Inhalation Exposure Of Rats Research Articles

Inhalation toxicity of methyl difluoromalonyl fluoride in rats.

Methyl 2,2-difluoromalonyl fluoride (MMF) is highly toxic by inhalation producing mortality in rats exposed for 4 hours to 0.55 mg/L. Repeated inhalation exposures of rats to 0.009 mg/L produced irritation but no other signs of a toxic response. Mortality was encountered following repeated exposures to 0.066 mg/L.

Comparative inhalation toxicity of nickel subsulfide to [formula omitted] rats and B6C3F 1 mice exposed for 12 days

Groups of F344 N rats and B6C3F 1 mice were exposed to aerosols of nickel subsulfide (Ni 3S 2) 6 hr/day for 12 days not including weekends. Actual exposure concentrations were within 3% of target (target = 10.0, 5.0, 2.5, 1.2, 0.6, and 0.0 mg Ni 3S 2/m 3). Nickel lung burdens of exposed rats and mice increased linearly with exposure concentration. Two male rats and all mice exposed to 10.0 mg Ni 3S 2/m 3 died before the end of the exposures. Exposure to Ni 3S 2 had no effect on the natural killer cell activity of mouse spleen cells. Lesions in rats and mice related to inhalation of Ni 3S 2 were found in the nasal epithelium, lung, and bronchial lymph nodes. The most extensive lesions were found in the lung and included necrotizing pneumonia. Emphysema developed in rats exposed to 5.0 or 10.0 mg Ni 3S 2/m 3, while fibrosis developed in mice exposed to 5.0 mg Ni 3S 2/m 3. Degeneration of the respiratory epithelium and atrophy of the olfactory epithelium of the nose occurred in rats exposed to as low as 0.6 mg Ni 3S 2/m 3 and mice exposed to 1.2 mg/m 3. Results indicate that inhalation exposure of rats and mice to Ni 3S 2 aerosol concentrations near the current threshold limit value (TLV) for nickel compounds (1 mg/m 3 for Ni metal and roasting fume and dust and 0.1 mg/m 3 as Ni for soluble compounds) can produce lesions in the respiratory tract. Atrophy of lymphoid tissues (spleen, thymus, and bronchial lymph nodes) was found in animals of the highest exposure concentration. Degeneration of the testicular germinal epithelium was also observed in mice and rats that survived 5.0 or 10.0 mg/m 3 exposure concentrations.

Inhalation Carcinogenesis of Various Alkylating Agents<xref ref-type="fn" rid="FN2">2</xref>

A series of earlier studies showed that inhalation exposures of rats to three water-reactive electrophilic compounds produced brisk yields of nasal cancer even when the animals were exposed for only 30 days (6 hr/day X 5 day/wk). In addition, carcinogenic potencies of the compounds appeared to relate to their chemical reactivities as measured by hydrolysis rates. For a further study of this phenomenon, inhalation exposures were conducted with five additional water-reactive compounds: beta-propiolactone [(BPL) CAS: 57-57-8], methylmethane sulfonate [(MMS) CAS: 66-27-3], ethylchloroformate [(ECF) CAS: 541-41-3], dichloroacetyl chloride [(DCAC) CAS: 79-36-7], and propylene oxide [(PO) CAS: 75-56-9] on male Sprague-Dawley rats. The hydrolysis rates of these compounds span 6 orders of magnitude. The compounds were administered for 30 days (6 hr/day X 5 days/wk) with the use of exposure concentrations that were inversely proportional to the respective hydrolysis rates. With this protocol, all compounds except PO (the slowest reacting compound) produced nasal cancer in rats. The concentrations of MMS and BPL employed in the studies produced similar nasal cancer yields, indicating that the carcinogenic potencies of these compounds in rat nasal mucosa were proportional to their hydrolysis rates. The nasal cancer yields of DCAC and ECF were less than expected. DCAC hydrolyzes so rapidly at in vivo temperatures (half-life much less than 0.01 min) that it may not reach target DNA in reactive form. Why the exposures to ECF produced yields of nasal cancer not predicted by its reactivity is currently under investigation. These results combined with our earlier results demonstrate that the carcinogenic potencies of some inhaled reactive electrophilic compounds are related to their hydrolysis rates.

Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the fischer-344 rat and B6C3F1 mouse

Inhalation exposure of rats and mice to glycol ether acetates and acrylate esters causes degeneration of the olfactory epithelium but not of the respiratory epithelium. Since these compounds are metabolized via carboxylesterase to acids that are toxic to the olfactory epithelium, the activity and cellular distribution of carboxylesterase in the nasal passages of rats and mice were studied. Olfactory mucosal carboxylesterase in both rats and mice was found to have a V max value for the hydrolysis of p-nitrophenyl butyrate approximately 3 to 6 times larger than that for respiratory mucosa. Similarly, the second-order rate constant for binding and catalysis, V K , was approximately four times greater in olfactory mucosa than in respiratory mucosa of both rats and mice. These data demonstrate that the olfactory mucosa of rats and mice hydrolyze carboxylesters more efficiently than the respiratory mucosae. Enzyme histochemistry was employed to identify the individual cells within the respiratory and olfactory mucosae which contain carboxylesterase activity. All cell types of the respiratory epithelium had some carboxylesterase activity, with varying intensities between individual cell populations. Ciliated and cuboidal epithelial cells were most active in this region. In the olfactory mucosa, however. Bowman's glands stained most intensely, sustentacular cells demonstrated moderate activity, and no activity was detectable in olfactory sensory cells. Together, these data quantitate carboxylesterase activity in nasal mucosal homogenates and localize the enzyme in individual cell types. The data suggest that olfactory mucosa may metabolize carboxylesters to acids more readily than respiratory mucosa. However, such metabolism does not occur in the target cell population, the olfactory sensory neurons, raising the possibility of intercellular migration of toxic acid metabolites.

Relative hepatotoxicity of some industrial solvents after intraperitoneal injection or inhalation exposure in rats

Intraperitoneal LD50 (lethal dose 50% kill) values and minimal liver toxic doses in female Sprague-Dawley rats were determined for the following industrial solvents: toluene, methylene chloride, carbon tetrachloride, 1,1,1-trichloroethane, 1,1,2-trichloroethane, trichloroethylene, ethanol, methyl ethyl ketone, and dioxane. For the following solvents LC50 values and minimal liver toxic air concentrations were also determined: xylene, styrene, chloroform, tetrachloroethylene, and dimethylformamide (DMF). The serum activity of the enzyme sorbitol dehydrogenase (SDH) was used as an indicator of liver damage. Carbon tetrachloride, chloroform, and DMF were hepatotoxic in low doses compared to LD50 values (TD50 (toxic dose 50%) values approximately 30, 90, and 50 mg/kg). Chloroform and DMF were hepatotoxic in comparatively low concentrations after a 4-hr inhalation exposure (TC50 (toxic concentration 50%) values approximately 590 and 740 mg/m3). Even relatively high doses of the other solvents did not raise the SDH activity. Significant direct (metabolite-mediated) hepatotoxicity seems to be an uncommon feature among commonly used industrial solvents.

The response of rat alveolar macrophages to chronic inhalation of coal dust and/or diesel exhaust

The use of diesel-powered equipment in underground mines has raised questions regarding possible synergistic effects of coal dust and diesel emissions. Therefore, the effects of chronic exposure of rats to coal dust and/or diesel exhaust on various properties of alveolar macrophages were investigated. Inhalation exposure of rats was 7 hr/day, 5 days/week for 2 years. Exposure groups were: filtered air controls, 2 mg/m 3 coal dust, 2 mg/m 3 diesel particulate, and 1 mg/m 3 coal dust plus 1 mg/m 3 diesel exhaust. Exposure to coal dust and/or diesel exhaust had little effect on oxygen consumption, membrane integrity, lysosomal enzyme activity, or protein content of alveolar macrophages. However, exposure to coal dust increased macrophage yield, enhanced chemiluminescence, and increased the activity of the cell membrane (i.e., increased cellular spreading and surface ruffling). In contrast, diesel emissions depressed chemiluminescence and decreased the ruffling of the cell membrane. Therefore, the data suggest that exposure to coal dust and/or diesel exhaust does not affect the viability of alveolar macrophages. However, coal dust may activate alveolar macrophages while diesel emissions may depress the phagocytic activity of these cells. The combination of exposures to coal dust and diesel exhaust results in a phagocytic activity which is an average of the effects of separate exposures.

Effects of a two-year inhalation exposure of rats to coal dust and/or diesel exhaust on tension responses of isolated airway smooth muscle.

This study was performed to determine whether chronic inhalation exposure of rats to levels of coal dust (CD) and/or diesel exhaust (DE) similar to those experienced by underground miners affects the pharmacologic characteristics of the animal's airway smooth muscle. Animals were exposed for 2 yr to CD alone (2 mg/m3 of respirable particulates), DE alone (2 mg/m3 of respirable particulates), or CD and DE (CD + DE) in combination (1 mg/m3 CD plus 1 mg/m3 DE). Concentration-response relationships for tension changes induced with acetylcholine, 5-hydroxytryptamine, potassium chloride, and isoproterenol were assessed in vitro on isolated preparations of rat airway smooth muscle (trachealis). Compared with control animals, the maximal contractile responses to acetylcholine of tissues from CD-, DE-, and CD + DE-exposed animals were significantly increased; the effects of CD and DE exposure were additive. The CD + DE exposure, but not the individual treatments, resulted in a significant increase in the maximal relaxation response elicited by isoproterenol; this interaction may have resulted from the addition of, or the synergism between, the nonsignificant effects of CD and DE alone. No treatment altered the sensitivity (EC50 values) of the muscles to the agonists used. The results indicate that chronic exposure to CD, DE, and CD + DE produces differential modifications in the behavior of rat airway smooth muscle. These findings may have some bearing on humans exposed to these substances.

Biochemical and morphological effects of long-term inhalation exposure of rats to ethylbenzene.

Male Wistar rats were exposed (six hours/day, five days/week) to 0, 50, 300 or 600 p.p.m. of ethylbenzene vapour in the air, and killed after 2, 5, 9 or 16 weeks of exposure. After 600 p.p.m., liver-microsomal protein but not cytochrome P-450 concn. was slightly increased; NADPH-cytochrome c reductase was increased maximally by 30% (1.3-fold), 7-ethoxycoumarin O-deethylase (1.8-fold) and UDPG-transferase (2.3-fold). The increase in liver-cytosolic D-glucuronolactone dehydrogenase paralleled the glucuronidation activity (less than or equal to 2-fold). In the kidneys, only 7-ethoxycoumarin O-deethylase (less than or equal to 3.5-fold) and UDPG-transferase (less than or equal to 1.8-fold) showed dose-related increases. Ethylbenzene exposure did not deplete hepatic glutathione (GSH); kidney GSH was slightly increased (less than or equal to 1.3-fold) according to dose. Urine excretion of thioethers was increased with dose, and at 600 p.p.m. was eight times control levels. At 600 p.p.m. there was no increase in serum alanine aminotransferase activity, and liver cells showed slight proliferation of smooth endoplasmic reticulum, slight degranulation and splitting of rough endoplasmic reticulum and enlarged mitochondria, but no necrosis.

Olefinic hydrocarbons: a first risk estimate for ethene.

The exhalation of ethene oxide by rats exposed to ethene now allows a first estimate of the genotoxic risk of ethene on a pharmacokinetic basis. The distribution (Keq, Kst) of ethene oxide under conditions of inhalation of ethene oxide, or high levels of ethene and consideration of the saturation behaviour of metabolism of ethene lead to the conclusion that inhalation exposure of rats to 1000 ppm ethene or more would theoretically correspond to about 7.5 ppm ethene oxide exposure. Available carcinogenicity data for inhaled ethene oxide were utilized into a comparison of the genotoxic risks of low levels of ethene oxide and ethene. It has been shown that consideration of ethene as a "simple asphyxiant" is inappropriate. The new intended TLV of 1 ppm for ethene oxide would be consistent with a TLV of 100 ppm for ethene.

A lifetime study of rats and mice exposed to vapors of bis(chloromethyl)ether

Groups of rats and mice were exposed to 100, 10, and 1 parts per billion (ppb) of bis(chloromethyl)ether (BMCE) 6 hr/day, 5 days/week for 6 months and subsequently observed for the duration of their natural lifespan. Evaluation of groups of rats sacrificed at the end of the 6-month exposure period revealed no abnormalities in hematology, exfoliative cytology of lung washes, or cytogenetic parameters of bone marrow cells. However, 86.5% of the surviving rats which had been exposed to 100 ppb of BCME subsequently developed nasal tumors (esthesioneuroepithelioma) and approximately 4% of the rats developed pulmonary adenomas. This tumorigenic response was not observed in rats exposed to 10 or 1 ppb of BCME. Mice exposed to 100 ppb of BCME did not develop nasal tumors, but showed a significant increase in incidence of pulmonary adenomas over the control mice. Mice exposed to 10 or 1 ppb of BCME did not show a significant increase in incidence of pulmonary adenomas. These data demonstrated the existence of nontumorigenic or no-observable-effect-levels of BCME vapor for a 6-month inhalation exposure in rats and mice.

Animal toxicity studies with ammonium perfluorooctanoate.

These studies were conducted to evaluate the potential toxicity of ammonium perfluorooctanoate, a commercial surfactant. They include acute and subchronic feeding studies with rabbits, mice, rats and monkeys as well as in vitro mutagenicity assays with Salmonella typhimurium and Saccharomyces cerevisiae. The compound was non-irritating to the skin and moderately irritating to the eyes of rabbits. The rat oral LD50 was 540 mg/kg; no deaths resulted from a one hour rat inhalation exposure at a nominal concentration of 18.6 mg/L. All in vitro assays were negative. The liver was the target organ in rodents in both the 28 day and 90 day feeding studies with males showing a greater response than females. Serum and liver concentrations of organic fluorine were greater in male than in female rats. In a 90 day oral study in rhesus monkeys the gastrointestinal tract and the reticuloendothelial system were the sites of toxic effects. The gastrointestinal effects were attributed to the potent surface activity of the compound. Histopathological effects wer noted in the spleen, lymph nodes and bone marrow. Unlike the rats, sex related differences were not evident in the monkeys. Toxicological evaluations of ammonium perfluorooctanoate are continuing.

Dose-related hepatotoxicity of 1,1,2-trichloro-1,2,2-trifluoroethane in short-term intermittent inhalation exposure in rats

Male Wistar rats were exposed to 200, 1000 or 2000 ppm of 1,1,2-tricholoro-1,2,2-trifluoroethane vapor 5 days a week 6 h daily for 1 or 2 weeks. Proliferation and vacuolisation of the smooth endoplasmic reticulum (SER) of the liver was seen electron microscopically after 1 and 2 weeks in the rats exposed to 1000 and 2000 ppm. Among the hepatic drug metabolizing enzymes, NADPH cytochrome c reductase activity showed a dose-related decrease whereas the tightly membrane-bound UDPglucuronosytransferase exhibited a dose-dependent enhancement in its measurable activity. The overall drug oxidation reaction, 7-ethoxycoumarin O-deethylase was not affected by the 1,1,2-trichloro-1,2,2-trifluoroethane inhalation at all, either in the liver or in the kidneys. 1,1,2-Trichloro-1,2,2-trifluoroethane binds to cytochrome P-450 with the production of a type I difference spectrum, suggesting that it may act as a substrate for this enzyme. The binding affinity is increased by phenobarbital-treatment of the rats.

Absence of dichloromethane teratogenicity with inhalation exposure in rats

Female rats were exposed by inhalation to dichloromethane (DCM) at a concentration of 4500 ppm to determine whether exposure before and during gestation is more detrimental to reproductive outcome than exposure either before or during gestation alone. Four treatment groups were utilized in a two by two factorial design: exposure to DCM for 3 weeks before and during the first 17 days of gestation; DCM before and filtered air during gestation; filtered air before and DCM during gestation; and filtered air before and during gestation. Maternal liver weights were increased and fetal body weights were decreased in the two groups exposed to DCM during gestation compared to those exposed to filtered air during gestation. The incidence of gross external, skeletal, or soft-tissue anomalies was not significantly increased in fetuses in any group. Exposure to DCM both before and during gestation resulted in the same low degree of maternal and embryotoxicity as exposure during gestation alone.

Disposition of tetrachloro( 14C)ethylene following oral and inhalation exposure in rats

Tetrachloro[ 14C]ethylene (Perc) was administered to adult, male Sprague-Dawley rats by gavage (1 or 500 mg/kg) or by inhalation (10 or 600 ppm, 6 hr duration). Within 72 hr following oral administration of 1 mg/kg or inhalation of 10 ppm [ 14C]Perc, approximately 70% of the body burden of radioactivity was excreted in expired air as Perc, 26% as 14CO 2 and nonvolatile metabolites in urine and feces, and 3 to 4% remained in the carcass. After oral administration of 500 mg/kg or inhalation of 600 ppm [ 14C]Perc, 89% of the radioactivity was recovered in expired air as Perc, 9% as 14CO 2 and urinary and fecal metabolites, and 1 to 2% remained in the carcass. The major urinary metabolite of Perc was identified as oxalic acid. Pulmonary elimination of Perc was monophasic with a half life ( t 1 2 ) of approximately 7 hr independent of dose or route of administration. Radioactivity remaining in the carcass 72 hr after exposure by either route was primarily distributed within liver, kidney and fat tissue. In liver, 85 to 90% of the total radioactivity was cleared within 72 hr following inhalation exposure to 10 or 600 ppm. Nonextractable radioactivity, either bound or incorporated into hepatic macromolecular material, was cleared at a slower rate. The tissue concentration of nonextractable radioactivity was dependent upon body burden and metabolic capacity but apparently not upon route of administration. Thus, the data indicate that disposition of Perc is a saturable, primarily dose-dependent process in rats.

Accumulation of styrene monomer and neurochemical effects of long-term inhalation exposure in rats.

A simplified compartment model indicated that fat styrene content might be used as an index of the whole body styrene burden. Intermittent exposure of adult male rats to 300 ppm 5 d a week, 6 h daily for 1 to 11 weeks showed an initial steady increase in the fat styrene content up to the 4th week and an exponential decrease thereafter. This phenomenon might have resulted from the enhancement of styrene oxidation due to the prolonged exposure. The effect of the increased oxidation on the body styrene burden is theoretically doubled after 9.1 weeks of exposure. Neurochemical effects after that time might have resulted from an increased binding of styrene oxide in the cellular macromolecules, e.g., to their sulfhydryl groups. The activity of the metabolite towards the cellular constituents could very well explain the increased proteolysis possibly caused by lysosomal labilization. The present data also lend support to the theory of the importance of metabolic activation to styrene and other solvent toxicity.

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.

1,1-Dichloroethylene Hepatotoxicity: Proposed Mechanism of Action and Distribution and Binding of 14 C Radioactivity Following Inhalation Exposure in Rats

1,1-Dichloroethylene Hepatotoxicity: Proposed Mechanism of Action and Distribution and Binding of 14 C Radioactivity Following Inhalation Exposure in Rats

Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats.

Studies on the fate of 14C-labeled vinyl chloride (VC) following oral administration and inhalation exposure in rats demonstrated that the disposition of VC in the body is a function of the dose. More importantly, from the data available, it appears that a correlation exists between doses of VC which cause tumors and those that saturate metabolic or detoxifying pathways. Additional studies characterized the depression of liver non-protein sulfhydryl content (primarily GSH) with the duration and concentration of exposure to VC. The results of these investigations indicate that statistical projections utilizing data collected from rats exposed to high doses of VC are invalid for predicting the hazard of low level exposure, because such projections violate a priori assumption that the dynamics governing the fate of VC in the body are unaltered.

Fate of [ 14C]Vinyl Chloride following inhalation exposure in rats

Inhalation exposure to vinyl chloride (VC) has been shown to be carcinogenic in rats and man. It is important in assessing the toxicological potential of inhaled VC to understand the disposition of VC in the body. Therefore, the objective of the present study was to determine the fate of inhaled [ 14 C]VC at different exposure concentrations in rats. Male rats were exposed to 10 or 1000 ppm [ 14 C]VC for 6 hr and the routes and rates of elimination of 14 C activity were followed for 72 hr after termination of exposure. Following exposure to 10 ppm of VC, urinary 14 C activity and expired VC comprised 68 and 2%, respectively, of the recovered radioactivity. After exposure to 1000 ppm of VC, the proportion of the radioactivity in the urine decreased while that expired as VC increased representing 56 and 12%, respectively. The pattern of pulmonary elimination of VC per se was described by similar apparent first-order kinetics following 10 or 1000 ppm with respective half-lives of 20.4 and 22.4 min. The elimination of 14 C activity in the urine occurred in accordance with a two-exponential equation; the half-lives for the initial phase of excretion were 4.6 and 4.1 hr following 10 and 1000 ppm, respectively. The percent of the recovered 14 C activity remaining in the carcass after 72 hr was 14 and 15% at the respective low and high exposure level. VC per se was not found in tissues. The urinary 14 C activity was separated by high pressure liquid chromatography into three major metabolites corresponding to N -acetyl- S -(2-hydroxyethyl)cysteine, thiodiglycolic acid, and a third unidentified metabolite. The proportions of the urinary metabolites were not markedly influenced by the exposure magnitude. The fate of inhaled [ 14 C]VC was shown to be dose-dependent; this is consistent with previous studies on the fate of VC following ingestion as well as inhalation.

Fate of [ 14C]vinyl chloride after single oral administration in rats

Male rats were given single oral doses of 0.05, 1, and 100 mg/kg of [ 14C]vinyl chloride (VC), and the routes and rates of elimination of 14C activity followed for 72 hr. Following 0.05 and 1 mg/kg, excretion in the urine as nonvolatile metabolites and as 14CO 2 in expired air accounted for 59–68% and 9–13%, respectively of the administered dose. Only 1–2% of the dose was expired by the lungs as VC. Conversely, after 100 mg/kg, 67% of the dose was eliminated by the lungs as VC, while urinary nonvolatile metabolites and 14CO 2 comprised 11 and 3%, respectively. Pulmonary elimination after 100 mg/kg showed an apparent biphasic clearance with haif-times ( t 1 2 ) of 14.4 and 40.8 min for the respective fast and slow phases. Following 0.05 and 1 mg/kg the pulmonary clearance of VC was monophasic with t 1 2 of 53.3 and 57.8 min. The percentage of the dose remaining in the carcass after 72 hr was 10, 11, and 2% for the 0.05-, 1- and 100-mg/kg doses, respectively. The urinary radio-activity was separated by high pressure liquid chromatography into three major metabolites. Two of the three major urinary metabolites have been identified as N-acetyl- S-(2-hydroxyethyl)-cysteine and thiodiglycolic acid by gas chromatography-mass spectrometry. The proportions of the urinary metabolites were not influenced by the dose. The fate of VC following an oral dose between 1 and 100 mg/kg was clearly dose-dependent. Consistent with our previous studies on the fate of VC following inhalation exposure in rats, the metabolism of VC appears to be a saturable process.