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Naphthalene vapor is a nasal cytotoxicant in the rat and mouse but is a nasal carcinogen in only the rat. Inhalation dosimetry is a critical aspect of the inhalation toxicology of inspired vapors and may contribute to the species differences in the nasal response. To define the nasal dosimetry of naphthalene in the B6C3F1 male and female mouse, uptake of naphthalene vapor was measured in the surgically isolated upper respiratory tract (URT) at inspiratory flow rates of 25 or 50 ml/min. Uptake was measured at multiple concentrations (0.5, 3, 10, 30 ppm) in controls and mice treated with the cytochrome P450 inhibitor 5-phenyl-1-pentyne. In both sexes, URT uptake efficiency was strongly concentration dependent averaging 90% at 0.5 ppm compared to 50% at 30 ppm (25 ml/min flow rate), indicating saturable processes were involved. Both uptake efficiency and the concentration dependence of uptake were significantly diminished by 5-phenyl-1-pentyne indicating inspired naphthalene vapor is extensively metabolized in the mouse nose with saturation of metabolism occurring at the higher concentrations. A hybrid computational fluid dynamic physiologically based pharmacokinetic model was developed for nasal dosimetry. This model accurately predicted the observed URT uptake efficiencies. Overall, the high URT uptake efficiency of naphthalene in the mouse nose indicates the absence of a tumorigenic response is not attributable to low delivered dose rates in this species., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Propylene oxide is a nasal toxicant and weak site-of-contact carcinogen in the mouse and rat. To aid in inhalation risk assessment of this vapor and to provide data for comparison to the rat, the current study was aimed at providing quantitative information on upper respiratory tract (URT) dosimetry of this vapor in the mouse. Toward this end, uptake efficiencies of propylene oxide were measured in the surgically isolated URT of the male B6C3F1 mouse under constant velocity inspiratory flow conditions at flow rates of 12 and 50 ml/min and exposure concentrations of 25, 50, 100, 300, or 500 ppm. URT uptake efficiencies were measured continuously during 1 h exposure; mice were terminated immediately after exposure and nasal respiratory and olfactory mucosal nonprotein sulfhydryl (NPSH) levels were determined. Propylene oxide was scrubbed with moderate efficiency in the URT, with uptake efficiencies of < or = 33 and < or = 16% at the low and high inspiratory flow rates, respectively. Uptake efficiencies were slightly (approximately 5%) higher at low (25 or 50 ppm) than high (300 or 500 ppm) exposure concentrations, suggesting that a saturable uptake pathway may exist. Nasal tissue NPSH levels were significantly depleted at exposure concentrations of 300 and 500 ppm but not at concentrations of 100 ppm or lower. Similar levels of NPSH depletion were observed in both nasal respiratory and olfactory mucosa. These data from mouse show some key differences when compared with those reported for the rat.

To investigate the role of sensory C-fiber stimulation and tachykinin release in the immediate nasal responses to the sensory irritant acrolein, the upper respiratory tract of the urethan-anesthetized male Fischer 344 rat was isolated via insertion of an endotracheal tube, and acrolein-laden air [2, 5, 10, or 20 parts/million (ppm)] was drawn continuously through that site at a flow rate of 100 ml/min for 50 min. Uptake of the inert vapor acetone was measured throughout the exposure to assess nasal vascular function. Plasma protein extravasation into nasal tissue and nasal lavage fluid was also assessed via injection of Evans blue dye. At 20 ppm, acrolein induced 1) a twofold increase in acetone uptake, indicative of vasodilation, followed by a progressive decline toward basal levels and 2) increased plasma protein extravasation, as indicated by dye leakage into nasal tissue and nasal lavage. These responses were inhibited by capsaicin pretreatment and the neurokinin type 1 antagonist N-acetyltrifluoromethyl tryptophan benzyl ester and were potentiated by the peptidase inhibitors phosphoramidon and captopril, suggesting that these responses were mediated by tachykinin. At lower exposure concentrations, acrolein was without effect on dye leakage but produced vasodilation, as indicated by increased acetone uptake. The responses at the lower concentrations were inhibited by capsaicin pretreatment, implicating nasal sensory C-fiber involvement, but were not influenced by N-acetyltrifluoromethyl tryptophan benzyl ester, phosphoramidon, or captopril, suggesting the involvement of a mediator other than the tachykinins substance P and neurokinin A.

At exposure concentrations of 750 ppm or more, acetaldehyde is a rodent inhalation carcinogen that induces nasal tumors. Aldehyde dehydrogenase (ALDH) is thought to be an important detoxifying enzyme for aldehydes. Although nasal tissues express ALDH, the importance of this enzyme relative to delivered dosage rates at high-inspired concentrations is not well defined. To provide such information, uptake of inspired acetaldehyde was measured at an inspiratory flow rate that approximated the minute ventilation rate in the surgically isolated nasal cavity of F 344 rats pretreated with either saline (control) or the ALDH inhibitor, cyanamide (10 mg/kg s.c.). ALDH activities (substrate concentration 3 times the K(m)) in anterior (respiratory mucosa) and posterior (olfactory mucosa) nasal tissues averaged 160 and 210 nmol/min), respectively, in control animals (total activity 370 nmol/min), compared to 60 and 80 nmol/min, respectively, in cyanamide-pretreated rats (p < 0.05), indicating that approximately 60% inhibition was obtained. Nasal uptake was measured at 3 inspired concentrations: 10, 300, and 1500 ppm. At these concentrations, acetaldehyde uptake efficiency averaged 54, 37, and 34% in saline-pretreated rats, respectively (p < 0.05). In absolute terms, the delivered dosage rates at these exposure concentrations averaged 21, 420, and 1990 nmol/min. The concentration dependence on uptake suggests a saturable process was involved. At inspired concentrations of 300 ppm or more, the delivered dosage rates exceeded the measured specific activity for nasal ALDH of 370 nmol/min. Cyanamide pretreatment abolished the concentration dependence. Specifically, uptake efficiencies in cyanamide-pretreated rats averaged 30, 27, and 31% at inspired concentrations of 10, 300, and 1500 ppm, respectively (p > 0.05); delivered dosage rates were 12, 310, and 1780 nmol/min. Thus, cyanamide pretreatment reduced nasal-delivered dosage rates at inspired concentrations of 10, 300, and 1500 ppm, respectively by 9, 110, and 210 nmol/min, values that correspond well with the total nasal ALDH activity of 370 nmol/min. In toto, these results suggest that inspired acetaldehyde is metabolized in situ by ALDH, but at exposure concentrations of 300 ppm or greater, the delivered dosage rate may equal or exceed the capacity of this enzyme.

Manganese chloride (50-800 micrograms) was injected unilaterally into the right nostril of rats and its accumulation in the central nervous system (CNS) was monitored. Brain manganese levels were elevated in a dose-dependent, time-dependent, and tissue-dependent manner. Elevated levels of manganese were detected in the right olfactory bulb and olfactory tubercle within 12 hr after instillation and remained elevated for at least 3 days. As little as 100 micrograms of manganese chloride was sufficient to increase brain manganese levels. No changes were detected on the left side of the brain. The manganese content of the striatum, the target site for manganese neurotoxicity, was unchanged following acute administration, but was elevated when two injections were made 1 week apart. These results suggest that air-borne manganese can be retrogradely transported along olfactory neurons to the CNS and can reach deeper brain structures under appropriate exposure conditions.

Acetaldehyde is a ubiquitous indoor and outdoor air pollutant. This vapor is a respiratory tract irritant and a rodent inhalation carcinogen. The current study was aimed at examining the upper respiratory tract (URT) deposition efficiency for this vapor at inspired concentrations of 1, 10, 100, or 1000 ppm in four rodent species: B6C3F1 mouse, Sprague-Dawley rat, Syrian hamster, and Hartley guinea pig. For measurement of vapor uptake, the URT was isolated in urethane-anesthetized animals via insertion of a polyethylene cannula in the trachea such that its tip lay at the larynx. Uptake was measured under constant velocity unidirectional inspiratory flow at flow rates of approximately 50, 100, 200, and 300% of the predicted minute ventilation of each species and also under pseudo-cyclic flow (sinusoidal flow at 100% of the predicted minute ventilation with a constant 7 ml/min bleed for analysis). In addition, aldehyde dehydrogenase (AldDH) activities were measured in whole nasal tissue homogenates from each species for comparative purposes. In all species a high-affinity (Km < 0.2 mM), low-capacity AldDH isozyme was observed. In the mouse, hamster, and rat, a low-affinity (Km > 10 mM), high-capacity isozyme was observed; this isozyme was not observed in nasal tissue homogenates of the guinea pig. In all species, URT deposition efficiency was strongly dependent on the inspired concentration, with uptake being two- to three-fold more efficient at inspired concentrations of 1 or 10 ppm than at 1000 ppm. For example, at flows approximating the twice-minute ventilation rate URT uptake efficiency averaged 43, 49, 28, and 43% in the mouse, hamster, rat, and guinea pig, respectively, at an inspired concentration of 10 ppm, compared to 27, 14, 16, and 6% at an inspired concentration of 1000 ppm. Species differences were observed in uptake efficiency. At an inspired concentration of 1000 ppm a two-factor analysis of variance followed by a Newman-Keuls test revealed that uptake was significantly higher in the mouse, rat, and hamster than in the guinea pig. In contrast, at 10 ppm uptake was significantly lower in the rat than in any other species. Thus, the rank order of these species on the basis of ability to scrub acetaldehyde from the airstream differed at high compared to low inspired concentrations. The documentation of greatly differing deposition efficiencies as well as differing relative dosimetric relationships among species at high compared to low exposure concentrations highlights the potential complexities of quantitative extrapolation of high-concentration rodent inhalation toxicity data.

The effect of m-xylene on the rat nasal cytochrome P450 (P450) mixed function oxidase system was analyzed in vitro utilizing microsomes isolated 2, 12, and 24 h following intraperitoneal administration of this solvent in vivo. For comparative purposes, pulmonary and hepatic activities were also measured. Benzyloxyresorufin O-deethylation (BROD) and ethoxyresorufin O-deethylation (EROD), catalytic activities linked with P450 isozymes IIB1 and IA1, respectively, were inhibited in nasal tissue at all times following m-xylene administration. Pulmonary tissue mimicked this m-xylene-dependent inhibition of BROD activity but did not display significant inhibition of EROD activity. In contrast, m-xylene caused a dramatic induction of both BROD and EROD activity in hepatic tissue. The metabolism of a third P450 substrate, cyclopentadienyl manganese tricarbonyl (CMT), was also analyzed. m-Xylene caused significant inhibition of CMT metabolism at all time points in both nasal and pulmonary microsomes but was without effect on hepatic microsomal metabolism of this compound. These data show an inhibitory effect of m-xylene on rat nasal and pulmonary but not hepatic cytochrome P450-dependent metabolism.

A PB-PK model has been developed for nasal nonreactive vapor uptake in the F344 rat which incorporates nasal enzyme distribution as well as nasal airflow patterns. Nasal tissue is separated into respiratory and olfactory mucosal areas with each area containing mucus, epithelial, and submucosal compartments. Metabolic activities are distributed among the compartments in accordance with published histochemical data, and intercompartmental transfer rate constants are based on molecular diffusivity. Two airflow paths are assumed: a lateral/ventral path which passes over only respiratory mucosa and a dorsal medial path which passes over both respiratory and olfactory mucosa. This model was fit to F344 rat nasal uptake data obtained for five vapors: acetone (an unmetabolized vapor), isoamyl alcohol (alcohol dehydrogenase substrate), ethyl acetate (carboxylesterase substrate), and o-xylene and bromobenzene (mixed function oxidase substrates). These vapors cover a wide span of uptake values ranging from a fractional uptake of less than 0.01 for xylene to 0.80 for isoamyl alcohol. The model accurately predicted the fractional uptake of these vapors, the maximal deviation between actual and predicted values being 0.04. The best fit for the data was obtained assuming: (1) an asymmetric blood flow pattern (with the majority of the blood flow being apportioned to the respiratory mucosa), and (2) only a small fraction of the total airflow (8%) following the dorsal medial pathway and penetrating to the olfactory mucosa. Since only a small fraction of the inspired air passes over the olfactory mucosa, a site with high metabolic activity, an inspiratory flow rate dependence on inspired vapor metabolism results. At low flows, olfactory metabolism is limited by low vapor delivery to that site, an effect that does not occur at high flows. This highlights the potential importance of regional nasal airflow and enzymatic activity patterns in influencing uptake and metabolism of inspired vapors and indicates the need for physiologically relevant models incorporating these factors.

Inhalation exposure of rodents to high concentrations of acetaldehyde produces lesions in the upper respiratory tract (URT, all regions of the respiratory tract anterior to and including the larynx). Information on the inhalation dosimetric relationships for this vapor are needed for a comprehensive understanding of its inhalation toxicity. Toward this end, uptake of acetaldehyde was measured in the surgically isolated URT of the urethane-anesthetized male F344 rat under unidirectional (50, 100, 200, or 300 ml/min) and cyclic (100 ml/min) flow conditions at inspired concentrations of 1, 10, 100, or 1000 ppm. Under all flow conditions URT deposition efficiency was strongly dependent on inspired concentration. URT deposition efficiency (under cyclic flow) averaged 76, 48, 41, and 26% at 1, 10, 100, and 1000 ppm, respectively. Nasal acetaldehyde dehydrogenase activity averaged 1.2 micrograms/min. Absolute acetaldehyde deposition rates (micrograms/min) at 100 and 1000 ppm exceeded this activity by 5- to 100-fold, suggesting a possible mechanism for the reduced deposition efficiency at high concentrations. URT deposition under unidirectional flow was strongly dependent on the inspiratory flow rate. The effect of flow rate on deposition was reasonably predicted by the mass-transfer model of Aharonson et al. (J. Appl. Physiol. 37, 654-657, 1974). The uptake coefficients determined from the unidirectional flow studies were used to predict uptake under cyclic flow by integration of the model. The predicted cyclic deposition efficiencies differed from the observed efficiencies by 2.3 +/- 4.3% (mean +/- SEM), suggesting this model might provide a reasonable first approximation for acetaldehyde uptake under cyclic breathing conditions.

Deposition of inspired acetone vapor in the surgically isolated upper respiratory tract (URT) of the anesthetized B6C3F1 mouse was measured under unidirectional constant velocity flow conditions for comparison with our previous studies on the rat, hamster and guinea-pig. Acetone metabolism in mouse nasal mucosal homogenates was examined in vitro. Acetone was metabolized by nasal homogenates via an NADPH-dependent pathway with a Vmax of 12 micrograms/min/whole nose and an apparent Km of 72 micrograms/ml. The enzyme responsible was not identified; however, metabolism was inhibited by pyrazole but not inhibited by metyrapone or incubation under nitrogen. URT deposition efficiency was measured at flow rates of 21, 33 or 70 ml/min and averaged 25, 20 and 14%, respectively; the efficiencies at each flow rate were significantly different (P less than 0.01). Deposition was measured at inspired concentrations ranging from 1,500-20,000 micrograms/liter. Deposition efficiencies were similar at all concentrations; the lack of saturation suggests this vapor was not metabolized when inspired. Kinetic analysis of the deposition data revealed that metabolism rates of inspired acetone were only a small fraction of that measured in vitro, suggesting that in vitro data could not be directly extrapolated to the in vivo setting. Deposition efficiency of acetone in the URT of the mouse was similar to that previously observed in the URT of the F344 rat, but was less efficient than that in the Sprague-Dawley rat and more efficient than that in the hamster or guinea-pig.

While it is thought that local metabolism may enhance nasal deposition of inspired vapors, there have been no studies designed to quantitate this effect. In the current study, deposition of 1-propanol (a metabolized vapor) and acetone (a nonmetabolized vapor) was studied in the surgically isolated upper respiratory tract (URT) of the anesthetized Syrian hamster. The effect of inspiratory flow rate on URT deposition of acetone could be described by a ventilation-perfusion (V-P) model with a nasal perfusion rate of 0.046 ml/min. Theoretical considerations predict that at enzyme saturation, deposition efficiency will be dependent upon the inspired concentration and the URT metabolism rates can be estimated from the concentration-dependence data. A concentration dependence on propanol deposition efficiency was observed at a flow rate of 200 ml/min, but not at 38 or 71 ml/min. At a flow rate of 200 ml/min, an apparent URT metabolism rate of 3.8 micrograms/min (95% confidence limits 0.5-7.1 micrograms/min) was estimated. In vitro studies on nasal tissue homogenates provided metabolism rates of approximately 2 micrograms/min, values which did not differ significantly from, and therefore, were in reasonable agreement with, the estimates from the deposition studies. After correction for the effect of metabolism, URT propanol deposition could be described by the V-P model with a nasal perfusion rate of 0.050 ml/min. This value did not differ significantly from that observed in the acetone studies. Thus, deposition of both propanol and acetone in the URT of the Syrian hamster could be described by the V-P model.(ABSTRACT TRUNCATED AT 250 WORDS)