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PubMed1997

Death due to asthma at workplace in a diphenylmethane diisocyanate-sensitized subject.

Total cases of fatal asthma in the occupational setting reported in the literature are reviewed and the case of a 39-year-old foundry worker who died at work is described. A diagnosis of occupational asthma induced by diphenylmethane diisocyanate (MDI) had been assessed 5 years in advance through a 0.005-ppm exposure inhalation challenge. Postmortem microscopic examination of the lung showed epithelial desquamation, eosinophilic/neutrophilic infiltration of the mucosa, dilatation of bronchial vessels, edema, hypertrophy and disarray of smooth muscle. Fatal asthma attack in a MDI-sensitized individual, to our knowledge, has not been previously described.

Acute Disease↗
PubMed2001

TNF-alpha and IL-1 beta are not essential to the inflammatory response in LPS-induced airway disease.

To determine the role of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta in the lower respiratory tract inflammatory response after inhalation of lipopolysaccharide (LPS), we conducted inhalation exposure studies in mice lacking expression of TNF-alpha and/or IL-1 receptor type 1 and in mice with functional blockade of these cytokines using adenoviral vector delivery of soluble receptors to one or both cytokines. Alterations in airway physiology were assessed by pulmonary function testing before and immediately after 4 h of LPS exposure, and the cellular inflammatory response was measured by whole lung lavage and assessment of inflammatory cytokine protein and mRNA expression. Airway resistance after LPS exposure was similarly increased in all groups of mice without evidence that blockade of either or both cytokines was protective from this response. Additionally, all groups of mice demonstrated significant increases in lung lavage fluid cellularity with a complete shift in the population of cells to a predominantly neutrophilic infiltrate as well as elevation in inflammatory cytokine protein and mRNA levels. There were no significant differences between the groups in measures of lung inflammation. These results indicate that TNF-alpha and IL-1 beta do not appear to have an essential role in mediating the physiological or inflammatory response to inhaled LPS.

Animals↗
PubMed1996

Hepatic and pulmonary glutathione conjugation of 1,2:3,4-diepoxybutane in human, rat, and mouse in vitro.

1,3-Butadiene (BD) is a carcinogen in rats and mice. Previous in vitro studies showed that mouse liver microsomes formed 1,2-epoxy-3-butene (BMO) from BD and 1,2:3,4-diepoxybutane (BDE) from BMO at much higher rates than rat or human microsomes. Blood and tissue levels of BDE were significantly lower in rats than in mice following exposure to BD. Since mice are much more susceptible to cancer induced by BD than rats, these findings suggest a key role for BDE in BD-induced carcinogenicity. The aim of this study was to characterize the glutathione (GSH) conjugation of BDE by cytosol from human liver and mouse and rat liver and lung in vitro. BDE and radiolabeled GSH were incubated with cytosol. Conjugates were identified by 13C-NMR and FAB mass spectroscopy and quantitated by HPLC. The enzyme kinetics for the conjugation of BDE with GSH suggest that the higher BDE blood concentrations in mice compared with rats following inhalation exposure to BD are not due to differences in GSH conjugation of BDE.

Animals↗
PubMed2000

Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling.

The development and validation of noninvasive techniques for estimating the dermal bioavailability of solvents in contaminated soil and water can facilitate the overall understanding of human health risk. To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored in real time using an ion trap mass spectrometer (MS/MS) to track the uptake and elimination of TCE from dermal exposures in rats and humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers and chamber air TCE concentration was quantified for 3-5 h postdosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, and exhaled breath was analyzed using the MS/MS. The total TCE absorbed and the dermal permeability coefficient (K(P)) were estimated for each individual by optimization of the PBPK model to the exhaled breath data and the changing media and/or dermal patch concentrations. Rat skin was significantly more permeable than human skin. Estimates for K(P) in a water matrix were 0.31 +/- 0.01 cm/h and 0.015 +/- 0.003 cm/h in rats and humans, respectively. K(P) estimates were more than three times higher from water than soil matrices in both species. K(P) values calculated using the standard Fick's Law equation were strongly affected by exposure length and volatilization of TCE. In comparison, K(P) values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration.

Administration, Cutaneous↗
PubMed1989

Differences in the pathways for metabolism of benzene in rats and mice simulated by a physiological model.

Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice were more sensitive to the carcinogenic effects of benzene than were F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice. Our objective was to determine if differences in toxic effects could be explained by differences in pathways for benzene metabolism or by differences in total uptake of benzene. Compartments incorporated into the model included liver, fat, a poorly perfused tissue group, a richly perfused tissue group, an alveolar or lung compartment and blood. Metabolism of benzene was assumed to take place only in the liver and to proceed by four major competing pathways. These included formation of hydroquinone conjugates (HQC), formation of phenyl conjugates (PHC), ring-breakage and formation of muconic acid (MUC), and conjugation with glutathione with subsequent mercapturic acid (PMA) formation. Values for parameters such as alveolar ventilation, cardiac output, organ volumes, blood flow, partition coefficients, and metabolic rate constants were taken from the literature. Model simulations confirmed that during and after 6-hr inhalation exposures mice metabolized more benzene on a mumole per kilogram body weight basis than did rats. After oral exposure, rats metabolized more benzene than mice at doses above 50 mg/kg because of the more rapid absorption and exhalation of benzene by mice. Model simulations for PHC and PMA, generally considered to be detoxification metabolites, were similar in shape and dose-response to those for total metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMedDate not supplied

Determination of atrazine metabolites in human urine: development of a biomarker of exposure.

Enzyme-linked immunosorbent assays (ELISAs) are reported for the detection of atrazine and its principle metabolite in human urine. The ELISAs can be used with crude urine or following extraction and partial purification by methods described in this report. GC, MS, and HPLC techniques were used to confirm and complement the ELISA methods for qualitative and quantitative detection of urinary metabolites. A series of samples from workers applying this herbicide confirmed a mercapturic acid conjugate of atrazine as a major urinary metabolite. The mercapturate was found in concentrations at least 10 times that of any of the N-dealkylated products or the parent compound. Atrazine mercapturic acid was isolated from urine using affinity extraction based upon a polyclonal antibody for hydroxy-s-triazines and yielded products sufficiently pure for structure confirmation by MS/MS. In a pilot study monitoring applicators, a relationship between cumulative dermal and inhalation exposure and total amount of atrazine equivalents excreted over a 10-day period was observed. On the basis of these data, we propose that an ELISA for the mercapturate of atrazine could be developed as a useful marker of exposure.

Acetylcysteine↗
PubMedDate not supplied

Exposure to toxic air contaminants in environmental tobacco smoke: an assessment for California based on personal monitoring data.

The contribution of environmental tobacco smoke (ETS) to the exposure of adult nonsmoking Californians was determined for selected toxic air contaminants (TACs). The assessment was based on published measurements of ETS emission factors and personal exposures to volatile organic compounds. The human exposure studies were conducted in three California areas--Los Angeles, Pittsburgh/Antioch, and Woodland--between 1984 and 1990. We derived unexposed and passive population exposure distributions by randomly sampling the monitoring results for individuals classified according to exposure status (active smoker, passively exposed or unexposed to ETS during monitoring). The differences between the unexposed and passive distributions were used to estimate the ETS-only contribution for exposure to benzene, styrene, o-xylene, and m,p-xylene. Emission factors were then employed to infer the ETS-caused exposure to thirteen other compounds. The estimated arithmetic mean increments of 24-hour exposure attributable to ETS for the nonsmoking Californian population (age > or = 7) exposed to ETS are as follows (results in units of microgram m-3 exposure concentration; results using two different emission factors presented as a range): acetaldehyde 11-15; acetonitrile 7.0; acrylonitrile 0.49; benzene 1.02; 1,3-butadiene 0.75-2.3; 2-butanone 1.4; o-cresol 0.17; m,p-cresol 0.41; ethyl acrylate < 0.015; ethylbenzene 0.49-0.64; formaldehyde 6.5-8.2; n-nitrosodimethylamine 0.0028; phenol 1.4; styrene 0.36; toluene 3.1-3.2; o-xylene 0.77; m,p-xylene 0.99. The 90% confidence limits on these estimates due to the limited sample size in the studies are roughly x/ divided by 6. For four widely studied compounds, ETS is estimated to contribute the following percentages to the total inhalation exposure of all nonsmoking Californians: o-xylene 5%; m,p-xylene 3%; benzene 5%; and styrene 8%.

Adolescent↗
PubMed1996

1,3-Butadiene metabolism by lung airways isolated from mice and rats.

1,3-Butadiene (BD) is oxidized by cytochrome P450 to reactive metabolites, including 1,2-epoxy-3-butene (BMO) and 1,2:3,4-diepoxybutane (BDE), which are thought to be responsible for BD genotoxicity and carcinogenicity. Alveolar-bronchiolar neoplasms were observed in mice but not rats following chronic exposure to BD. The site-specific carcinogenicity of BD in mice may result from metabolic activation in pulmonary tissue. We have incubated bronchioles isolated from both male B6C3F1 mice and male Sprague-Dawley rats with 34 microM BD (final concentration in the aqueous reaction medium) to assess species differences in pulmonary metabolism of BD and to enhance our understanding of species- and site-dependent BD carcinogenicity. Bronchioles from both mice and rats formed BMO, although mouse tissue produced 2-fold more than rat tissue. These preliminary results suggest that pulmonary activation of BD may play a role in the carcinogenicity of BD following inhalation exposure; however, other factors in addition to metabolic differences, probably contribute to the observed differences in susceptibility to BD toxicity.

Animals↗
PubMed1989

Metabolism of antipyrine and m-xylene in rats after prolonged pretreatment with xylene alone or xylene with ethanol, phenobarbital or 3-methylcholanthrene.

1. The metabolic disposition of antipyrine (AP) and m-xylene (XYL) has been studied in rats pretreated for a prolonged period with XYL, dosed alone or in combination with ethanol, phenobarbital (PB), or 3-methylcholanthrene (MC). 2. XYL inhalation exposure at 300 ppm in air (7 h/day, 4 days/week, for 1 or 4 weeks) did not alter the total 24-h recovery of AP and its major metabolites in urine, but the excretion profile changed compared with controls: 3-hydroxymethylantipyrine (3-HMA) increased (less than or equal to 14%, P less than 0.001), norantipyrine (NORA) (less than or equal to 23%, P less than 0.01) and AP (less than or equal to 53%, P less than 0.01) decreased. 4-Hydroxyantipyrine (4-OHA) was unchanged. 3. Oral dosage of XYL at 800 mg/kg per day (5 days/week, for 12 days) altered the metabolic disposition of AP similarly to inhalation. 4. XYL + ethanol did not alter the xylene-type effect on AP metabolism. This was at variance with the changes following XYL + PB and, to a greater extent, XYL + MC pretreatments: 4-OHA increased (53-74%, P less than 0.01), 3-HMA (11-42%, P less than 0.05) and AP (greater than or equal to 50%, P less than 0.05) decreased. The effect on NORA was less clear. 5. XYL pretreatment accelerated metabolic disposition of its major urinary metabolite, methylhippuric acid (MHA) and formation of thioethers. 6. Thioether excretion in 24 h urine was enhanced about 10-fold after XYL inhalation and 20-fold after oral administration. Only XYL + PB treatment enhanced further the excretion of xylene-derived thioethers (P less than 0.05). 7. Drug-metabolizing activity (phase I and II reactions) in liver, lung and kidney showed that the treatments resulted in marked and differential biochemical alterations. 8. In conclusion, m-xylene enhanced the rate of its own metabolism and induced differential changes on urinary AP metabolite profile depending on the pretreatment.

Administration, Inhalation↗
PubMed1996

The effects of abused inhalants on mouse behavior in an elevated plus-maze.

Previous research has shown that abused inhalants (i.e., the volatile solvents) share some of the pharmacological properties of drugs used in the treatment of anxiety. In an attempt to further examine commonalities in the effects of inhalants and central nervous system depressant drugs, the behavioral effects of inhaled 1,1,1-trichloroethane, toluene, methoxyflurane and the convulsant vapor flurothyl were examined and compared to those of diazepam in the elevated plus-maze, a test used to predict antianxiety effects. After inhalant exposure or diazepam injection, mice were placed in the center of an elevated plus-maze and the number of entries and time spent in each type of arm (open versus closed) were measured during 5-min tests. Exposure to increasing concentrations of toluene produced concentration-related increases in the total number of open arm entries and the total time spent on the open arms, a pattern of behavioral effects similar to that produced by diazepam. A similar pattern was observed for increasing concentrations of 1,1,1-trichloroethane and methoxyflurane but changes in open arm activity were only observed at concentrations that increased locomotor activity. Conversely, only decreases in open arm time and number of entries were observed for flurothyl. The increasing evidence for commonalities in the behavioral effects of volatile solvents and depressant drugs may provide a foundation for understanding the neurobehavioral basis of inhalant abuse.

Administration, Inhalation↗
PubMed1990

Concentration-response curves for ethylene-oxide-induced heritable translocations and dominant lethal mutations.

Male mice were subjected to repeated inhalation exposures to different concentrations (165, 204, 250, or 300 ppm) of ethylene oxide (EtO) during an 8.5-week period. Transmitted clastogenic effects of these exposures were measured in terms of induction of dominant lethal mutations and heritable translocations. The concentration-response curves for both endpoints are not linear but are markedly concave upward. Significant increases in dominant lethals were detected at all concentrations, except the lowest one. In comparison, the incidences of heritable translocations were significantly increased at all concentrations.

Administration, Inhalation↗
PubMed1989

Acute electrophysiologic effects of inhaled toluene on adult male Long-Evans rats.

Experiments were carried out in Long-Evans rats to verify and extend previous findings about the effects of toluene on sensory-evoked potentials (EPs) of Fischer-344 rats. Inhalation exposures to 3000 and 8000 ppm in Long-Evans rats confirmed that toluene 1) transiently enhances certain components of somatosensory, flash- and click-evoked (brainstem) potentials, 2) increases the latencies and interwave times of brainstem auditory-evoked responses, 3) depresses late components of the flash EP, 4) induces high frequency oscillations in the visual cortex, and 5) produces both facilitatory and suppressant effects on EPs, dependent on exposure concentration and time. New results indicated that toluene 1) has similar effects on Long-Evans as it does on Fischer-344 rats, 2) increases EEG theta activity, 3) has minor effects on cortical auditory and pattern-reversal EPs (PREP), but suppresses the steady-state PREP, and 4) induces oscillations in the visual cortex, irrespective of the presence of flashes.

Administration, Inhalation↗
PubMed2000

Concentration dependency of rat blood: air partition coefficients of some volatile organic chemicals.

The rat blood:air partition coefficient (PC) of lipophilic volatile organic chemicals (VOCs) cannot be predicted with the sole consideration of their solubility in blood water and lipids, suggesting an important role of blood proteins. The possible concentration dependency and the quantitative nature of VOC binding to blood proteins [i.e., association constant (Ka), number of binding sites (n)] have not been investigated previously. The objectives of this study were therefore (1) to determine the concentration dependency of the blood:air PC (P(b:a)) of four VOCs, bromoform (BF), chloroform (CF), chlorobenzene (CB), and ethylbenzene (EB), hypothesized to display binding to rat blood proteins; and (2) to derive Ka and n values for these chemicals in rat blood. In vitro studies were conducted using 0.1-0.5 ml whole blood, or an equivalent mixture of water and n-octanol exposed to varying amounts of VOCs (BF, 0.11-11.4 micromol; CB, 0.11-24.6 micromol; CF, 0.11-186.6 micromol; and EB, 0.11-20.2 micromol) in sealed glass vials. The P(b:a) of CB, CF, and EB decreased significantly at higher amounts added, with no significant change in their n-octanol + water mixture:air PC. For each in vitro exposure situation, the concentration of free chemical (Cfree) in rat blood was calculated with the PC for the n-octanol + water mixture, whereas the concentration of bound plus free chemical (Ctot) was calculated from knowledge of the PC determined experimentally with whole blood. The respective values of Ka and n for hemoglobin binding estimated by linear regression of a plot of the reciprocal of the molar ratio of bound chemical versus 1/Cfree were: BF, 0.8, 4; CB, 2.8, 1.4; CF, 1.8, 1.2; and EB, 2, 1.4. The results of this study suggest that the concentration-dependent nature of P(b:a) need not be considered for modeling rat inhalation exposures to these VOCs for up to several thousand parts per million.

1-Octanol↗
PubMed1988

Metabolism of 1,3-butadiene by lung and liver microsomes of rats and mice repeatedly exposed by inhalation to 1,3-butadiene.

1,3-Butadiene, a colorless gas widely used as an intermediate in the production of synthetic rubber, is carcinogenic in rats and mice. Species differences exist in the sensitivity to inhaled 1,3-butadiene and the target tissue specificity for tumor formation. We examined whether repeated inhalation exposure of rats and mice to 1,3-butadiene would affect the rate of metabolism of 1,3-butadiene by lung and liver microsomes in these species. Male Sprague-Dawley rats and B6C3F1 mice were exposed nose-only to air (control) or 7600 +/- 170 ppm 1,3-butadiene (13,600 +/- 300 micrograms/l) and 740 +/- 10 ppm 1,3-butadiene (1300 +/- 20 micrograms/l), respectively, for 6 h/day for 5 days. After the last exposure, nasal tissue (rats only), lungs and livers were removed from the animals and microsomes were prepared. Microsomes from the different tissues were incubated with 6 mumol 1,3-butadiene and 10 mumol NADPH for 30 min and the rate of disappearance of 1,3-butadiene from the reaction flasks was quantitated. There was a statistically significant (P less than 0.05) depression in the rate of 1,3-butadiene metabolism (50%) in microsomes from lungs of both rats and mice that were exposed repeatedly to 1,3-butadiene compared to control animals. There was no effect of repeated 1,3-butadiene exposure on liver or nasal tissue (rats only) metabolism of 1,3-butadiene in rats or mice. The data from these studies indicate that it is unlikely that species differences in sensitivity or tissue susceptibility are due to an inductive or inhibitory effect of 1,3-butadiene on its own metabolism in the tissues examined.

Administration, Inhalation↗
PubMed2003

Estimate of the time zero lung burden of depleted uranium in Persian Gulf War veterans by the 24-hour urinary excretion and exponential decay analysis.

The aim of this study was to estimate the amount of depleted uranium (DU) in the respiratory system of Allied Forces Gulf War Veterans. Mass spectrometry (thermal ionization mass spectrometry) analysis of 24-hour urinary excretion of DU isotopes in five positive (238U/235U > 191.00) and six negative (238U/235U > 138.25) veterans was utilized in the mathematical estimation of the pulmonary burden at the time of exposure. A minimum value for the biological half-life of ceramic DU oxide in the lungs was derived from the Battelle report of the minimum dissolution half-time in simulated interstitial lung fluid corresponding to 3.85 years. The average DU concentration was 3.27 x 10(-5) mg per 24 hours in DU-positive veterans and 1.46 x 10(-8) mg in DU-negative veterans. The estimated lung burden was 0.34 mg in the DU-positive and 0.00015 mg in the DU-negative veterans. Our results provide evidence that the pulmonary concentration of DU at time zero can be quantitated as late as 9 years after inhalational exposure.

Algorithms↗
PubMed1994

Computer assisted recognition and quantitation of the effects of airborne chemicals acting at different areas of the respiratory tract in mice.

The pattern and timing of a normal breath in unanesthetized mice was analyzed from measurement of inspiratory and expiratory airflows (VI and VE). Airflow was measured via a differential pressure transducer, attached to a pneumotachograph, which itself was attached to a body plethysmograph into which a mouse was placed. The analog voltage from the differential pressure transducer was digitized and stored for analysis on a microcomputer. Criteria were developed to classify each breath as normal (N) or belonging into one of seven abnormal categories. The abnormal categories were arrived at by computer analysis, recognizing specific modifications of the normal pattern into patterns of: sensory irritation of the upper respiratory tract (S), airflow limitation within the conducting airways of the lungs (A) or pulmonary irritation at the alveolar level (P). Combinations of these effects, i.e., S+A, P+A, P+S and P+S+A were also recognized. Computer analysis of each breath also permitted quantitative evaluation of the degree of S, A or P abnormalities. To induce each type of effect we used inhalation exposures to 2-chlorobenzylchloride, carbamylcholine or propranolol. We propose that this approach will permit rapid evaluation of the possible effects of airborne chemicals at three levels of the respiratory tract, with the classification of the type of effect easily obtained in an objective way using well defined criteria, followed by quantitation of the degree of each effect.

Administration, Inhalation↗
PubMed2003

Effects of di-n-butylamine on the respiratory system of Wistar (WU) rats after subchronic inhalation.

Aim of the study was to investigate the potential toxic effects of di-n-butylamine (DBA), a known skin and eye irritating compound, on the respiratory tract after inhalation exposure for up to 91 days in male and female rats [Crl:(WI)WU BR]. To check whether and to what degree the no-observed-(adverse)-effect level (NO(A)EL) decreases with increasing study duration, serial sacrifices were performed after 3 and 28 days, respectively. Based on two dose range-finding studies, the concentrations for this study were determined with 0 (clean air), 50, 150, and 450 mg/m(3). Animals were exposed for 3 days (6 h/day) 28, and 91 days (5 days/wk, 6 h/day), respectively, and immediately sacrificed thereafter. The results show clear irritating effects only in the upper part of the respiratory tract, that is, the nasal cavities. While after 3 and 28 days effects were found only in the high-dose group, slight adaptive effects, expressed as mucous (goblet) cell hyperplasia, could be diagnosed in the medium- and low-dose groups after 91 days of exposure. Pathological changes were most prominent after 3 days of exposure. In the lung, only marginal effects could be observed (increased relative lung weight only in females of the high concentration after 28 days, slight, not statistically significant histopathological effects in the high concentration after 3 days, no effects on parameters of bronchoalveolar lavage fluid), while no effects were found in the remaining groups.

Administration, Inhalation↗
PubMed1994

The regional hydrolysis of ethyl acrylate to acrylic acid in the rat nasal cavity.

Cytotoxicity is primarily limited to the olfactory epithelium of the dorsal meatus region of the nasal cavity of rodents following inhalation exposure to acrylic monomers. To investigate the biochemical basis for this effect, three regions of the Fischer F344N rat nasal cavity were evaluated for carboxylesterase activity for the representative acrylic ester, ethyl acrylate. Prior studies have indicated that the rodent olfactory epithelium is sensitive to the cytotoxic effects of short chain organic acids. In this study, no regional difference in carboxylesterase activity was observed between sensitive and non-sensitive regions of olfactory epithelium. Respiratory epithelium (resistant to cytotoxicity) was found to be have a much lower rate of carboxylesterase activity than olfactory epithelium. These results suggest that the regional distribution of cytotoxicity observed in the rat nasal cavity at high concentrations of inhaled acrylic monomers may be due in part to the amount of released organic acid following deposition. However, the observation of the same esterase activity in sensitive and nonsensitive olfactory regions suggests that nasal air flow patterns and regional deposition may also be critical factors.

Acrylates↗