J. Enrique Cometto-Muñiz

Thresholds for odor and nasal pungency.

Detection thresholds were measured repeatedly for 11 chemicals in normosmic and anosmic subjects. The stimuli comprised the first eight members of the series of n-aliphatic alcohols, phenyl ethyl alcohol, pyridine, and menthol. Results showed that anosmics could detect, via pungency, all but phenyl ethyl alcohol reliably. In the aliphatic series, both odor and pungency thresholds declined with chain length in a way that implied dependence of both in part on phase distribution in the mucosa. Odor thresholds, however, declined more rapidly than pungency thresholds: the ratio of anosmics threshold/normosmics threshold increased from 23 for methanol to 10,000 for 1-octanol. The outcome of a scaling experiment employing normosmic subjects indicated that, with the exception of methanol and ethanol, pungency arose when perceived intensity reached a narrowly tuned criterion level. When thresholds were expressed as percentages of saturated vapor, an index of thermodynamic activity, thereby accounting for differences in solubility and in phase distribution in the mucosa among the various stimuli, both odor and pungency thresholds depicted a striking constancy across stimuli.

Assessment of Upper Respiratory Tract and Ocular Irritative Effects of Volatile Chemicals in Humans

ABSTRACT Accurate assessment of upper respiratory tract and ocular irritation is critical for identifying and remedying problems related to overexposure to volatile chemicals, as well as for establishing parameters of irritation useful for regulatory purposes. This article (a) describes the basic anatomy and physiology of the human upper respiratory tract and ocular mucosae, (b) discusses how airborne chemicals induce irritative sensations, and (c) reviews practical means employed for assessing such phenomena, including psychophysical (e.g., threshold and suprathreshold perceptual measures), physiological (e.g., cardiovascular responses), electrophysiological (e.g., event-related potentials), and imaging (e.g., magnetic resonance imaging) techniques. Although traditionally animal models have been used as the first step in assessing such irritation, they are not addressed here since (a) there are numerous reviews available on this topic and (b) many rodents and rabbits are obligate nose breathers whose nasal passages differ considerably from those of humans, potentially limiting generalization of animal-based data to humans. A major goal of this compendium is to inform the reader of procedures for assessing irritation in humans and to provide information of value in the continued interpretation and development of empirical databases upon which future reasoned regulatory health decisions can be made.

Nasal pungency, odor, and eye irritation thresholds for homologous acetates

We measured detection thresholds for nasal pungency (in anosmics), odor (in normosmics) and eye irritation employing a homologous series of acetates: methyl through octyl acetate, decyl and dodecyl acetate. All anosmics reliably detected the series up to heptyl acetate. Only the anosmics without smell since birth (congenital) reliably detected octyl acetate, and only one congenital anosmic detected decyl and dodecyl acetate. Anosmics who lost smell from head trauma proved to be selectively less sensitive. As expected, odor thresholds lay well below pungency thresholds. Eye irritation thresholds for selected acetates came close to nasal pungency thresholds. All three types of thresholds decreased logarithmically with carbon chain length, as previously seen with homologous alcohols and as seen in narcotic and toxic phenomena. Results imply that nasal pungency for these stimuli rests upon a physical, rather than chemical, interaction with susceptible mucosal structures. When expressed as thermodynamic activity, nasal pungency thresholds remain remarkably constant within and across the homologous series of acetates and alcohols.

Agonistic sensory effects of airborne chemicals in mixtures: Odor, nasal pungency, and eye irritation

Threshold responses of odor, nasal pungency (irritation), and eye irritation were measured for single chemicals (1-propanol, 1-hexanol, ethyl acetate, heptyl acetate, 2-pentanone, 2-heptanone, toluene, ethyl benzene, and propyl benzene) and mixtures of them (two three-component mixtures, two sixcomponent mixtures, and one nine-component mixture). Nasal pungency was measured in subjects lacking a functional sense of smell (i.e., anosmics) to avoid interference from olfaction. Various degrees of stimulus agonism (additive effects) were observed for each of the three sensory channels when testing mixtures. As the number of components and the lipophilicity of such components in the mixtures increased, so did the degree of agonism. Synergistic stimulus agonism characterized the eyeirritation response for the most complex (the nine-component) and the most lipophilic (one of the sixcomponent) mixtures. Physicochemical properties play a large role in the determination of sensitivity to airborne chemicals, particularly to their ability to evoke irritation. While this has revealed itself previously with respect to single chemicals, it seems to have relevance to mixtures as well.

Trigeminal and olfactory chemosensory impact of selected terpenes

In Experiment 1, four normosmics and four anosmics (three congenital, one idiopathic) provided odor and nasal pungency thresholds, respectively, for the following terpenes: delta3-carene, p-cymene, linalool, 1.8-cineole, and geraniol, plus the structurally related compound cumene. Additionally, all subjects provided nasal localization (i.e., right/left) and eye irritation thresholis. Trigeminally mediated thresholds (i.e., nasal pungency, nasal localization, and eye irritation) lay about three orders of magnitude above odor thresholds, which ranged between 0.1 and 1.7 ppm. The results implied uniform chemesthetic sensitivity across tasks and sites of impact. In Experiment 2, normosmics and anosmics provided odor and nasal pungency thresholds, respectively, for three pairs of isomeric terpenes: alpha- and gamma-terpinene, alpha- and beta-pinene, and R(+)- and S(-)-limonene. Odor thresholds ranged between 1.4 and 19 ppm, that is, about an order of magnitude higher than those of the previous terpenes, with no substantial differences between odor thresholds of members of a pair. Regarding chemesthetic impact, only alpha-terpinene evoked nasal pungency. The overall outcome suggests comparable trigeminal chemosensitivity between nose and eyes and between normosmics and anosmics, as shown before for homologous n-alcohols. It also lends support to a previously derived solvation model of the chemesthetic potency of airborne substances, and indicates the likely importance of certain molecular-size restrictions for effective trigeminal impact.

Efficacy of volatile organic compounds in evoking nasal pungency and odor

Sensory irritation (pungency) figures prominently among the symptoms associated with polluted indoor environments. In order to separate the pungent from the olfactory response, we measured nasal pungency thresholds in subjects lacking olfaction (anosmics) and odor thresholds in normal controls (normosmics) for a homologous series of ketones and for selected secondary and tertiary alcohols and acetates. As seen previously for homologous alcohols and acetates, both types of nasal thresholds decreased with increasing carbon chain length. Pungency thresholds decreased exponentially with chain length. With respect to all nonreactive chemicals studied so far, threshold nasal pungency is achieved at a fairly constant percentage of vapor saturation, irrespective of molecular size or chemical functional group. Such a relationship does not hold for odor thresholds. The outcome for pungency implies an important role for a physical, rather than chemical, interaction with nasal mucosa.

Connection between chromatographic data and biological data

There are no previous references to the direct use of GLC data in the correlation of biological processes, but we show that GLC retention data can be used in the correlation of several such processes involving gaseous solutes. There are a number of reports of RP-HPLC and MEKC data being used in the correlation of biological processes, but they are mostly restricted as to the number and type of solute studied. We show that if chromatographic data are used to obtain solvation descriptors for solutes, and if these descriptors are then used in the correlation of biological processes, that this indirect connection is a much more powerful and generally applicable method than is the direct connection between chromatographic data and biological data.

PART III. ASSESSING IRRITATION: Sensory Irritation: Relation to Indoor Air Pollution

Author(s): COMETTO-MUNIZ, J. ENRIQUE; CAIN, WILLIAM S | Abstract: All mucosae of the body possess chemical sensitivity provided by the common chemical sense (CCS). Airborne chemicals can stimulate the CCS through the ocular, nasal, and respiratory mucosae, evoking different pungent sensations, e.g., stinging, irritation, burning, piquancy, prickling, freshness, tingling. Pungent sensations elicited in the nose differ from odor sensations in various characteristics. They are achieved at considerably higher concentrations than those necessary to elicit odor, but they increase with the concentration of the stimulus in a steeper fashion than odor. Pungent sensations from mixtures of compounds show a higher degree of addition - relative to the pungency of the individual components - than that of odor sensations. Pungency is more resistant to adaptation than odor, and, unlike it, displays considerable temporal integration with continuous stimulation. Measurement of a reflex, transitory apnea produced upon inhalation of pungent chemicals holds promise as an objective indicator of the functional status of the CCS. Results from the measurement of this reflex have agreed quantitatively with sensory data in a number of studies, showing higher common chemical sensitivity in nonsmokers - compared to smokers -, in females - compared to males -, and in young adults - compared to elderly. Research issues mentioned here include the following: - We can rarely validate the symptoms putatively caused by indoor air pollution objectively. Without such means, we will always have the potential problem of over-reporting and embellishment. Although one person may seem more sensitive than another, the difference may lie in a greater proclivity to complain. - Studies of anosmic persons offer a simple means to understand the functional characteristics of the nasal CCS. Studies of chemical series in such subjects should eventually allow construction of quantitative structure-activity models for human pungency perception. The human data can be compared with relevant animal data when possible. - The rules of additivity of pungency in mixtures need explication. Regarding the possible role of VOCs in the creation of irritation, we need to ask whether subthreshold levels add up or even amplify each other to produce noticeable irritation. Do repetitive or continuous exposures to subthreshold concentrations increase sensitivity to those substances, so that they evoke pungency when they otherwise would not? Do the various mucosae - ocular, nasal, throat - differ in their sensitivity? - Modulation of CCS sensitivity by long-term and short-term inhalation of various agents (e.g., environmental tobacco smoke) would seem a suitable topic for further research.

Sensory Reactions of Nasal Pungency and Odor to Volatile Organic Compounds: The Alkylbenzenes

Research assessed the independent contribution of the trigeminal and olfactory nerves to the detection of airborne chemicals by measuring nasal detection thresholds in subjects clinically diagnosed as lacking a functional sense of smell (anosmics) and in matched normal controls (normosmics). Anosmics can provide only odor-unbiased pungency thresholds. Normosmics provided odor thresholds. Stimuli included homologous alkylbenzenes (from toluene to octylbenzene), chlorobenzene, 1-octene, and 1-octyne. As seen before with homologous alcohols, acetates, and ketones, both types of threshold declined with increasing carbon chain length. Anosmics failed to detect alkylbenzenes above propylbenzene. The strong linear correlation between pungency thresholds and saturated vapor concentration for all tested compounds, as a whole, and the constancy of pungency thresholds expressed as percent of vapor saturation, suggests that nasal pungency from these substances relies heavily on a broadly tuned physicochemical interaction with a susceptible biophase within the cell membrane. Through such a nonspecific mechanism, low, subthreshold levels of a wide variety of volatile organic compounds of low reactivity-as found in many polluted indoor spaces-could add their sensory impact to precipitate noticeable sensory irritation.

Human olfactory detection of homologous n-alcohols measured via concentration-response functions.

We explored in humans concentration-detection functions for the odor of the homologous n-alcohols ethanol, 1-butanol, 1-hexanol, and 1-octanol. These functions serve to establish structure-activity relationships, and reflect the pharmacology of the olfactory sense at the behavioral level. We tested groups of 14 to 17 subjects (half of them females), averaging 31 to 35 years old. An 8-station vapor delivery device (VDD8) presented the stimulus under a three-alternative forced-choice procedure against carbon-filtered air. The VDD8 was built to meet the demands of typical human sniffs in a short-term (<5 s) olfactory detection task, and to accurately control odorant generation, delivery, and stability. Actual stimulus concentration was quantified by gas chromatography before and during testing. The functions obtained were log normally distributed and were accurately modeled by a sigmoid (logistic) function, both at the group and at the individual level. Sensitivity to ethanol was the lowest and to 1-octanol the highest. Functions became steeper with increasing carbon chain length. For all alcohols the concentration detected halfway between chance and perfect detection (threshold) was at the ppb (or nM) level. Females were slightly more sensitive than males. Intersubject variability across participants was between one and two orders of magnitude. The present odor thresholds were lower than many reported in the past but their relative pattern across alcohols paralleled that in our earlier data and in compilation studies. A previously described quantitative structure-activity relationship for odor potency holds promise to model thresholds that, like those obtained here, best reflect the intrinsic sensitivity of human olfaction.