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Biomedical subjects

Y Alarie

Publications and source records attributed to Y Alarie.

At least 19 recordsLinked to original sources
PubMed1995

Physicochemical properties of nonreactive volatile organic chemicals to estimate RD50: alternatives to animal studies.

This article presents the correlations obtained between the results on the potency of nonreactive airborne chemicals as sensory irritants and several of their physicochemical properties. The potency of airborne sensory irritants obtained from a reflexively induced decrease in respiratory frequency has been measured in the past using mice. Typically, their potency has been expressed as the exposure concentration necessary to decrease respiratory frequency by 50% (RD50). A large database of RD50 values is now available and such values are highly correlated with occupational exposure guidelines such as threshold limit values (TLVs). We used the nonreactive volatile organic chemicals from this database, for which relevant physicochemical variables are available or can be calculated. These variables were vapor pressure (P) or Ostwald gas-liquid partition coefficients (L). The liquids used for L values were n-hexadecane, octanol, N-formylmorpholine, tri-(2-ethylhexyl)phosphate, and olive oil. Excellent correlations were found between log RD50 and log P, as well as between log RD50 and log L16, log L(Oct), log L(NFM), log L(EHP), or log L(Oil). It follows that as an alternative to the bioassay, these physicochemical variables can be used to estimate RD50 of nonreactive volatile organic chemicals. Appropriate exceptions to general estimation of RD50 values from physicochemical variables are also presented, as well as the most appropriate estimates which can be obtained within homologous series.

Air Pollutants, Occupational↗
PubMed1995

Possible mechanisms for the respiratory tract effects of noncarcinogenic indoor-climate pollutants and bases for their risk assessment.

This review outlines the effects of pollutants on the lungs. Mechanisms and effects relevant to the assessment of indoor-air risk are especially dealt with. Important mediators have also been considered. Concentration-effect relationships exist for toxic reactions, sensitization reactions, and neurogenic effects. If Harber's Law is used for extrapolations from higher concentrations to the lower indoor-air levels, the indoor-air risk estimate may exceed the real risk. Additivity seems to apply to toxic and neurogenic effects of low doses. Only already sensitized subjects and possible subjects with a profound alpha 1-antitrypsin deficiency appear to be extremely sensitive, and a safety factor of 10 seems adequate for the protection of other groups. Thus combining occupational exposure limits (OEL), Harber's Law, and the safety factor suggests that no direct lung effects should be expected from a substance if the exposure level does not exceed 1/40.OEL.

Adult↗
PubMed1993

Autoradiographic analyses of guinea pig airway tissues following inhalation exposure to 14C-labeled methyl isocyanate.

Through the use of radioactively labeled methyl isocyanate (MIC), the deposition, penetration, and clearance of this highly reactive compound in the airway at the tissue and cellular levels have been directly examined. Guinea pigs were exposed to 14C-MIC vapors at concentrations ranging from 0.38 to 15.2 ppm for periods of 1-6 hr. Solubilization of tissues from these animals showed the airway tissues to have the highest level of radioactivity. In the nasal region, 14C deposition, as monitored by histoautoradiography, was limited to the epithelial layer, was related to dose, and was dependent on the specific epithelial cell type. The squamous epithelium was minimally labeled on the surface and the label did not penetrate the cell layer. However, radioactivity was detected throughout the entire nasal respiratory epithelial layer. The lack of nasal deposition in tracheotomized animals demonstrated that the 14C accumulation at this site was due to the scrubbing action of the nasal region with no contribution from blood recirculation. Cellular localization in the tracheobronchial region showed epithelial and subepithelial deposition in a dose-dependent manner with accumulation of the label at the subepithelial region. Radioactivity penetrated to the level of the terminal bronchiole but was not detected in the alveolar region. The persistence of airway radioactivity over the 48-hr postexposure period monitored suggests the covalent modification of airway macromolecules. Despite its broad specificity and high reactivity, MIC undergoes selective reactions in the airways which are dependent on respiratory region and cell type.

Administration, Inhalation↗
PubMed1992

Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation.

Rejection remains a major obstacle to long-term success of pulmonary transplantation. Direct delivery of cyclosporine to lung allografts may produce better control of rejection by generating high intragraft concentrations of drug with decreased systemic delivery and toxicity. The efficacy of inhaled cyclosporine in preventing allograft rejection was compared with systemic delivery by intramuscular injections in a rat model of lung transplantation (Brown-Norway to Lewis). Group 1 animals were given no immunosuppression. Group 2 received a single i.m. injection of 25 mg/kg CsA on the day of operation while group 3 received daily doses on postoperative days 0-3. Groups 4-7 received aerosolized CsA daily for seven days. The aerosol generator produced an airborne concentration of CsA of 180 mg/m3 with a mean particle size of 0.7 mu and estimated pulmonary depositions of CsA of 0.98-3.6 mg/kg/day. Animals were killed on POD 7, and the transplanted lungs graded histologically in a blinded fashion. All control animals showed destructive grade 4 changes by POD 7. Animals receiving high-dose aerosolized CsA (groups 6 and 7) showed minimal changes with a mean rejection grade of 1.3. A single i.m. dose of CsA (group 2) failed to prevent rejection; the mean grade was 2.2. Animals given four i.m. doses of CsA had a mean grade of 1.8. Aerosolized CsA provided significantly better control of rejection than did systemic CsA (groups 6 and 7 vs. groups 2 and 3; P less than 0.0002 and less than 0.0054, respectively). Local delivery of CsA by aerosol inhalation is effective in limiting acute rejection of the rat lung allograft.

Aerosols↗
PubMed1991

Long term pulmonary impairment following a single exposure to methyl isocyanate.

Groups of guinea pigs were exposed for 3 hr to 6, 13, 19, 27, or 37 ppm of methyl isocyanate (MIC). Pulmonary performance was evaluated immediately postexposure and for a period of 1 year in the animals surviving 19 or 37 ppm of MIC. At 6 and 13 ppm deterioration of pulmonary performance was observed but complete recovery occurred within a few weeks. In those animals surviving 19 or 37 ppm some recovery occurred but a long lasting impairment of pulmonary performance was observed. One year after a single exposure to MIC these animals presented a condition best described as chronic obstructive lung disease. Using flow-volume measurements during air breathing and during CO2 challenge, animals surviving at 19 or 37 ppm presented typical abnormalities associated with airflow limitation along the conducting airways. One year after exposure lung hyperinflation was also present. At this time the poor ventilatory response to CO2 was due to mechanical limitation of lung expansion during inspiration and airflow limitation during expiration. The findings were similar to humans with severe obstructive lung disease. Microscopic examination substantiated the flow-volume measurements in that the main bronchi, small bronchi, and bronchioles were found to have an increase in dense fibrous tissue, while the alveolar level was characterized by destruction of alveolar walls and an increase in septal thickness. Thus a single exposure to MIC, if the concentration is high enough, is sufficient to induce permanent pulmonary toxicity.

Administration, Inhalation↗
PubMed1990

Sensory irritant receptor compartment properties. Equipotent vapour concentrations related to saturated vapour concentrations, octanol-water, and octanol-gas partition coefficients.

Receptor compartments can be hydrophilic or hydrophobic. The hydrophobic character can be revealed from the logarithmic relationship between the octanol-water partition coefficient (Po/w) and the equipotent equilibrium concentration (Cw) measured in the water compartment (Franke: Theoretical Drug Design Methods. Elsevier, Amsterdam 1984). For activation of the sensory irritant receptor during exposure to airborne chemicals the Cw values at equilibrium can be obtained from the gas or vapour concentrations [( A]a) and the water-gas partition coefficients (Pw/g). However, if the octanol-gas partition coefficients (Po/g) are used, the analysis can be carried out directly from the gas or vapour concentrations. The thermodynamic activity can also be used to reveal whether the environment of the receptor is hydrophobic or not. We have adapted Franke's theory to a series of homologous airborne sensory irritants. Our results suggest that the environment of the sensory irritant receptor is likely to be a hydrophobic site within the polar part of the nerve membrane. The extended theory is general and it is therefore suggested that it applies to other airborne exposure concentrations which are in equilibrium with a hydrophobic receptor.

Chemical Phenomena↗
PubMed1989

Uptake and distribution of 14C during and following inhalation exposure to radioactive toluene diisocyanate.

Inhalation of toluene diisocyanate (TDI) results in toxic responses ranging from pulmonary irritation to immunological sensitization. The use of radioactively labeled isocyanate has made it possible to follow the initial uptake of the compound into the bloodstream independent of the final fate of the isocyanate. This study shows that the rate of uptake into the blood is linear during exposure to concentrations ranging from 0.00005 to 0.146 ppm and that the uptake continues to increase slightly postexposure. It also demonstrates that the radioactivity clears from the bloodstream to a level corresponding to approximately a 100 nM concentration of tolyl group after 72 hr and persists at a nanomolar level even 2 weeks following the exposure. This is similar to the response previously reported by this group for radioactively labeled methyl isocyanate. The initial rate of 14C uptake is also a linear function of the concentration of TDI when expressed either as concentration (ppm) or as concentration multiplied by duration of exposure (ppm.hr). This is discussed in comparison with the toxic responses as a function of both ppm and ppm.hr. Finally, the inclusion of the data on methyl isocyanate indicates that the uptake into arterial blood is a function of exposure concentration, independent of isocyanate structure.

Administration, Inhalation↗
PubMed1989

Alteration of respiratory cycle timing by propranolol.

The present study was undertaken to explore the effect of propranolol on respiratory cycle timing and breathing pattern using mice and guinea pigs. Propranolol was administered via aerosol or via injection. Mice exposed to propranolol aerosols exhibited a breathing pattern that was characterized by a pause between breaths. The length of such pauses (TP) increased as the propranolol exposure concentration was raised. We also observed at increasing propranolol concentrations that the time of inspiration (TI) and time of expiration (TE) decreased. Thus, the respiratory rate of these animals was seen to increase, remain unchanged, or decrease depending on the balance between TP versus TI and TE. Guinea pigs also exhibited pauses between breaths during exposure to propranolol aerosols, but such pauses were not observed as consistently as in mice. TP again rose while TI and TE fell in guinea pigs exposed to increasing propranolol concentrations. This species was, however, less sensitive than mice. Intraperitoneal injections of propranolol failed to elicit such alterations in respiratory pattern or timing in either species. These changes in respiratory timing obtained with an aerosol of propranolol were most probably due to a local effect on vagal nerve endings or to its bronchoconstricting effect.

Administration, Inhalation↗
PubMed1989

Ergometer within a whole-body plethysmograph to evaluate performance of guinea pigs under toxic atmospheres.

A guinea pig ergometer was constructed within an enclosure, with inlet and outlet ports for continuous ventilation, designed so that the enclosure would work as a whole-body plethysmograph as well as an inhalation exposure chamber. This system provided continuous measurement of tidal volume, respiratory frequency, oxygen uptake, and carbon dioxide output which enabled an evaluation of performance in terms of distance traveled over time with the animals running at a known speed and constant oxygen uptake. The effects of CO or HCl in running versus sedentary animals were investigated using this apparatus. For CO, exercise increased the rapidity of the onset of incapacitation as would be predicted by the increase in metabolic rate. HCl produced a more severe incapacitating effect in exercising animals that was out of proportion with the increase in minute volume induced by exercise.

Air Pollutants↗
PubMed1989

Effects of inhaled municipal refuse incinerator fly ash in the guinea pig.

Fly ash was collected from two municipal refuse incinerators. It was analyzed for heavy metals, elements, and a wide range of toxic organics. It was resuspended in air for inhalation exposure of guinea pigs. These animals were exposed at high concentrations of each ash 6 h/d for 5 d, and tissues were taken 45 d after the exposure. Following the first exposure and after each daily exposure the ventilatory response of these animals upon challenge with CO2 was found to be depressed. Recovery occurred following exposure. Heavy metals, cadmium, lead, zinc, and mercury were elevated in the lungs of these animals. Histologic evaluation of pulmonary tissue revealed multifocal pneumoconiosis. Interstitial infiltration by macrophages and smooth muscle hypertrophy of blood vessels and bronchioles were also observed. There was no evidence of a dioxinlike toxic effect following inhalation of these ashes.

Air Pollutants↗
PubMed1988

Uptake and distribution of 14C during and following exposure to [14C]methyl isocyanate.

Guinea pigs were exposed to [14C]methyl isocyanate (14CH3-NCO, 14C MIC) for periods of 1 to 6 hr at concentrations of 0.5 to 15 ppm. Arterial blood samples taken during exposure revealed immediate and rapid uptake of 14C. Clearance of 14C was then gradual over a period of 3 days. Similarly 14C was present in urine and bile immediately following exposure, and clearance paralleled that observed in blood. Guinea pigs fitted with a tracheal cannula and exposed while under anesthesia showed a reduced 14C uptake in blood indicating that most of the 14C MIC uptake in normal guinea pigs occurred from retention of this agent in the upper respiratory tract passages. In exposed guinea pigs 14C was distributed to all examined tissues. In pregnant female mice similarly exposed to 14C MIC, 14C was observed in all tissues examined following exposure including the uterus, placenta, and fetus. While the form of 14C distributed in blood and tissues has not yet been identified, these findings may help to explain the toxicity of MIC or MIC reaction products on organs other than the respiratory tract, as noted by several investigators.

Animals↗
PubMed1988

Irritation of the upper airways from mixtures of cumene and n-propanol. Mechanisms and their consequences for setting industrial exposure limits.

The immediate irritation response induced by mixtures of vapours of cumene (isopropyl benzene) and n-propanol was evaluated in mice according to the standard method (Designation: E 981-84) from The American Society for Testing and Materials. The animal model allows prediction of the irritation response in humans. Analyses of the results from the initial periods of the experiments leads to the hypothesis that competitive agonism exists between the two substances. Extrapolation of the results to TLV concentration levels taking into account the apparent dissociation constants leads further to expectation of additivity of the effects of mixtures of vapours. Following the initial response there is a fading or a desensitization stage. After desensitization, the responses were close to those of cumene alone. This may suggest that the receptor contains different binding sites which desensitize to a different extent.

1-Propanol↗
PubMed1988

Arterial blood gas measurements in guinea pigs and inspired CO2 concentrations for ventilatory performance challenges.

Guinea pigs were fitted with a carotid cannula under anesthesia and used 2 days later for exposure to increasing CO2 concentrations to evaluate their ventilatory response (tidal volume and respiratory frequency) while blood samples were taken for measurement of O2, CO2, and pH. The same measurements were made on another group of animals while changing O2 concentrations. The ventilatory response increased with increasing CO2 concentrations up to 10% while there was little change induced by low oxygen. Decreasing O2 during challenge of animals with 10% CO2 had no effect on the ventilatory response induced by 10% CO2 alone. The ventilatory response of guinea pigs is greater than for other small laboratory animals tested under similar conditions but is not as pronounced as in humans. Challenging guinea pigs with 10% CO2 has revealed that their ventilatory response can be abnormal following pneumotoxicity induced by a variety of agents and blood gas measurements as described here may add to our understanding of such abnormal responses.

Animals↗
PubMed1988

Induction of abnormal ventilatory responses to CO2 and evaluation of agents given to prevent or reverse these responses.

This study demonstrates how a previously described animal model can be utilized to evaluate the effects of multiple aerosols. For the exposures presented in this report, unanesthetized but mildly restrained guinea pigs were used. Airflow (V), tidal volume (VT), and respiratory frequency (f) were continuously measured in all animals and their flow-volume (V-VT) loops were also obtained. The animals were first exposed to room air and then challenged with a 10% CO2 (in 19% O2, 71% N2) mixture. The normal ventilatory response to 10% CO2 consists of increases in V, VT, and f. This response is very stable for long periods of time and is highly reproducible. It is possible, however, to alter the normal CO2 response by adding an aerosol to the CO2 mixture. Two types of acute responses can be induced, Type I and Type II. In this study, histamine and carbamylcholine aerosols were used to induce the Type I response while propranolol aerosols were used to induce the Type II response. Serotonin aerosols were used to induce both types of effects. We report that the bronchodilator, isoproterenol, reversed the Type I pulmonary effects where the level of reversal was dependent upon isoproterenol concentration. The rapid, shallow breathing, characteristic of the Type II response, was not reversed by isoproterenol but could be prevented by blocking the vagus nerve with cocaine. Since no invasive techniques are required and the same animals can be used repeatedly, combinations of aerosols can be tested in order to delineate how Type I or Type II abnormal ventilatory responses to CO2 are induced by a wide variety of airborne chemicals.

Aerosols↗
PubMed1988

Inhibition of methyl isocyanate toxicity in mice by starvation and dexamethasone but not by sodium thiosulfate, atropine, and ethanol.

Effects of starvation (24 and 48 h), dexamethasone, sodium thiosulfate, atropine, and ethanol on the toxicity of methyl isocyanate (MIC) vapor, which escaped during the Bhopal accident of December 3, 1984, were studied in male Swiss-Webster mice. Toxicity to MIC appeared to be biphasic; majority of animals died between 1 and 2 d or between 7 and 21 d after exposure to 40 ppm MIC. Starvation (24 or 48 h) or an injection of 2 mg dexamethasone/kg prior to exposure inhibited the toxicity of MIC, especially during the first 6-7 d; administrations of sodium thiosulfate, alcohol, and atropine before or of dexamethasone after the exposure to MIC were ineffective. Starvation increased serum corticosterone levels. The antidotal effects of both starvation and dexamethasone might be due to suppression of the inflammatory response to MIC.

Animals↗
PubMed1988

Pulmonary effects of repeated exposures to paraquat aerosol in guinea pigs.

Exposure to paraquat, a widely used herbicide, has been shown to produce a concentration dependent rapid, shallow breathing pattern in guinea pigs 18 hr following exposure (H. Burleigh-Flayer and Y. Alarie, 1987, Arch. Toxicol. 59(6), 391-396). To further explore the pulmonary effects following exposure to paraquat, two experiments were carried out. The first experiment consisted of exposing a group of guinea pigs for a period of 4 hr to 0.7 mg/m3 paraquat aerosol and monitoring respiratory variables for 2 weeks following the exposure. In the second experiment, three groups of guinea pigs were repeatedly exposed to three concentrations of paraquat aerosol (0.1, 0.4, and 0.8 mg/m3) for 6 hr a day, 5 days a week for 3 weeks. Respiratory variables were measured each day of these 3-week experiments. The respiratory variables evaluated in both experiments were tidal volume (VT) and respiratory frequency (f). These variables were monitored during air breathing and upon challenge with 10% CO2 in 20% O2 and 70% N2 in order to evaluate the pulmonary effects of exposure to paraquat. Following a single exposure to 0.7 mg/m3 paraquat aerosol, a decrease in VT and increase in f were seen during air and 10% CO2 challenge which reached a maximum several days following exposure. After reaching maximal changes, the respiratory variables returned to control values. With repeated 6-hr exposures to paraquat aerosol, guinea pigs exposed to 0.4 and 0.8 mg/m3 also displayed a rapid, shallow breathing pattern. Adaptation to the exposures for these two concentration groups was evidenced by a return of the respiratory variables toward control levels. This adaptation typically occurred during the first 7 days of exposures. A cumulative effect was therefore not detected with repeated exposures to paraquat aerosols.

Aerosols↗
PubMed1987

Concentration-dependent respiratory response of guinea pigs to paraquat aerosol.

Six groups of male English smooth-haired guinea pigs were exposed to a paraquat aerosol for 4 h. Concentrations of the paraquat ion aerosols ranged from 0.83 to 2.07 mg/m3. Over 85% of the particles in the aerosol were found to be under 0.65 micron. Tidal volume and respiratory frequency of each animal were measured prior to exposure, immediately following exposure, and 18 h following exposure. These parameters were monitored during air breathing and a 10% CO2 challenge using a whole body plethysmograph fitted with a head chamber. A concentration-related decrease in tidal volume and increase in respiratory frequency were found 18 h following exposure when breathing air and the CO2 mixture. Inspection of the flow-volume (V-VT) loops showed abnormal rectangular shapes 18 h following exposure, also varying with the concentration and indicative of lung restriction with a hyperventilation pattern. This study provides quantitative information on the respiratory toxicity following a paraquat inhalation exposure and qualitative description of its effect on the respiratory pattern. The measurements made may be of value in the search of antidotes for this important herbicide.

Aerosols↗