pretreatment; (2) mice pretreated with 1,2-trans-dichloroethylene (DCE), a specific CYP2E1 inhibitor; and (3) mice pretreated with 1-aminobenzotriazole (ABT), an irreversible inhibitor of cytochromes P450. Mice in all 3 groups were exposed to an initial BD concentration of 1100 ppm, and the decline in concentration of BD in the inhalation chamber with time, due to uptake and metabolism of BD, was monitored using gas chromatography. A physiologically based pharmacokinetic model was used to analyze the gas uptake data, estimate V(max) for BD oxidation, and compute the total amount of BD metabolized. Model simulations of the gas uptake data predicted the maximum rate of BD oxidation would be reduced by 60% and 100% for the DCE- and ABT-pretreated groups, respectively. Bone marrow was harvested 24 h after the onset of the inhalation exposure and analyzed for frequency of micronuclei in polychromatic erythrocytes (MN-PCE). The frequency of MN-PCE per 1000 PCE in mice exposed to BD was 28.2 +/- 3.1, 19.8 +/- 2.5, and 12.3 +/- 1.9, for the mice with no pretreatment, DCE-pretreated mice and ABT-pretreated mice, respectively. Although inhibition of CYP2E1 decreased BD-mediated genotoxicity, it did not completely eliminate genotoxic effects. These data suggest that other P450 isoforms may contribute significantly to the metabolic activation of BD and resultant genotoxicity.

Administration, Inhalation↗
PubMed2003

Evaluation of risk factors for lung tumour induction in rats exposed to either NpO(2) or PuO(2) aerosols.

PURPOSE: To compare the incidence of each lung tumour type after inhalation exposure of rats to either NpO(2) or industrial PuO(2) aerosols, which have a similar size. MATERIALS AND METHODS: Male Sprague-Dawley rats were exposed once and followed during their whole life span. At the end of their life, the whole lungs were fixed, embedded and cut into thin sections for histological analysis. The presence of tumours was evaluated on three distinct levels of the lobes for phenotype determination to establish dose-effect relationships. RESULTS: In the range of lung doses studied (0.05 to more than 50 Gy), the general trend was an increased frequency of all types of tumours after inhalation exposure to neptunium compared with plutonium. The linearity of the lower part of the dose-effect relationships for all malignant lung tumours leads to the conclusion that NpO(2) is 3.3-fold more carcinogenic than PuO(2). CONCLUSIONS: According to a linear extrapolation of the data on malignant lung tumour incidence collected among all studies reported on actinide oxide carcinogenesis, the risk of lung tumour appears to vary over a factor of about 10 depending on the nature and/or size of the aerosol. This variation has to be taken into account for a realistic assessment of tumour risk.

Actinoid Series Elements↗
PubMed1981

Chronic exposure to inhaled anesthetics increases cholesterol content in Acholeplasma laidlawii.

Acholeplasma laidlawii cells were grown in cholesterol-enriched medium and exposed continuously to either air (control), 4.0 vol.% halothane in air at 1 atm pressure (4% atm halothane), or 80% cyclopropane in oxygen for 24 h at 37 degrees C. Cells grown in the presence of 4% atm halothane or 80% cyclopropane had approximately twice as much membrane cholesterol content/mg protein as the control cells. Cells grown in an anesthetic environment also tended to have a higher membrane cholesterol/phospholipid molar ratio compared to control cells. Membranes isolated from halothane-exposed cells grown in a cholesterol-enriched medium were more ordered at 37 degrees C (measurements were made with no anesthetic present) than membranes from control cells grown in an identically enriched medium. This difference in membrane physical state between control and anesthetic-exposed cells decreased as the temperature decreased, and disappeared at approx. 23 degrees C. Continuous exposure of A. laidlawii to 4% atm halothane or 80% cyclopropane for 24 h did not markedly affect membrane fatty acid composition, either in cells grown on an unsupplemented medium or in cells grown in a medium enriched in myristic, palmitic or stearic acids. These results further support the hypothesis that an increased membrane cholesterol content may play a role in the tolerance or dependence that develops after chronic exposure to anesthetic agents.

Acholeplasma laidlawii↗
PubMedDate not supplied

Toxic volatile organic compounds in simulated environmental tobacco smoke: emission factors for exposure assessment.

Environmental tobacco smoke (ETS) is suspected to be a major source of exposure to many of the compounds identified as toxic air contaminants. However, we lack emission factors for many of the ETS air toxics for the brands of cigarettes which currently dominate the market and therefore cannot adequately estimate contributions of ETS to such exposures. This study provides up-to-date emission factors for selected air toxics and other volatile organic compounds (VOCs) in simulated ETS and uses them in a mass balance model to evaluate the potential contribution of ETS to air toxics in indoor air and, therefore to indoor exposures to air toxics. Emission factors (microgram/cigarette) were determined for 21 VOCs (including two aldehydes), nicotine and particulate matter in a room-sized (20-m3) environmental chamber with stainless-steel walls, operated under static conditions, using diluted sidestream smoke (no exhaled mainstream smoke) to simulate ETS. Experiments were conducted for Kentucky Reference cigarette 1R4F and for each of six commercial cigarette brands with major market shares. The variabilities in the ETS emission factors among brands of cigarettes were relatively small, ranging from 16 to 31% (expressed as the coefficient of variation) among the six brands. The concentrations of most of the VOCs did not change over the 4-hour periods of the experiments. However, concentrations of 3-ethenylpyridine, phenol, o-cresol and m,p-cresol showed consistent decreases over time, indicating removal by means other than the very low air infiltration rate (0.03 h-1), e.g., deposition onto the chamber surfaces. Emission factors for these compounds were calculated to take these losses into account and the rate constants for these losses were estimated. To estimate indoor concentrations and inhalation exposures to 16 VOCs, nicotine and PM-2.5, the average emission factors for the six commercial brands were used in a time-dependent mass-balance model for two scenarios: a typical office building and an average residence. In general, the indoor concentrations of the air toxics from ETS, under conditions selected to be "typical" rather than extreme, are comparable in magnitude to average outdoor concentrations, indicating that ETS can be a significant contributor to the total indoor concentration and the inhalation exposure for these species. At higher smoking rates, exposures to VOCs from ETS could be several times higher than those modeled under more "typical" conditions.

Air Pollution, Indoor↗
PubMed1987

Sequence of bronchoalveolar lavage and histopathologic findings in rat lungs early in inhalation asbestos exposure.

To assess the early cellular inflammatory response of the lungs, 7 rats per group were exposed nose-only to 13 mg/m3 of chrysotile asbestos, 7 h/day for 2, 4, or 6 wk. Lung histopathology and bronchoalveolar lavage (BAL) were analyzed. In exposed animals, dose-related bronchiolitis and fibrosis were found that were not seen in control rats (p less than 0.001). In exposed rats, total BAL cells were increased six-to sevenfold over matched controls, and more cells were retrieved with longer exposure (p less than 0.001). In the BAL, counts of macrophages, lymphocytes, and polymorphonuclear cells (PMNs) were each elevated in the exposed rats (each p less than 0.001). PMNs seen histologically and in the BAL may be related to the time period examined. PMNs and lymphocytes observed throughout this 6-wk study support the idea that these cells may have an important role in the early events of asbestos lung injury.

Administration, Inhalation↗
PubMed1993

Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat.

The present study was undertaken to investigate the mechanism of toxicokinetic interaction between toluene (TOL) and m-xylene (XYL) in vivo in the male Sprague-Dawley rat by physiologically based toxicokinetic (PBTK) modeling. First, the metabolic constants (Vmax and Km) were determined for TOL and XYL individually by conducting a series of closed-chamber inhalation exposures of three rats to starting concentrations of 500 to 4000 ppm. The values of Km (TOL, 0.55 mg/liter; XYL, 0.20 mg/liter) and Vmax (TOL, 4.8 mg/hr/kg; XYL, 8.4 mg/hr/kg) were obtained following best visual fit of PBTK model simulations to experimental data. Then using the same experimental set-up, rats were exposed to three different mixtures of both solvents (500 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 1000 ppm XYL; 1000 ppm TOL + 500 ppm XYL). The data from the time course of chamber solvent concentrations were analyzed with a binary chemical mixture PBTK model that had four mechanistic hypotheses of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition) quantitatively defined in the liver compartment. The validity of the various model descriptions was verified with open-chamber inhalation exposure data on toxicokinetics of TOL and XYL. Overall, the results of this combined experimental and modeling approach are consistent with a competitive metabolic inhibition between XYL and TOL in the rat.

Animals↗
PubMed1990

Bioaccumulation of metals from nickel smelter waste in P and F1 generation of exposed animals. Part III. Morphological responses.

Inhalation exposure experiments were conducted on a group of female adult Chinchilla rabbits placed in a field biomonitoring station located downwind from dumped nickel refinery wastes. Their F1 generation offsprings were exposed prenatally and 6 weeks postnatally. After termination of exposure, both P and F1 generation rabbits were sacrificed, their organs removed and subjected to a histologic examination using light and electron microscopy techniques. The histological responses were most marked in P generation female rabbits, namely hypertrophy of the muscle layer of pulmonary artery walls and foci of atelactasis. Electron microscopic examinations of the myocardium of chamber-exposed rats revealed evidence of muscle fibre lesions at sites of intercalary discs and changes in mitochondrial structure as a result of accumulated Ni, Cr and/or other metals. Histologically remarkable was interstitial accumulation of an unidentified electron-dense crystalloid substance situated near blood capillaries and between myofibrils and collagenous fibres; this substance is believed to be a result of metal-protein interaction. The rats injected intravenously with a suspension of metal waste displayed mitochondrial lesions analogous to those observed after inhalation exposure, but no presence of the electron-dence substance could be noted. It is concluded that chronic exposure to metal waste may give rise to cardiovascular lesions.

Animals↗
PubMedDate not supplied

Toluene-induced ototoxicity by subcutaneous administration.

Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.

Air Pollutants↗
PubMed2003

Liquid chromatographic-atmospheric pressure chemical ionization mass spectrometric analysis of opiates and metabolites in rat urine after inhalation of opium.

To examine the urinary excretion of opiates and their metabolites following inhalation exposure of rats to opium, analytical procedures for the simultaneous determination of the compounds in opium, the vapor derived by the volatilization of opium and the urine of rats exposed to the opium vapor were developed using liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MS). Seven compounds were determined in the opium, namely morphine, codeine, thebaine, noscapine, papaverine, meconic acid and meconin. All seven were extracted with 2.5% acetic acid solution and subjected to LC-APCI-MS analysis. The separation was performed on an ODS column in acetonitrile-50 mM ammonium formate buffer (pH 3.0) using a linear gradient program and quantitative analysis was carried out in the selected ion monitoring mode ([M+H](+)). For the analysis of the volatilization of opium, the opium (1 g) was added to a glass pipe, which was then heated at 300 degrees C for 20 min. Negative pressure (air flow-rate; 300 ml/min) was used to draw the vapor through a series of glass wool and methanol traps. The total amount of each compound in the vapor was estimated by measurement of the compounds trapped in the glass wool and methanol. Wister rats (n=3) were exposed to the vapor derived from the volatilization system and the urinary amounts (0-72 h) of the six opiates and metabolites including morphine-3-grucronide (M3G) and morphine-6-grucronide (M6G) were measured after solid-phase extraction. The calibration curves for those compounds in the rat urine were linear over the concentration range 10-500 ng/ml. The recoveries for each analyte from the rat urine sample spiked with standard solution were generally greater than 80%, and the relative standard deviation for the analytical procedure was less than 8% with the exception of meconin. After inhalation exposure of rats to opium, M3G (5.45-14.38 micro g), morphine (2.27-4.65 micro g), meconin (0.54-1.85 micro g), codeine (0.54-1.85 micro g), noscapine (0.34-0.40 micro g) and papaverine (0.01-0.04 micro g) were detected in the urine over 72 h. However, only trace levels of thebaine were observed despite it being one of the major alkaloids found in the opium. On the other hand, a relatively large amount of meconin was detected in the vapor and the urine as compared with the opium. It is suggested that the presence of meconin in biological fluids could be indicative of opium ingestion by inhalation.

Administration, Inhalation↗
PubMedDate not supplied

Comparison of behavioral teratogenic effects of ethanol and n-propanol administered by inhalation to rats.

Despite extensive testing of ethanol, there has been little research on the reproductive effects of other alcohols. We investigated the behavioral teratogenicity of inhalation exposures to ethanol and n-propanol. Groups of 18 male (approximately 450 g) and 15 pregnant female Sprague-Dawley rats were exposed 7 hours/day for six weeks or throughout gestation, respectively, to 16 000, 10 000, or 0 ppm ethanol or to 7 000, 35 000, or 0 ppm n-propanol. Pregnant females exposed to 7 000 ppm n-propanol, but not to ethanol, showed reduced weight gain, and female offspring also had reduced weight gain through three weeks of age; there was also slight teratogenicity observed at this concentration. Exposed males were mated with unexposed females; fertility was reduced in males exposed to 7 000 ppm n-propanol (two viable litters from 17 matings), but there were no differences from controls in maternal weight gain, feed intake, or water consumption in any other groups. In both maternally- and paternally-exposed groups, litters were culled to four pups of each sex and fostered to untreated females. One female and one male pup per litter were administered tests of neuromotor coordination (ascent on wire mesh screen, rotorod), activity levels (open field, running wheel), or learning ability (avoidance, operant conditioning), but no significant differences from controls were found with either alcohol, despite the reduction in maternal and female offspring body weight and minimal teratogenicity with 7 000 ppm n-propanol. Calculations for predicting blood ethanol levels with inhalation exposure are also presented.

Animals↗
PubMed2006

Exposure pathway assessment at a copper-beryllium alloy facility.

Controlling beryllium inhalation exposures to comply with regulatory levels (2 micro g m(-3) of air) does not appear to prevent beryllium sensitization and chronic beryllium disease (CBD). Additionally, it has proven difficult to establish a clear inhalation exposure-response relationship for beryllium sensitization and CBD. Thus, skin may be an important route of exposure that leads to beryllium sensitization. A 2000 survey had identified prevalence of sensitization (7%) and CBD (4%) in a beryllium alloy facility. An improved particulate migration control program, including dermal protection in production areas, was completed in 2002 at the facility. The purpose of this study was to evaluate levels of beryllium in workplace air, on work surfaces, on cotton gloves worn by employees over nitrile gloves, and on necks and faces of employees subsequent to implementation of the program. Over a 6 day period, we collected general area air samples (n = 10), wipes from routinely handled work surfaces (n = 252), thin cotton glove samples (n = 113) worn by employees, and neck wipes (n = 109) and face wipes (n = 109) from the same employees. In production, production support and office areas geometric mean (GM) levels of beryllium were 0.95, 0.59 and 0.05 micro g per 100 cm(2) on work surfaces; 42.8, 73.8 and 0.07 micro g per sample on cotton gloves; 0.07, 0.09 and 0.003 micro g on necks; and 0.07, 0.12 and 0.003 micro g on faces, respectively. Correlations were strong between beryllium in air and on work surfaces (r = 0.79), and between beryllium on cotton gloves and on work surfaces (0.86), necks (0.87) and faces (0.86). This study demonstrates that, even with the implementation of control measures to reduce skin contact with beryllium as part of a comprehensive workplace protection program, measurable levels of beryllium continue to reach the skin of workers in production and production support areas. Based on our current understanding of the multiple exposure pathways that may lead to sensitization, we support prudent control practices such as use of protective gloves to minimize skin exposure to beryllium salts and fine particles.

Air Pollutants, Occupational↗
PubMed1993

Applications of biological monitoring in occupational health practice: practical application of urinary 2-ethoxyacetic acid to assess exposure to 2-ethoxyethyl acetate in large format silk-screening operations.

A practical application of urinary 2-ethoxyacetic acid (EAA) to assess occupational exposure to 2-ethoxyethyl acetate (EGEE-Ac) during a large format silk-screening operation is described. Industrial hygiene air monitoring of employees of a silk-screen shop producing large aircraft interior panel coverings revealed a broad range of exposures to EGEE-Ac. Time weighted exposures averaged 12 ppm (range 2.9-34 ppm) in press operators during production press runs, exceeding the 5 ppm Washington State permissible exposure limit. Employees were instructed to use organic vapor respirators until engineering controls could be developed. Urinary monitoring of EAA was conducted on 30 employees by the company medical department to aid in exposure risk assessment and to assess compliance. Results obtained ranged from 1.1-27 mg EAA/g creatinine which compares favorably with the proposed Biological Exposure Index (BEI) of 100 mg EAA/g creatinine. Results of representative air and biological monitoring, and observations of work practices for different exposure groups indicated that inhalation exposure was the predominant route of exposure. Follow-up testing to assess the efficacy of a newly installed ventilation upgrade is planned.

Acetates↗
PubMed2002

Chapter three: methodology of exposure modeling.

In this chapter, the concept of exposure assessment and its evolution is introduced, and evaluated by critically appraising the pertinent literature as it applies to exposures to Particulate Matter (PM). Exposure measurement or estimation methodologies and models are reviewed. Three exposure/measurement methodologies are assessed. Estimation methods focus on source evaluation and attribution, sources include those outdoors and indoors as well as in occupational and in-transit environments. Fate and transport models and their inputs are addressed to estimate concentrations outdoors and indoors; source attribution techniques help focus on the contributing sources. Activity pattern techniques are also reviewed and their use in exposure models to estimate inhalation exposure to PM is presented. Deterministic, regression and other stochastic models of exposure to PM are reviewed and evaluated. Strengths, limitations, assumptions and affirmations of the use of exposure assessment as an integral component of risk assessment and risk management are discussed in the conclusions and discussions section of this work.

Air Pollutants↗