Lea Frimann Hansen

Irritation of the upper airways from mixtures of cumene andn-propanol

The immediate irritation response induced by mixtures of vapours of cumene (isopropyl benzene) andn-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.The immediate irritation response induced by mixtures of vapours of cumene (isopropyl benzene) andn-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.

Effects of intranasal ZnSO4 irrigation on olfactory and trigeminal cues

Intranasal irrigation with ZnSO4 solutions is used for experimental induction of anosmia. It is, however, unknown whether the trigeminal nerve is affected by the treatment. One day after irrigation (concentrations investigated were between 0.05-1%) the ability of food finding, an olfactory cue, was decreased in a concentration-dependent manner. The trigeminal effect was investigated from a reflexively induced decrease in respiratory rate due to n-propanol exposure. No impairment occurred at 1% ZnSO4. Anosmia was also seen 2-3 h after an irrigation with solutions of 0.05-1% ZnSO4. At the same time, 0.2 and 1% solutions in themselves decreased the respiratory rate due to reflexes from the upper and lower respiratory tract. A conspicuous systemic effect can be ruled out as the Zn++ antidote, CaNa2EDTA, had no effect on the decrease. A direct activation of the trigeminal nerve due to a reaction with a thiol group may explain the effect from the upper airways.

Sensory irritation mechanisms investigated from model compounds : trifluoroethanol, hexafluoroisopropanol and methyl hexafluoroisopropyl ether

Abstract Quantitative structure-activity relationships (QSAR) have suggested the importance of hydrogen bonding in relation to activation of the sensory irritant receptor by nonreactive volatile organic chemicals. To investigate this possibility further, three model compounds with different hydrogen bond acidity, trifluoroethanol, hexafluoroisopropanol and methyl hexafluoroisopropyl ether, were selected for study. The potency of each chemical is obtained from the concentration necessary to reduce respiratory rate in mice by 50% (RD50). The RD50 values obtained were: methyl hexafluoroisopropyl ether (?160 000 ppm), trifluoroethanol (11 400–23 300 ppm), and hexafluoroisopropanol (165 ppm). QSAR showed that trifluoroethanol and methyl hexafluoroisopropyl ether behaved as predicted as nonreactive sensory irritants, whereas hexafluoroisopropanol was much more potent than predicted. The higher than predicted potency of hexafluoroisopropanol could be due to a coupled reaction, involving both strong hydrogen bonding and weak Brönsted acidity. A concerted reaction could thus be more efficient in activation of the receptor. Hydrogen bonding properties and concerted reactions may be important in the activation of the sensory irritant receptor by nonreactive volatile organic chemicals.

Sensory irritation and pulmonary irritation of n-methyl ketones: receptor activation mechanisms and relationships with threshold limit values

Activation of the trigeminal nerve endings in eyes and nose, termed sensory irritation, was determined from the reflexively induced decrease in respiratory rate in mice for methyl propyl ketone, methyl butyl ketone, methyl amyl ketone and methyl hexyl ketone. The relationship between exposure concentration and the decrease in respiratory rate followed Michaelis-Menten equations. Two estimates of each agonist-receptor dissociation constant were obtained, one from the Michaelis-Menten equation and one from the threshold (RD-0) of the log concentration-effect curve. The values were equal and thus one receptor type could account for the activation process. The hydrophobic properties of the receptor biophase were found to approach that of the internal part of the bilayer membrane. It therefore follows that the receptor-air partition coefficients increase with the size of the ketones, thus accounting for the observed increase in potency. Estimates of Threshold Limit Values (TLV) were obtained and compared with established values. Close agreements were found for methyl propyl ketone and methyl amyl ketone, but not for methyl butyl ketone, where the neurotoxic effect constituted a more sensitive endpoint that sensory irritation.

Airway-irritating effect of carbonless copy paper examined by the sensory irritation test in mice

Abstract The use of a new batch of carbonless copy forms (Paper I) gave rise to irritation in humans. Similarly, airway irritation was observed in mice when compared with white typing paper. A static test system, which is a modification of the American standard test method (ASTM: E981-84), was applied. The irritation in mice was long lasting and dose-dependent. The differentiation between irritating and nonirritating papers and an established dose-response relationship were considered as criteria for accepting the modified method. The layer of the microcapsules, which contains the colorformers dissolved in an organic mixture may not give rise to irritation, as opposed to what was found for the color developing layer. The irritating substance seems to be one or more volatile components possibly including formaldehyde. Aeration decreased the irritating capacity. The results suggest that the method may be applied for testing of other materials offgassing.

Sensory irritation, pulmonary irritation and structure-activity relationships of alcohols

Sensory irritation due to inhalation of n-pentanol, n-heptanol, sec-butanol and tert-pentanol was determined from the reflexively induced decrease in respiratory rate in CF-1 mice. The concentration-effect relations followed Michaelis-Menten equations, complying with receptor mediated processes. The relations were transformed into nearly rectilinear relationships in log concentration-effect plots, and the extrapolated threshold concentrations (RD-0) from the lines were 120, 28, 640 and 1210 ppm, respectively, obtained from the first 2 min of the exposure period. These values were comparable to those found in Swiss-Webster mice and to those obtained by electrophysiological experiments in Sprague-Dawley rats. The hydrophobic properties of the receptor biophase were found to approach that of the internal part of the bilayer membrane. Estimates on threshold limit values (TLV) were obtained and were found in reasonable agreement with the established values. The nose has a scrubbing effect, which reduces the concentration in the lungs in normal mice. n-Pentanol, sec-butanol and tert-pentanol decreased tidal volume in normal mice, explained either by an activation of receptors in the upper airways or by a sensitization of the stretch receptors. Two types of pulmonary responses were seen in tracheal-cannulated mice, which could be explained by an effect on stretch receptors and another type of lung receptors.

Irritation of the upper airways. Mechanisms and structure-activity relationships

Irritation from the eyes and nose, termed sensory irritation, is the effect mediated by the trigeminal nerves. The effect is quantified by psychophysical methods, by electrophysiological methods or from the reflexively induced effect. The first step in the generation of the irritation response occurs due to interaction between an airborne substance and a protein receptor in the nerve. The classical receptor theory and the tools known from medicinal chemistry can therefore be applied also to the sensory irritation processes. The “linear free energy models” and the “thermodynamic activity” concepts are discussed in depth. Both these methods, if combined with rational test strategies, offer the possibility, in a cost-efficient manner, to give estirnates on effects of nontested substances. The basic biological knowledge on sensory irritation is far behind the knowledge on the exposure concentrations in the indoor environment. This seriously limits the possibility of interpreting the chemical measurements.

Determination of Vapors of Cumene-Propanol Mixtures by Single-Beam Infrared Spectrophotometry

Abstract This investigation shows that the vapor concentration of a mixture of cumene and propanol in an animal exposure chamber can be determined by single-beam infrared spectrophotometry. The method is not influenced by deviations from Beers law and is not dependent on the possibility of selecting wavelengths where only one of the substances absorbs the light. The determination was based on a calibration with the substances in four combinations of concentrations at two different wavelengths. A chamber trial (i.e., operating the exposure system without the presence of animals) was carried out, and the absorbance of the gas-air mixture was measured at the two wavelengths. The exposure experiment with animals was then carried out under exactly the same conditions, and the concentration in air was monitored at one of the wavelengths to ensure that no change occurred in the experimental conditions. The method was evaluated in a real toxicological investigation dealing with interactions between two solvents ...