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PubMed1994

Cyanide induced changes in dynamic pulmonary mechanics in rats.

Effect of subcutaneously (s.c.) administered potassium cyanide (0.5 and 1.0 LD50) and inhalation of hydrogen cyanide (55 ppm or 60.6 mg/m3) for 30 minutes was studied on various physiological parameters related to dynamic pulmonary mechanics in anaesthetized rats. Total pulmonary phospholipid with its fractions were also estimated. Both s.c. (1.0 LD50) and inhalation exposures increased air flow, transthoracic pressure and tidal volume accompanied by significant decrease in pulmonary phospholipids. Inhalation of hydrogen cyanide also exhibited direct effect on the pulmonary cells as evidenced by decreased compliance. The study suggests that inhalation of cyanide is more injurious compared to parenteral route.

Animals↗
PubMed2005

Multi-pathway risk assessment of trihalomethanes exposure in Istanbul drinking water supplies.

The lifetime cancer risk and the hazard index of trihalomethanes (THMs) through oral ingestion, dermal absorption, and inhalation exposure from tap water of 15 districts in Istanbul are estimated. The most dominant THM compounds are chloroform, bromodichloromethane (BDCM), and dibromochloromethane (DBCM) in Istanbul tap water. The results indicate that within three different pathways, Istanbul residents had a higher cancer risk through oral ingestion than through the other two pathways. The lifetime cancer risks of oral ingestion for total THMs was highest in Esenyurt district, while the lowest lifetime cancer risk for total THMs was in Basaksehir district. The lifetime cancer risks of chloroform, BDCM, and DBCM from tap water of all 15 districts were higher than 10(-6), the negligible risk level defined by the USEPA. Among the 15 districts, people living in Esenyurt have the highest risk of cancer due to the THM exposure through the multi-pathways, mainly because of the exposure to BDCM and DBCM. The total cancer risk analysis concluded that each year approximately 5 of the 8 million Istanbul residents could get cancer from the daily intake of tap water.

Aged↗
PubMed1994

Development of methods for measuring biological markers of formaldehyde exposure.

Formaldehyde, a widely used industrial chemical that is also present in automobile exhaust, causes nasal tumors in rats and mice after prolonged inhalation exposure to high concentrations. The induction of squamous cell carcinomas in rats by formaldehyde displayed a highly nonlinear dose response with a disproportionately large number of tumors at higher exposure concentrations. A sufficient amount of formaldehyde reaching target cells, and the saturation of formaldehyde metabolism to formate can increase the covalent binding of formaldehyde to DNA. The carcinogenicity of formaldehyde may result from its ability to induce DNA-protein cross-links and/or hydroxymethyl adducts in DNA. Measuring these products can indicate the dose of this carcinogen at a critical target site, and such assessment has been conducted for formaldehyde by measuring DNA-protein cross-links. The objective of this study was to develop methods for measuring hydroxymethyl adducts in DNA that do not require the use of radiolabeled formaldehyde. The detection of N6-hydroxymethyldeoxyadenosine and N2-hydroxymethyldeoxyguanosine, the major adducts formed by the reaction of formaldehyde with DNA in vitro, is complicated by their instability. The stabilization of hydroxymethyl adducts by reaction with sodium bisulfite in aqueous solution at 4 degrees C before isolating DNA from homogenates was investigated. On treatment of calf thymus DNA or isolated rat liver nuclei with [14C]formaldehyde, followed by reaction with bisulfite and isolation of DNA, radioactive peaks corresponding in retention time to N6-sulfomethyldeoxyadenosine and N2-sulfomethyldeoxy-guanosine were detected by high-performance liquid chromatography of nucleoside digests. However, on treatment of cultured lymphoblasts with [14C]formaldehyde, extensive metabolic incorporation of radioactivity into normal nucleosides precluded the detection of the derivatives. Methods for detecting these derivatives that do not involve the use of radiolabeled formaldehyde, such as 32P-postlabeling and electrophore postlabeling, were investigated. For electrophore postlabeling, several reactions for preparing a derivative suitable for analysis by gas chromatography with mass spectrometry were investigated unsuccessfully. For 32P-postlabeling, a method was developed for detecting sulfomethyldeoxyadenosine 3',5'-diphosphate that involved separating sulfomethyldeoxyadenosine 3'-monophosphate from normal nucleotides by reverse-phase high-performance liquid chromatography using two columns with column switching. The purified adduct fractions were subjected to 32P-postlabeling, and the labeled adduct was separated by two-dimensional thin-layer chromatography on polyethyleneimine-cellulose plates. The adduct spots were quantitated by comparing them with standards labeled directly or mixed with normal nucleotide 3'-monophosphates and separated by high-performance liquid chromatography.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine↗
PubMed1998

Biological monitoring of occupational exposure to arsenic by determining urinary content of inorganic arsenic and its methylated metabolites.

A study was undertaken to assess the relationship between inhalation exposure to arsenic in copper smeltery workers and urinary excretion of total inorganic arsenic metabolites (Asitm), including inorganic arsenic (Asi), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). The methods applied made it possible, in principle, to determine all forms of airborne arsenic and to eliminate the influence of seafood-derived organoarsenicals on the level of urinary Asitm. Air samples were collected on the second day of work after the weekend break. Urine samples were collected just after shift-end on the same workday. The time-weighted average (TWA) concentrations of arsenic in the workers' breathing zone varied between 1 and 746 microg/m3 and Asitm concentrations in urine between 2 and 850 microg/l (s.g. 1.024). The urine samples with a specific gravity of lower than 1.010 and higher than 1.030 were not considered; neither were those subjects with an Asitm excretion efficiency of higher than 100% of the dose absorbed during the day of measurement. In total, 53 air samples and corresponding urine samples were obtained. The correlation coefficient between the airborne arsenic concentration in microg/m3 (X) and the concentration of urinary Asitm in microg/l, s.g. 1.024 (Y), was 0.723. The relation between the two variables can be presented using the following formula: Y = 6.29 x X0.616. According to the findings of this study, as well as the results of three other studies based on similar principles, the daily exposure to arsenic concentrations of 10 microg/m3 and 50 microg/m3 led to concentrations of Asitm in urine of about 30 microg/l and 70 microg/l (s.g. 1.024), respectively.

Arsenic↗
PubMed1994

Endotoxin responsiveness and grain dust-induced inflammation in the lower respiratory tract.

To identify the role of endotoxin responsiveness in grain dust-induced airway disease, we used two models of extotoxin hyporesponsiveness to perform inhalation exposure studies in mice. In the first model, we investigated whether genetic resistance to endotoxin would alter the inflammatory response to inhaled grain dust by comparing the inflammatory response in the lower respiratory tract of endotoxin-sensitive and -resistant male mice after inhalation of pyrogen-free saline, corn dust extract (CDE), sterile CDE (SCDE), or lipopolysaccharide (LPS). Endotoxin-sensitive and -resistant mice were exposed for 4 h to nebulized solutions of LPS, SCDE, or CDE. Another group of endotoxin-sensitive and -resistant mice was sham exposed for 4 h to nebulized sterile saline. Dose-response relationships for endotoxin were explored for LPS, SCDE, and CDE. Bronchoalveolar lavage (BAL) 5 h after the start of exposure demonstrated a higher concentration of total cells, neutrophils (PMNs), and tumor necrosis factor-alpha (TNF-alpha) in BAL fluid after inhalation of CDE, SCDE, or LPS in endotoxin-sensitive than in endotoxin-resistant mice. Whereas endotoxin-sensitive mice demonstrated a dose-response relationship between the endotoxin concentration in each of the solutions and the concentration of cells, PMNs, and TNF-alpha in BAL fluid, concentrations of TNF-alpha were significantly higher only in BAL fluid of endotoxin-resistant mice exposed to higher concentrations of SCDE or CDE. In the second model, we investigated whether acquired endotoxin tolerance would alter the inflammatory response to SCDE.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed2006

Gestational toluene exposure effects on spontaneous and amphetamine-induced locomotor behavior in rats.

Gestational Toluene Exposure Effects on Spontaneous and Amphetamine-Induced Locomotor Behavior in Rats. Bowen, S.E., Mohammadi, M.H., Batis, J.C., and Hannigan, J.H. Neurotoxicology and Teratology, XX, 2006. The abuse of volatile organic solvents (inhalants) continues to be a major health concern throughout the world. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. The neurobehavioral teratogenic sequelae of solvent abuse (i.e., repeated, brief inhalation exposures to very high concentrations of solvents) have not been examined thoroughly. In a preclinical model of inhalant abuse, timed-pregnant Sprague-Dawley rats were exposed to 0, 8000, or 12,000 parts per million (ppm) for 15 min twice daily from gestation day 8 (GD8) through GD20. In the first experiment, separate groups of offspring were observed individually in an open-field on postnatal day 22 (PN22), PN42 or PN63. In the second experiment, other offspring given identical prenatal toluene exposures were observed in an "open-field" following an acute i.p. injection of amphetamine (0, 0.56, 1.78 mg/kg) on PN28. Automated measurements of distance traveled and ambulatory time were recorded. Prenatal toluene exposure resulted in small alterations in spontaneous activity compared to non-exposed rats. Prenatal exposure to 12,000 ppm toluene resulted in significant hyposensitivity to the locomotor stimulatory effects of the amphetamine challenge in male but not female rats on PN28. The results demonstrate that prenatal exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous and amphetamine-induced locomotor behavior in rats. The expression of these effects also appears to depend upon the postnatal age of testing. These results imply that abuse of organic solvents during pregnancy in humans may also produce long-lasting effects on biobehavioral development.

Age Factors↗
PubMed1990

Brief inhalation of asbestos compromises superoxide production in cells from bronchoalveolar lavage.

Production of superoxide (O-.2) was measured in alveolar macrophages (AM) exposed to asbestos in vitro and in cells obtained from bronchoalveolar lavage (BAL) of rats inhaling asbestos. Steady state levels of O-.2 released by AM in vitro were dose and time dependent in response to crocidolite, chrysotile, and opsonized zymosan, a particulate used to trigger O-.2 generation. In contrast, an inhalation exposure for 1 h to crocidolite or for 6 days to either crocidolite or chrysotile asbestos resulted in a decreased production of O-.2 by BAL cells. Likewise, BAL cells from rats inhaling chrysotile for 1 h or crocidolite for 9 days exhibited a diminished capacity to secrete O-.2 when challenged with the particulate opsonized zymosan. Diminished generation of O-.2 by asbestos occurred in BAL cell populations containing either significantly increased numbers of polymorphonuclear leukocytes and lymphocytes (6- and 9-day exposures) or 99% AM (1-h exposure). Thus, these novel observations suggest that short-term inhalation of asbestos compromises the ability of BAL cells to produce O-.2 in the presence or absence of an additional phagocytic stimulus.

Administration, Inhalation↗
PubMed1993

Phase-specific developmental toxicity in mice following maternal methanol inhalation.

Methanol is toxic to embryos of mice and rats when inhaled by dams at high concentrations. The present studies examined methanol-induced developmental toxicity following inhalation exposure (6 hr/day) of pregnant CD-1 mice to 5000, 10,000 or 15,000 ppm either throughout organogenesis (GD 6-15), during the period of neural tube development and closure (GD 7-9), or during a time of potential neural tube reopening (GD 9-11). Transient neurologic signs and reduced body weights were observed in up to 20% of dams exposed to 15,000 ppm. Examination of near-term fetuses revealed embryotoxicity (increased resorptions, reduced fetal weights, and/or fetal malformations) at 10,000 and 15,000 ppm, while 3-day exposures at 5000 ppm yielded no observable adverse effects. Terata included neural and ocular defects, cleft palate, hydronephrosis, deformed tails, and limb (paw and digit) anomalies. Neural tube defects and ocular lesions occurred after methanol inhalation between GD 7-9, while limb anomalies were induced only during GD 9-11; cleft palate and hydronephrosis were observed after exposure during either period. These findings were consistent with prior reports that maternal methanol inhalation at high levels induces developmental toxicity in a concentration-dependent manner. Furthermore, our data indicate that the spectrum of teratogenic effects depended upon both the timing (i.e., stage of embryonic development) and the number of methanol exposures.

Abnormalities, Drug-Induced↗
PubMed1995

Acute tolerance to the cardiovascular effects of volatilized cocaine free base in rats.

The cardiovascular effects elicited by volatilized cocaine were compared to those produced by i.v. drug administration. All of the subjects exposed to volatilized cocaine exhibited an initial increase in mean arterial pressure (MAP), profound bradycardia, and heart blocks. Intravenous administration of cocaine (1.5 mg/kg i.v.), a dose equivalent to the amount of drug subjects received from inhalation exposure, led to a transient increase in MAP but failed to produce any obvious ECG abnormalities or bradycardia; however, increasing the dose to 4.5 mg/kg resulted in considerable toxicity. Finally, the hemodynamic effects elicited by inhalation cocaine were found to undergo rapid tolerance during the first 5-min exposure period and the three subsequent drug exposures.

Administration, Inhalation↗
PubMedDate not supplied

Relative neurotoxicological properties of five unsaturated aliphatic nitriles in rats.

Motor and sensory conduction velocities (MCV and SCV) and amplitudes of the sensory and motor action potentials (ASAP and AMAP) of the tail nerve were studied in male Sprague-Dawley rats during chronic oral treatment with five unsaturated aliphatic nitriles. Rats were given doses of 12.5, 25 and 50 mg kg(-1) of acrylonitrile, 50, 70 and 90 mg kg(-1) of methacrylonitrile, 25, 50 and 100 mg kg(-1) of trans-3-pentenenitrile and 50, 100 and 200 mg kg(-1) of either 3-methyl-2-butenenitrile or 4-pentenenitrile once a day, 5 days per week for 12 weeks. Moreover, due the the early results obtained after oral treatment, neurophysiological examinations were also carried out in rats exposed by inhalation to 25, 50 and 100 ppm of acrylonitrile for 6 h a day, 5 days per week for 24 weeks. Rats given acrylonitrile orally developed behavioural sensitization characterized by salivation, locomotor hyperactivity and moderately intense stereotypies. Moreover, rats in the high dose group developed weakness in hindlimbs associated with decreases in SCV and ASAP. Rats exposed to acrylonitrile vapours exhibited time- and concentration-dependent decreases in MCV, SCV and ASAP, which were partially reversible after 8 weeks of recovery. None of the other four nitriles caused any abnormal behaviour or any changes in the electrophysiological parameters in spite of an obvious general toxicity. Based upon these results, it can be concluded that the nervous system of the rat appears to be a target following either oral or inhalation exposures of acrylonitrile.

Acrylonitrile↗
PubMed1987

Urinary excretion of acrylonitrile and its metabolites in rats.

Quantitative analysis of the dose-dependent urinary excretion of acrylonitrile and its metabolites was carried out in male Wistar rats following inhalation exposure of the animals to 1, 5, 10, 50 and 100 ppm acrylonitrile for 8 h. Quantitative analysis of acrylonitrile in urine was performed by gas chromatography. The urinary metabolites cyanoethyl mercapturic acid, S-carboxymethyl cysteine and hydroxyethyl mercapturic acid were measured by a modified amino acid analysis, and thiodiglycolic acid by GC-MS. The excretion pattern of the compound and its metabolites was dependent on the exposure level; it is concluded that urinary determination of the unmetabolized acrylonitrile and two of its metabolites, cyanoethyl mercapturic acid and thioglycolic acid, may be useful for biological monitoring of industrial exposure.

Acrylonitrile↗
PubMed1991

Carboxylesterase-dependent cytotoxicity of dibasic esters (DBE) in rat nasal explants.

Dibasic esters (DBE) are a solvent mixture of dimethyl adipate (DMA), dimethyl glutarate (DMG), and dimethyl succinate (DMS) used in the paint and coating industry. Subchronic inhalation toxicity studies have demonstrated that DBE induce a mild degeneration of the olfactory, but not the respiratory, epithelium of the rat nasal cavity. Carboxylesterase-mediated hydrolysis of the individual dibasic esters is more efficient in olfactory than in respiratory mucosal homogenates. In the present study, an in vitro system of cultured rat nasal explants was utilized to determine if DBE toxicity is dependent on a metabolic activation by nonspecific carboxylesterase. Explants from both the olfactory and the respiratory regions of the female rat nasal cavity were incubated for 2 hr in Williams' medium E containing 10-100 mM DMA, DMG, or DMS. DBE caused a dose-related increase in nasal explant acid phosphatase release, a biochemical index of cytotoxicity. HPLC analysis demonstrated parallel increases in the carboxylesterase-mediated formation of monomethyl ester metabolites. Diacid metabolite production in the nasal explant system was not entirely concentration-dependent. Metabolite concentrations and acid phosphatase release were generally greater in olfactory than respiratory tissues. DBE-induced cytotoxicity and acid metabolite production were markedly attenuated in nasal tissue excised from rats which were pretreated with bis(p-nitrophenyl)phosphate, a carboxylesterase inhibitor. This study presents a viable in vitro method for assessing organic ester cytotoxicity in the rat nasal cavity. It was shown that DBE are weak nasal toxicants under the conditions of this system. It was further demonstrated that DBE toxicity is dependent on a carboxylesterase-mediated activation. A similar mechanism was proposed for the nasal toxicity induced by other organic esters following inhalation exposure.

Acid Phosphatase↗
PubMed2002

The relationship of particle size to olfactory nerve uptake of a non-soluble form of manganese into brain.

The essential element, manganese, can produce chronic neuromotor impairment related to basal ganglia (BG) damage when it is presented in excessive quantities. The uptake and elimination patterns of manganese following ingestion have been well studied and, under normal conditions, excretion appears to keep manganese levels under tight control. Less is known about inhalation exposure, but it has been proposed that the lung might serve as a long-term reservoir for manganese transport into blood. Recent data suggest that a third route of exposure, transport by the olfactory nerve directly to the brain, might have importance in toxicology since such a route would bypass liver uptake and biliary excretion of manganese. In this study, we sought to determine how particle size and the use of a poorly soluble form of manganese might influence net systemic absorption of manganese dust and the potential role of the olfactory nerve in transport of manganese dioxide. Rats were exposed in nose-only exposure chambers to manganese dioxide (MnO2) aerosols of 1.3 and 18 microm mass median aerodynamic diameter (MMAD). The concentration of aerosols was kept constant at 3 mg/m3 as Mn. Following 15 days of exposure (five times per week for 3 weeks), rats were euthanized and tissues harvested for manganese determination carried out by graphite furnace atomic absorption spectroscopy. Small-particle MnO2 exposure resulted in an elevation in olfactory bulb manganese concentration, presumably through uptake by the olfactory nerve, but the effect was highly variable. While small increases in cortical and neostriatal manganese levels were also observed in these rats, they did not reach statistical significance. By contrast, there was no evidence of olfactory nerve MnO2 uptake in rats receiving the large-particle exposure.

Administration, Inhalation↗
PubMedDate not supplied

Acute exposures to p-xylene and toluene alter visual information processing.

Long-Evans hooded rats were exposed to single doses of toluene (PO) at 0, 250, 500 and 1000 mg/kg, to p-xylene (PO) at 0, 125, 250, 500, 1000 and 2000 mg/kg, and to inhalation of p-xylene for 4 hr at 0, 800 or 1600 ppm. The functional integrity of the visual system was evaluated using flash-evoked potentials (FEPs). The data indicated a significant depression in amplitude of FEP peak N3 at 250 mg/kg and higher dosages of toluene and p-xylene. A similar depression in peak N3 amplitude was observed following inhalation exposure to 1600 ppm p-xylene. The effects produced by oral administration of 500 mg/kg p-xylene or toluene lasted at least 8 hr, while the effect of inhaled p-xylene dissipated within 75 min of removal from the exposure. FEP peak N3 is presumed to be related to arousal, such that increases in arousal from a relaxed state should decrease amplitude. Rats administered amphetamine in dosages of 0.6, 1.2 and 2.5 mg/kg (known to increase arousal) also had reduced N3 amplitude. The effects of p-xylene and toluene on FEPs, while indicative of altered processing of visual information, may be secondary to changes in arousal or excitability.

Amphetamine↗
PubMed2002

Inhalation of organic dusts and lipopolysaccharide increases gelatinolytic matrix metalloproteinases (MMPs) in the lungs of heaves horses.

We report the effects of mouldy hay/straw exposure, inhaled hay dust suspension (HDS) and inhaled lipopolysaccharide (LPS) on bronchoalveolar lavage fluid (BALF) gelatinolytic matrix metalloproteinase (MMP) levels and degree of activation in healthy (n = 6) and heaves- (previously termed chronic obstructive pulmonary disease) affected (n = 6 or 7) horses. Gelatinolytic MMPs in BALF were quantified by zymography, and gelatinases were shown by Western immunoblotting to be MMP-2 and MMP-9. Hay/straw and HDS challenges increased BALF total gelatinolytic activity only in heaves horses, with the majority of gelatinolytic activity comprising pro- and active MMP-9. The 5 h duration hay/straw challenge increased BALF gelatinolytic MMP activity in heaves horses at 5 and 24 h after the start of this challenge, with activity returning to baseline by Day 4. In contrast to hay/straw and HDS challenges, LPS inhalation increased BALF gelatinolytic MMP activity in both groups. For all challenges, absolute BALF neutrophil counts were highly significantly correlated (P<0.0001) with levels of proMMP-9 and active MMP-9, but not with levels of MMP-2 (P>0.05). As gelatinolytic MMPs are pro-inflammatory agents, they may contribute to lung dysfunction and tissue destruction in heaves horses exposed to airborne organic stable dusts.

Animals↗
PubMed1999

Is it safe to apply the additivity rule to evaluating health effects of exposure to Farbasol?

Neurotoxic and sensory respiratory irritation effects of Farbasol in male rats and male Balb/C mice were investigated in condition of acute inhalation exposure. Rotarod performance and pain sensitivity behaviour were tested in rats exposed to Farbasol at concentrations of 4665-9622 mg/m3 immediately after termination of a four-hour exposure. The respiratory rate was measured in mice by the whole body plethysmographic method in 6 min duration exposure to various concentrations of Farbasol. Exposure to Farbasol resulted in concentration-dependent disturbances in rotarod performance and decrease in pain sensitivity in rats, and depression of respiratory rate in mice. The EC50 value for rotarod performance behaviour disturbances was 5497 mg/m3 and for pain sensitivity EC50 was 6589 mg/m3. The concentration depressing the respiratory rate to 50% (RD50) was 3139 mg/m3. The comparison of Farbasol EC50 and RD50 values and its individual constituents such as trimethylbenzene isomers and 4-ethyl toluene established in similar experimental conditions indicate their similar toxic effects potency. Application of additivity rule for establishing the MAC value for Farbasol seems to be safe.

Animals↗
PubMed1986

A method for repeated evaluation of benzene uptake in rats and mice during a six hour inhalation period.

Benzene uptake measurements and respiratory minute volume (RMV) were assessed in rats and mice during a 6-hour inhalation exposure to 300 ppm (v/v) of benzene vapor. The values for benzene uptake and RMV were used to compare predictions of inhaled dose in both species. The theoretical prediction assumed an unchanging RMV. The next prediction allowed adjustments for changes in RMV during exposure. The final prediction addressed benzene uptake directly. The uptake characteristics of benzene in both species were different from the theoretical prediction, from the prediction adjusted for changing RMV and from each other. The greatest difference was seen in rats where the observed benzene dose was only 28% of the theoretical value. The experiment was not designed to elucidate the causes for the difference between the predictions, nor was the data sufficient to suggest whether the rat or the mouse was a suitable model of benzene uptake in humans.

Animals↗
PubMed2005

Experimental approaches to evaluate respiratory allergy in animal models.

Asthma is defined as a chronic disease of the entire lung and asthma attacks may either be immediate, delayed or dual in onset. Allergic asthma is a complex chronic inflammatory disease of the airways and its etiology is multifactorial. It involves the recruitment and activation of many inflammatory and structural cells, all of which release mediators that result in typical pathological changes of asthma. A wealth of clinical and experimental data suggests that allergic asthma is due to an aberrant lung immune response mediated through T-helper type 2 (Th2) cells and associated cytokine-signaling pathways. The pathology of asthma is associated with reversible narrowing of airways, associated with prominent features that involve structural changes in the airway walls and extracellular matrix remodeling including abnormalities of bronchial smooth muscle, eosinophilic inflammation of the bronchial wall, hyperplasia and hypertrophy of mucous glands. The primary objective of respiratory allergy tests is to determine whether a low-molecular-weight chemical (hapten) or high-molecular-weight compound (antigen) exhibits sensitizing properties to the respiratory tract. This may range from reactions occurring in the nose (allergic rhinitis), in the bronchial airways (i.e., allergic bronchitis, asthma) or alveoli (e.g., hypersensitivity pneumonitis). Current assays utilize several phases, viz. an induction phase, which includes multiple exposures to the test compound (sensitization) via the respiratory tract (e.g., by intranasal or intratracheal instillations), by inhalation exposures or by dermal contact, and a single or multiple challenge or elicitation phase. The challenge can either be with the chemical (hapten), the homologous protein conjugate of the hapten or the antigen. The choice depends both on the irritant potency and the physical form (vapor, aerosol) of the hapten. The appropriate selection of concentrations (dosages) both for the induction and elicitation of respiratory allergy appears to be paramount for the outcome of test. Endpoints to characterize positive response range from the induction of immunoglobulins, cytokine or lymphokine patterns in serum (or the lung) to (patho-)physiological reactions typifying asthma. None of the currently applied animal models duplicate all features of human asthma. Accordingly, the specific pros and cons of the selected animal model, including protocol variables, animal species and strain selected, must be interpreted cautiously in order to arrive at a meaningful extrapolation for humans.

Animals↗