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.

KEYWORDS:

• cilia
• electrophysiology
• glossopharyngeal nerve
• irritation
• magnetic resonance imaging
• psychophysics
• rhinomanometry
• thresholds
• trigeminal nerve
• vagus nerve

ACKNOWLEDGMENTS

Supported, in part, by a grant from the American Chemistry Council and grants PO1 DC 00161, P50 DC 00214, RO1 DC 02741, RO1 DC 03740, RO1 DC 04278, RO1 DC 02974, and RO1 AG 27496 from the National Institutes of Health, Bethesda, MD. We thank Dr. Soren Kjærgaard for his scientific contributions to the paper, Dr. David A. Morgott for both his scientific advice and his gracious efforts in organizing the references, and Dr. Bala Palacanda for aid in developing one of the figures. We also owe a debt of gratitude to Kate Schroen, whose administrative and organizational acumen were crucial for the success of this endeavor.

Notes

* Studies involving humans require prior approval by an institutional human subject review board and the board must conduct continuing reviews of the research. Federal guidelines are available from the Office for Human Research Protections at ohrp.osophs.dhhs.gov and from specific review boards.

* It should be noted that, in addition to trigeminal nerve afferents, two other neural or pseudoneural systems are present within the human nose—the nervus terminalis (CN O), a plexus of fine unmyelinated fibers of unknown function, and a rudimentary and presumably vestigial vomeronasal organ. Neither of these is believed to serve a sensory function in humans and they are not further mentioned in this review (Bhatnagar et al., 1987; Doty, 2001; Wirsig-Wiechmann, 1997).

* Some normosmics reportedly detect chemesthetic sensations at concentrations below those that elicit such sensations in anosmics (Cometto-Muñiz and Cain, 1990; Kendal-Reed et al., 1998). Whether this is due to physiologically different trigeminal sensitivities or a confusion between CN V- and CN I-mediated sensations is controversial. An investigation of irritation-induced reflex changes in respiration in mice found no influence of anosmia on trigeminal sensitivity to nasal irritation, and a number of human studies have noted equivalent nasal and ocular irritation thresholds in anosmic and normosmic subjects (Cometto-Muñiz et al., 1998b, 1998c; Cometto-Muñiz and Cain, 1998). Nonetheless, one electrophysiological study found a marginally larger peak-to-peak amplitude in the early P1N1 response to CO₂ (a CN V stimulant with little or no odor) in normosmics than in hyposmics and anosmics (Hummel et al., 1996). The selection of anosmics for such studies may be critical. For example, viruses that induce anosmia conceivably produce, at least in some individuals, subtle changes in CN V function. In such anosmics, the decreased CN V function may have no physiological connection with the decreased CN I function, as such, emphasizing the need to choose subjects with congenital or head trauma-based anosmia.