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PubMedDate not supplied

Longitudinal distribution of ozone absorption in the lung: effect of continuous inhalation exposure.

The effect of continuous exposure to ozone on the absorption of ozone in the conducting airways of human lungs was investigated with a bolus-response method. Eleven healthy nonsmoking college students (8 males, 3 females) were exposed at rest for 2 h on 3 separate days to air containing 0 ppm, 0.12 ppm, and 0.36 ppm ozone. A personal inhalation chamber equipped with a head-only clear plastic dome was used for exposure. Every 30 min a subject removed the dome and orally inhaled a series of five ozone-air boluses, each in a separate breath. Penetration of the boluses distal to the lips was targeted in the range of 70-120 ml (corresponding to the central conducting airways). By integrating the inhaled and exhaled-ozone concentration curves, we obtained the absorbed fraction (lambda) and the dispersion (sigma2) of the ozone bolus for each test breath. In addition, the subtraction of baseline measurements made just before exposure enabled us to determine the changes in absorbed fraction (deltalambda) and in dispersion (deltasigma2) that resulted from exposure alone. Absorbed fraction decreased, but sigma2 increased during O3 exposure, and the differences in deltalambda and in deltasigma2 between breathing air and exposure to either 0.12 ppm or 0.36 ppm O3 were significant. We concluded that exposure of the conducting airways to O3 reduced their capacity to absorb O3, possibly by the depletion of biochemical substrates that are normally oxidized by O3.

Administration, Inhalation↗
PubMed2006

Inhalational exposure to carbonyl sulfide produces altered brainstem auditory and somatosensory-evoked potentials in Fischer 344N rats.

Carbonyl sulfide (COS), a chemical listed by the original Clean Air Act, was tested for neurotoxicity by a National Institute of Environmental Health Sciences/National Toxicology Program and U.S. Environmental Protection Agency collaborative investigation. Previous studies demonstrated that COS produced cortical and brainstem lesions and altered auditory neurophysiological responses to click stimuli. This paper reports the results of expanded neurophysiological examinations that were an integral part of the previously published experiments (Morgan et al., 2004, Toxicol. Appl. Pharmacol. 200, 131-145; Sills et al., 2004, Toxicol. Pathol. 32, 1-10). Fisher 334N rats were exposed to 0, 200, 300, or 400 ppm COS for 6 h/day, 5 days/week for 12 weeks, or to 0, 300, or 400 ppm COS for 2 weeks using whole-body inhalation chambers. After treatment, the animals were studied using neurophysiological tests to examine: peripheral nerve function, somatosensory-evoked potentials (SEPs) (tail/hindlimb and facial cortical regions), brainstem auditory-evoked responses (BAERs), and visual flash-evoked potentials (2-week study). Additionally, the animals exposed for 2 weeks were examined using a functional observational battery (FOB) and response modification audiometry (RMA). Peripheral nerve function was not altered for any exposure scenario. Likewise, amplitudes of SEPs recorded from the cerebellum were not altered by treatment with COS. In contrast, amplitudes and latencies of SEPs recorded from cortical areas were altered after 12-week exposure to 400 ppm COS. The SEP waveforms were changed to a greater extent after forelimb stimulation than tail stimulation in the 2-week study. The most consistent findings were decreased amplitudes of BAER peaks associated with brainstem regions after exposure to 400 ppm COS. Additional BAER peaks were affected after 12 weeks, compared to 2 weeks of treatment, indicating that additional regions of the brainstem were damaged with longer exposures. The changes in BAERs were observed in the absence of altered auditory responsiveness in FOB or RMA. This series of experiments demonstrates that COS produces changes in brainstem auditory and cortical somatosensory neurophysiological responses that correlate with previously described histopathological damage.

Animals↗
PubMed2003

Inhalation exposure to methylene chloride does not induce systemic immunotoxicity in rats.

Methylene chloride (dichloromethane) is used in a variety of industrial applications. To date, there has been no formal assessment of immunotoxicity attributed to methylene chloride. Studies were undertaken to examine whether methylene chloride has any potential to influence the integrity of immune function. For this purpose, Sprague-Dawley rats of both genders were exposed by inhalation to a single high dose (5000 ppm) of methylene chloride for 6 h/d, 5 d/wk for 28 d. This was considered the relevant route of administration, as not only is inhalation a primary route for human exposure to methylene chloride, but, also, the chemical is absorbed rapidly via the lungs. Under these conditions of exposure, methylene chloride failed to influence absolute or relative thymus weights in either gender and produced a significant reduction in relative, but not absolute, spleen weight in female rats only. Immunocompetence was measured as a function of the ability of treated animals to mount immunoglobulin M (IgM) antibody responses to sheep red blood cells (SRBC) as determined by enzyme-linked immunosorbent assay (ELISA). Exposure to methylene chloride did not affect antibody production. Evidence indicates that under these conditions of exposure, methylene chloride did not compromise immune function.

Administration, Inhalation↗
PubMed1999

Toxicology and humoral immunity assessment of octamethylcyclotetrasiloxane (D4) following a 28-day whole body vapor inhalation exposure in Fischer 344 rats.

Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluid consisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D4 exposure levels.

Adjuvants, Immunologic↗
PubMedDate not supplied

Effect of ascorbic acid supplementation during the inhalation exposure of guinea-pigs to industrial dust on bronchoalveolar lavage and pulmonary enzymes.

The aim of this study was to investigate the interaction between ascorbic acid (AA) and inhaled particles separated from the dumped waste of a nickel smelter and refinery. Tricoloured male guinea pigs were exposed in an inhalation chamber to 50 mg kg-1 of < 5 microns particles that mainly consisted of metal oxides. Exposure lasted for 4 weeks (5 days per week and 5 h per day). The drinking water of half of the exposed and half of the control groups was supplemented with 1 g l-1 AA. Each group received 0.4 mmol kg-1 AA in their food. Ascorbic acid supplementation increased the pulmonary AA concentration in both exposed and control groups to the same extent, but in bronchoalveolar lavage fluid the increase was higher in control than in exposed guinea pigs. The number of alveolar macrophages was increased by exposure and AA increased the number only in the exposed group; the acid phosphatase activity of the alveolar macrophages was increased only by AA, and more in the exposed than in the control group. Alkaline phosphatase activity in bronchoalveolar lavage fluid was the same in both supplemented groups, but it was enhanced in the exposed group with a low intake of AA. Effects on lactate dehydrogenase were not consistent. Neither exposure nor AA influenced significantly this enzyme in bronchoalveolar lavage fluid, but in the lung both AA and exposure caused an increase in the activity. The levels were similar in the AA-treated control and exposed guinea pigs.

Acid Phosphatase↗
PubMed1989

[Inhalation exposure to welding fumes of arc welders in processing Cr-Ni steel in large chemical industry].

For clearing up the inhalative load by welding fumes and gases of arc welders in industrial workshops mainly working on Cr-Ni-steels the following welding processes were studied: tungsten inert-gas (TIG), electrode-by-hand (EH), metal inert-gas (MIG), and plasma cutting (plasma). From the total load by welding fumes follows the rank TIG less than EH less than plasma less than MIG. Observing the maximum allowable concentration (MACD) for the total welding fume, no MACD for Cr and Ni was found exceeded. Regarding the welding gases ozone and CO no limit values were exceeded. From the results conclusions were made.

Air Pollutants, Occupational↗
PubMed1989

Pharmacokinetics of S-[3-chloroprop-2-enyl]glutathione in rats following acute inhalation exposure to 1,3-dichloropropene.

1. An h.p.l.c. method has been developed to quantify the GSH conjugate of 1,3-dichloropropene (DCP). 2. The GSH conjugate of DCP (GSCP) was detected in the blood of rats exposed to DCP by inhalation, and elimination of GSCP from rat blood fitted a one-compartment model. 3. Exposure of rats to 78, 155, or 404 ppm DCP gave an elimination t 1/2 of 17 h, independent of exposure concentration.

Acetylcysteine↗
PubMed2000

Disposition of radioactivity in fischer 344 rats after single and multiple inhalation exposure to [(14)C]Octamethylcyclotetrasiloxane ([(14)C]D(4)).

The retention, distribution, metabolism, and excretion of [(14)C]octamethylcyclotetrasiloxane (D(4)) were studied in Fischer 344 rats after single and multiple exposures to 7, 70, or 700 ppm [(14)C]D(4). Subset groups were established for body burden, distribution, and elimination. Retention of inhaled D(4) was relatively low (5-6% of inhaled D(4)). Radioactivity derived from [(14)C]D(4) inhalation was widely distributed to tissues of the rat. Maximum concentrations of radioactivity in plasma and tissues (except fat) occurred at the end of exposure and up to 3 h postexposure. Maximum concentrations of radioactivity in fat occurred as late as 24 h postexposure. Fat was a depot, elimination of radioactivity from this tissue was much slower than from plasma and other tissues. With minor exceptions, there were no consistent gender effects on the distribution of radioactivity and the concentrations of radioactivity were nearly proportional to exposure concentration over the exposure range. Excretion of radioactivity was via exhaled breath and urine, and, to a much lesser extent, feces. Urinary metabolites included dimethylsilanediol and methylsilanetriol plus five minor metabolites. Relative abundance of these metabolites was the same from every test group. Elimination was rapid during the first 24 h after exposure and was slower thereafter (measured up to 168 h postexposure). In singly-exposed female (but not male) rats, small dose-dependent shifts in elimination pathways were seen. After multiple exposures, the elimination pathways were dose- and gender-independent. These data define possible pathways for metabolism of D(4) and allow estimation of the persistence of D(4) and/or its metabolites in rats.

Administration, Inhalation↗
PubMed1996

HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats.

1. HFA-134a was administered to AHA rats by snout-only inhalation for 1 h daily to assess the effects of treatment on reproduction and development. 2. In a fertility study, rats were exposed to atmospheres of 2500, 10,000 or 50,000 p.p.m. HFA-134a throughout gametogenesis, mating, pregnancy and lactation. 3. In a peri- and post-natal study, rats were exposed to HFA-134a from days 17 to 20 of pregnancy and days 1 to 21 post partum to atmospheres of 1800, 9900 or 64,400 p.p.m. 4. The only treatment-related effect was a slight reduction in body weight gain of males of the treated parental generation at 50,000 p.p.m. (fertility study). 5. In neither study were there any adverse effects of HFA-134a on the reproductive performance of treated animals or on the development, maturation or reproductive performance of up to two successive generations.

Animals↗
PubMedDate not supplied

Disseminated thrombosis and bone infarction in female rats following inhalation exposure to 2-butoxyethanol.

Groups of 10 male and 10 female F344/N rats were exposed to 0, 31, 62.5, 125, 250, and 500 ppm of 2-butoxyethanol (BE) by inhalation, 6 hr/day, 5 days/wk, for 13 wk. Four moribund female rats from the 500 ppm group were sacrificed during the first 4 days of exposure, and 1 moribund female from the same group was sacrificed during week 5. Dark irregular mottling and/or loss of the distal tail were noted in sacrificed moribund rats. Similar gross lesions were noted in the terminally sacrificed females exposed to 500 ppm BE. Histologic changes noted in the day 4 sacrificed moribund rats included disseminated thrombosis involving the coccygeal vertebrae, cardiac atrium, lungs, liver, pulp of the incisor teeth, and the submucosa of the anterior section of the nasal cavity. Alterations noted in coccygeal vertebrae from the 500 ppm sacrificed moribund rats included ischemic necrosis and/or degeneration of bone marrow cells, bone-lining cells, osteocytes (within cortical and trabecular bone), and chondrocytes (both articular and growth plate), changes that are consistent with an infarction process. The moribund female rat that was sacrificed during week 5 and those female rats treated with 500 ppm and sacrificed following 13 wk of treatment lacked thrombi, but they had coccygeal vertebral changes consistent with prior infarction and transient or complete bone growth arrest. No bone lesions or thrombi were noted in the male rats treated with the same doses of BE. In conclusion, exposure to 500 ppm BE vapors caused acute disseminated thrombosis and bone infarction in female rats. Possible pathogenic mechanisms are discussed.

Administration, Inhalation↗
PubMedDate not supplied

Lack of changes in brain muscarinic receptor and motor activity of mice after neonatal inhalation exposure to d-allethrin.

Synthetic pyrethroids are among the most common pesticides and insecticides currently in worldwide use. Eriksson and co-workers postulated that oral exposure of mice to pyrethroids during a neonatal brain growth spurt induces permanent disturbance in the cerebral muscarinic cholinergic receptor (MAChR) and behaviour. However, the scientific basis for these phenomena is now under discussion. The present study was performed to determine whether the experimental findings of Eriksson's study could be reproduced in newborn mice by inhalation. Male and female NMRI mice were exposed to d-allethrin by whole-body inhalation for 6 h per day between postnatal days 10 and 16. Actual concentrations of d-allethrin were 0.43, 1.35, 3.49 and 74.2 mg m(-3) (equivalent to 0.70, 2.2, 5.7 and 120.2 mg kg(-1) day(-1), respectively), and the mass median aerodynamic diameter and geometric log-standard deviation of mist particles ranged from 2.58 to 2.98 micro m and from 1.58 to 2.09 micro m for all groups, respectively. The highest exposure level in the present study (74.2 mg m(-3)) was ca. 13,000 times as high as the concentration used in practice. The MAChR in the three brain areas (cortex, hippocampus and striatum) and motor activity were examined at the ages of 17 days and 4 months. In addition, a water-maze test was performed at the age of 11 months. There was no systemic toxicity interfering with the interpretation of assay results. The neonatal exposure to d-allethrin by inhalation did not induce effects either on the brain MAChR density and motor activity at 17 days and 4 months or on performance in the learning/memory test at the age of 11 months. The effects of allethrins on developmental neurotoxicity that Eriksson and co-workers reported previously were not reproduced in the present study.

Administration, Inhalation↗
PubMed1977

1,1-Dichloroethylene hepatotoxicity: proposed mechanism of action and distribution and binding of 14C radioactivity following inhalation exposure in rats.

1,1-Dichloroethylene is reported to produce renal tumors in male mice. It is an hepatotoxin in fasted rats after inhalation. We found that trichloropropane epoxide, an inhibitor of epoxide hydrase, enhances hepatic injury as measured by serum sorbitol dehydrogenase elevation. A significant elevation of hepatic citric acid concentration was seen in fasted but not fed rats. We hypothesized that mitochondrial injury was associated with inhibition of the tricarboxylic acid cycle and postulated that monochloroacetic acid was a toxic metabolite of 1,1-DCE. Fluoroacetic acid and chloroacetic acid were similar in their ability to inhibit oxygen uptake when pyruvic and malic acids were substrates in isolated mitochondria supplemented with adenosine diphosphate. In experiments where 1,1-DCE metabolism was estimated, no difference between the rate of uptake in a 2-hr period was detected between fed and fasted animals. Urinary output of radioactivity at 26 hr for fed and fasted rats was similar. Water-soluble (i.e. TCA-soluble) 1,1-DCE metabolites were found in tissues of fasted rats in excess of that seen in fed rats. The kidney had the largest concentration of total metabolites. Tissue-bound, or TCA-insoluble, radioactivity was associated with the mitrochondrial and microsomal fraction of fasted rats in excess of that seen in fed rats. The disappearance of TCA-insoluble radioactivity from the mitochondrial and microsomal fractions was comparable in rate between fed and fasted rats respectively. These results suggest that 1,1-DCE is metabolized quite rapidly in the organism to TCA-soluble components which are excreted by the kidneys. Metabolites of 1,1-DCE may enter the metabolic pool, since a reasonably short turnover of (14)C-labeled, bound material was observed. The metabolite of 1,1-DCE appears to inhibit the mitochondria so that citric acid accumulates. This may occur by a process of lethal synthesis.

Acetates↗
PubMed2002

Chloroform inhalation exposure conditions necessary to initiate liver toxicity in female B6C3F1 mice.

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodent liver and kidney, including the female B6C3F1 mouse liver. Because tumors are secondary to events associated with cytolethality and regenerative cell proliferation, these end points are valid surrogates for tumor formation in cancer risk assessments. The purpose of the experiments presented here was to more clearly define the combinations of atmospheric concentration and duration of exposure necessary to induce cytolethality and regenerative cell proliferation in the sensitive female B6C3F1 mouse liver. Female B6C3F1 mice were exposed to chloroform by inhalation for 7 consecutive days using atmospheres of 10, 30, or 90 ppm and selected exposure times of 2, 6, 12, or 18 h/day. Bromodeoxyuridine (BrdU) was given the last 3.5 days via an implanted osmotic pump to label cells in S-phase. Labeled hepatocytes were visualized immunohistochemically, and the labeling index (LI) was determined as the percentage of cells in S-phase. LI was a more sensitive indicator of cellular damage than histopathological examination and is the more conservative end point for use in risk assessments. Significant concentration and exposure time related increases in LI were observed at 30 and 90 ppm but not at any 10-ppm exposure. These data defined an empirical relationship for the combinations of airborne exposure concentration and duration needed to induce cytolethality. These results suggest that concentrations of about 10 ppm or below will not induce hepatotoxicity in these mice regardless of exposure duration. Thus, the rate of production of toxic metabolites and the subsequent rate of cellular damage produced by a continual exposure of approximately 10 ppm chloroform are less than the maximum rates at which hepatocytes can detoxify those metabolites and repair any induced cellular damage. A physiologically based pharmacokinetic (PBPK) dosimetry model was used to compare anticipated responses in mice and humans and predicted that chloroform concentrations of approximately an order of magnitude greater than 10 ppm would be required to induce human liver toxicity. Thus, no safety factor to account for species to species extrapolation should be required in formulating a chloroform inhalation cancer risk assessment based on the dose x time inhalation data presented here.

Administration, Inhalation↗
PubMed1989

Immunologic tolerance in rats during 13 weeks of inhalation exposure to trimellitic anhydride.

Trimellitic anhydride (TMA) causes several immunologically based pulmonary syndromes in humans. We developed a rat model representative of some of those syndromes whereby rats exposed for 2 weeks to TMA by inhalation developed hemorrhagic lung foci and pneumonitis accompanied by the appearance of TMA-specific serum antibody. The purpose of the study reported here was to examine the long-term, low-dose effects of TMA inhalation. Rats were exposed to target concentrations of 0, 2, 15, or 50 micrograms/m3 TMA 6 hr/day, 5 days/week for 13 weeks. The study included an interim 6.5-week termination and two recovery periods of 3 and 38 weeks, each with and without a final TMA inhalation challenge. Additional rats were bled regularly throughout the study and monitored for the appearance of TMA-specific antibody; other rats were terminated periodically during the 13-week exposure and examined for lung lesions. These serially terminated rats showed that TMA-induced lung lesions reached a maximum after approximately 2 weeks of exposure, but began to diminish thereafter. Rats bled regularly showed increasing TMA-specific antibody titers through the first 6 weeks of exposure, after which antibody titers diminished. Serum antibody levels rose sharply after the 13-week exposure ended and tapered off throughout the recovery period. Rats terminated after 6.5 weeks of exposure showed a dose-dependent increase in lung lesions and serum antibody. However, rats exposed to TMA for 13 weeks showed greatly reduced lung lesions and antibody titers. Rats exposed for 13 weeks and allowed to recover for 3 weeks showed increased antibody titers but few lesions, even after a TMA challenge. Rats exposed for 13 weeks and allowed to recover 38 weeks had reduced but still significant antibody titers; however, no lung lesions were noted even after a TMA inhalation challenge prior to termination. These results indicated that rats became tolerant to TMA and that 13 weeks of exposure to TMA did not produce lesions of any type, even after 38 weeks of recovery.

Administration, Inhalation↗
PubMed1987

Effect of oral and inhalation exposure to cadmium on the oestrous cycle in rats.

Female rats were administered by gavage an aqueous solution of CdCl2 for 14 weeks, 5 days per week, at doses of 0.04, 0.4, 4 and 40 mg Cd/kg/day or exposed by inhalation to CdO for 20 weeks (5 h per days, 5 days per week) at concentrations of 0.02, 0.16 and 1 mg Cd/m3. A pronounced increase in the mean duration of the oestrous cycle mainly due to lengthening of dioestrus was noted already 6 weeks after treatment of females given per os 40 mg Cd/kg or exposed to a concentration of 1 mg Cd/m3. No changes in the mean duration of the oestrous cycle were found in other experimental groups, although in the 0.16 mg Cd/m3 group an increased percentage of females with oestrous cycles lasting over 6 days was shown 18 weeks after exposure. Since Cd-induced lethality and decrease in body weight gain were observed in females given by gavage 40 mg Cd/kg or exposed by inhalation to a concentration of 1 mg Cd/m3, it is concluded that exposure to cadmium does not affect the sexual cycle unless other overt signs of Cd-toxicity are induced.

Administration, Inhalation↗
PubMed1996

Subchronic toxicity of 4-vinylcyclohexene in rats and mice by inhalation exposure.

This study was conducted to evaluate the subchronic toxicity of 4-vinylcyclohexene (VCH). Male and female Sprague-Dawley rats and B6C3F1 mice were exposed by inhalation to VCH 6 hr/day, 5 days/week for 13 weeks. Rats were exposed to 0, 250, 1000, or 1500 ppm, and mice were exposed to 0, 50, 250, or 1000 ppm. In addition, another group of rats and mice was exposed to 1000 ppm butadiene so that a comparison could be made between the two compounds. Exposure to 1000 ppm VCH resulted in deaths of all male mice and 5/10 female mice on Test Days 11 or 12. Three additional female mice exposed to 1000 ppm VCH died prior to study completion. The most notable compound-related clinical sign was lethargy observed in the 1500 ppm VCH-exposed rats and 1000 ppm VCH-exposed mice. Male rats exposed to 1500 ppm VCH had significantly lower body weights compared to controls, and male and female rats in the 1500 ppm group had significantly lower body weight gains. None of the VCH-exposed animals or butadiene-exposed rats showed any compound-related hematological effects. However, mice exposed to 1000 ppm butadiene exhibited mild macrocytic anemia. Clinical chemistry evaluation and urinalysis showed no compound-related effects in rats exposed to either VCH or butadiene. Male and female rats exposed to 1000 or 1500 ppm VCH or 1000 ppm butadiene had increased absolute and/or relative liver weights, and male rats in these same exposure groups had increased relative kidney weights. Microscopically, increased accumulation of hyaline droplets was observed in the kidneys of male rats from all VCH exposure groups. Although compound-related, the droplets were not accompanied by cytotoxicity. In mice, the most notable adverse histopathological effect was ovarian atrophy in females exposed to 1000 ppm VCH or 1000 ppm butadiene. The atrophy was slightly more severe in the VCH-exposed females than in the butadiene-exposed females. There were no other compound-related pathological effects in male or female mice exposed to VCH. Additionally, butadiene-exposed male mice had decreased testicular weights, accompanied by slight testicular degeneration and atrophy. For VCH exposure, the no-observed-adverse-effect-level is 1000 ppm for rats based on lethargy and lowered body weights and 250 ppm for mice based on mortality and ovarian atrophy.

Administration, Inhalation↗