Monell Chemical Senses Center, Philadelphia, Pennsylvania, 191043308
1 To whom correspondence should be addressed at Monell Chemical Senses Center, 3500 Market Street, Philadelphia, PA 191043308. Fax: 2158982084. E-mail: pwise{at}monell.org.
Received February 3, 2005; accepted June 9, 2005
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ABSTRACT |
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INTRODUCTION |
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Government regulators view irritation as a material impairment of health and set many occupational exposure limits based on irritation (Cain, 1996; NIOSH, 1994
). Accordingly, irritation has received increasing attention in the toxicological literature (Doty et al., 2004
). Researchers have made considerable progress (Bryant and Silver, 2000
; Doty and Cometto-Muñiz, 2003
). However, basic data on the relationship between stimulus and sensation remain limited in some areas, particularly in humans.
One area where data are scarce is temporal integration in detection of nasal irritation. Sensory scientists use the term "temporal integration" to indicate that systems can integrate stimulus energy over time to detect weaker signals than they otherwise could (Baumgardt, 1972; Garner and Miller, 1947
). The term "time-concentration trading" is also used to indicate that one can often achieve a given sensory effect either by presenting a relatively weak stimulus for a long time or a strong stimulus for a shorter duration. Because of integration, it is necessary to study the domain of time to fully understand any sensory system.
Investigators have demonstrated integration of nasal irritation in the supra-threshold range i.e., for clearly detectable concentrations (see Frasnelli et al., 2003; Hummel, 2000
; Hummell et al., 2003). Perceived irritation grows with stimulus duration. This can be seen both over the course of seconds (Anton et al., 1992
; Cometto-Muñiz and Cain, 1984
; Wise et al., 2003
) and over the course of minutes (Cain et al., 1986
; Hempel-Jorgensen et al., 1999
). Work at threshold level has been more limited, but one study examined short-term integration in nasal lateralization of carbon dioxide (Wise et al., 2004
).
In nasal lateralization, subjects simultaneously receive chemical vapor in one nostril and clean air in the other. They try to determine which nostril received chemical vapor. Humans cannot lateralize odors (Kobal et al., 1989). However, the somatosensory system, which mediates irritation, registers location. When subjects feel chemicals, they can determine which nostril was stimulated. Investigators commonly use this technique to measure irritation thresholds for odorous chemicals, because thresholds for odor typically fall below thresholds for irritation (Doty and Cometto-Muñiz, 2003
; Wysocki and Wise, 2003
).
Wise and colleagues measured the minimum stimulus duration required for reliable lateralization of fixed concentrations (1065%) of CO2 (Wise et al., 2004
). Fixed-ratio increases in stimulus duration compensated for fixed-ratio decreases in concentration to maintain a constant level of lateralization, at least for durations up to
2.5 s (Wise et al., 2004
). This finding suggests a model in which detection depends in some simple way on total mass delivered to the nose, i.e., the product of concentration (C) and time (T). Haber's rule, which states that C multiplied by T equals a constant for a fixed outcome, is a commonly used model of this type (see Miller et al., 2000
).
However, for lateralization of CO2, a 3.4-fold increase in duration was necessary to compensate for a 2-fold decrease in concentration. This finding suggests an imperfect mass-integrator, consistent with a more general form of Haber's rule: CnT = k (see Bliss, 1940; Miller et al., 2000
). Solving for T gives T = kCn. The equation is a power function, so plotting stimulus duration versus concentration in log-log coordinates makes it possible to fit data with the following linear equation:
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Carbon dioxide stimulates nerve endings through tissue acidification (Hummel, 2000; Shusterman and Avila, 2003
). Because liberation of H+ depends on carbonic anhydrase (reviewed in Tarun et al., 2003
), CO2 may be unusual. Experiment 1 in the current report begins to test the hypothesis that a simple but imperfect mass integrator describes temporal integration for lateralization of other irritants. The alkaline compound ammonia (NH3), a common irritant in industrial and agricultural settings (Korhonen et al., 2004
; Omland, 2002
; Proctor et al., 1988
), serves as a model stimulus.
An older study examined temporal integration for ratings of supra-threshold nasal irritation from NH3 (Cometto-Muñiz and Cain, 1984). Subjects sniffed NH3 (47 to 434 ppm) for brief durations (1.253.75 s). As in the threshold-level study using CO2, Cometto-Muñiz and Cain (1984)
found simple but imperfect integration. This finding suggests that similar rules may govern short-term integration at both threshold levels and supra-threshold levels. In contrast to the threshold-level study of CO2, supra-threshold integration of irritation from NH3 was nearly perfect, i.e., a 2.1-fold increase in duration would compensate for a 2-fold decrease in concentration. Integration may be more nearly perfect for NH3 than for CO2. Integration may also be more nearly perfect for supra-threshold irritation. However, the fact that the two studies differed substantially in methodology makes comparisons problematic. Experiment 2 used the same apparatus as Experiment 1 to vary both concentration and duration of supra-threshold NH3 delivered to the nose. Subjects rated nasal irritation, and integration was assessed both by examining how ratings for given concentration increased with stimulus duration, and how concentration and time could be traded to maintain a fixed level of intensity.
In both experiments, a simple but imperfect mass-integrator model described integration for exposures up to 34 s reasonably well. Integration over such brief periods, i.e., integration that might occur within a single natural breath, may have limited immediate significance in predicting whether a given stimulus will cause irritation under natural conditions. Increased understanding of short-term integration may have more immediate relevance for interpretation of data from brief exposures in the laboratory (see General Discussion). Regardless, a model that provides such a concise description of the relationship between stimulus and sensation, based on measurements of just a few points on the integration function, is a potentially powerful tool for basic research.
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EXPERIMENT 1 |
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Materials and Methods
Subjects.
Approval came from the institutional review board (IRB) of the University of Pennsylvania. Subjects provided written, informed consent on IRB approved forms prior to any manipulations. Four men (ages 2652 years) and two women (ages 27 and 28 years) participated. Two of the men were authors P.W. and T.C. (subjects 1 and 6, respectively, in Figure 2). Other subjects were paid volunteers. Like all subjects, the authors were blind to any conditions that might cue responses trial-by-trial. Data from the authors resembled data from other subjects.
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Two parallel pressure sources generated flow (Fig. 1, top). The first was an air pump. Flow from the pump was dried, carbon-filtered, and then re-humidified by bubbling it through distilled water in a warm, temperature-controlled enclosure. The pump generated a steady background flow, which entered each nostril at 35°C, 85% RH, and 5 l/min. The pump also generated an air flow (4.7 l/min) used to dilute ammonia vapor from the second pressure source.
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Nitrogen that passed through an NH3 solution joined with 4.7 l/min of air from the pump to comprise a target, i.e., the stimulus to be lateralized. Nitrogen that passed through water joined with air to comprise a blank. Three-way solenoid values determined whether odorized or blank nitrogen joined with air from the pump, i.e., whether the nostril in question received a target or blank. For both the target and blank, total flow entered each nostril at 35°C, 81% RH, and 5 l/min. Stimulus flow had slightly lower humidity than background flow because the added nitrogen was drier. All flows in the system were continuous. When a given stream did not pass into the nose, it was vented from the room.
Both the stimulus flow and the background flow passed to a switching mechanism located close to the nose (Fig. 1, bottom). The mechanism consisted of four 3-way solenoid-valves (two per nostril) with 15 ms response time. For each nostril, stimulus flow (ammonia vapor or blank) entered one valve and vented from the room. Background flow entered the other valve and flowed into the nostril. Energizing both valves simultaneously redirected the stimulus flow into the nostril and the background flow to the vent. Analog signals from a computer (PCI-6023E DAQ card; National Instruments; Austin, TX) provided switching signals with millisecond accuracy. Needle valves (not shown) equalized back pressure between nostril tubes and vent lines to minimize pressure transients. The path from the valves to the end of the tube in the nostril had a volume of 0.18 ml (
2.2 ms transit-time at 5 l/min).
Stimuli were injected through flexible Tygon tubes (4 mm outer diameter) extending approximately 0.75 cm into the nostril. Flow exited the nostril around the tubing. Subjects practiced velopharyngeal closure during stimulation. This breathing technique isolates the nasal cavity from the rest of the upper and lower airways using the soft palate (Kobal and Hummel, 1991). Closure helps minimize exposure by preventing inhalation of vapor, and it also prevents fluctuations in pressure in the nasal cavity from respiration.
Experimenters checked flow rate (Gillibrator 2 flow meter; Gillian Instrument Corp.; Wayne, NJ), humidity (Digitron 2020R hygrometer; Topac Instruments; Hingham, MA), and temperature (BAT-12 thermocouple reader; Physiotemp Instruments; Clifton, NJ) at the output of the olfactometer after the device warmed up, and they rechecked flow rate periodically throughout the day. A fast-response pressure transducer (CyQ line, custom made; Cybersense; Nicholasville, KY) verified that minimal changes in flow occurred with switching between background and stimulus. A photo-ionization detector (MiniRAE 2000; RAE Systems; Sunnyvale, CA) measured vapor-phase concentration at the output of the olfactometer. Experimenters used the resulting calibration curve, viz., ppm at output versus liquid-phase concentration in odor vessels, to calculate vapor-phase concentrations. The following concentrations (in ppm) were used: 37, 48, 52, 67, 98, 131, 205, 289, and 721.
Procedure.
Subjects began a trial by placing the tubes in their nostrils, establishing velopharyngeal closure, and clicking a computer mouse. The mouse click began a 10-s countdown. The last three seconds of the countdown were accompanied by beeps, after which the computer triggered a stimulus-presentation of variable duration. The nostril that received NH3 varied randomly between trials. Subjects remained in position for several seconds after stimulus offset; they then recorded which nostril received NH3. Before final data collection began, subjects received an explanation of the lateralization task and had extensive practice. At least 45 s elapsed between successive trials. More than 55 s separated actual stimulus presentations, including the time the subjects needed to reposition, start the trial with a mouse click, and the 10-s countdown to stimulus presentation.
Within runs, subjects received a fixed concentration. Pulse duration was varied to find the briefest pulse that subjects could reliably lateralize. Duration varied according to a 2-up, 1-down staircase procedure (Wetherill and Levitt, 1965), but the protocol required four consecutive correct responses before the first reversal was counted (Wise et al., 2004
). After this point, six reversals were collected. Consecutive steps changed by a factor of 1.12. For example, a 100-ms pulse would increase by 12 ms (or decrease by 11 ms), whereas a 2000 ms pulse would increase by 240 ms (or decrease by 214 ms). Experimental sessions started with stimuli about 20% longer than the best estimate of duration threshold. Initial estimates were based on six practice runs at various concentrations that subjects had completed previously. Long starting stimuli gave subjects a relatively clear sample of the target sensation and helped avoid spurious thresholds. Most runs required about 30 trials. Subjects rarely completed more than one run in a day, but at least 15 min separated successive runs when they did. Subjects completed at least three runs for each concentration they received, in random order.
Concentrations ranged from the lowest each subject could reliably lateralize with pulses no longer than 10 s, to the highest concentration each subject could lateralize with presentations no briefer than
0.1 s. Concentrations for individuals were selected based on practice runs at 37, 52, 67, 97, 131, and 289 ppm. Subjects who lateralized at 37 ppm were also tested at lower concentrations. Below 37 ppm all subjects failed to lateralize. Based on practice runs, the highest concentration S1 received was reduced to 205 ppm. The highest concentration S4 received was increased to 721 ppm, and the lowest was increased to 67 ppm. Most subjects received six concentrations. S3 received only four concentrations because a change in work schedule limited S3's availability. S2 received an extra concentration (48 ppm) because S2's duration threshold for 52 ppm deviated a great deal from a simple integrator model. An extra concentration was included to help detect any systematic deviation that might occur for S2 in this concentration range (in the final runs, no obvious deviation occurred).
Data analysis.
To further reduce the risk of spurious thresholds, only thresholds at or below the duration where subjects first achieved four consecutive correct responses counted; runs that failed to meet this criterion were repeated. Thresholds for each concentration were estimated by averaging the last five reversals for each run and averaging the results across runs. Threshold pulse duration was plotted versus concentration in log-log coordinates for each subject. Mass-integrator models (linear functions) were fit to the resulting curves by least-squares regression (see introduction).
Results
Figure 2 shows plots of threshol pulse duration versus concentration. Subjects could lateralize increasingly weaker concentrations if stimulus duration increased. Reliable lateralization failed at concentrations below 37 to 67 ppm, depending on the individual, even for long pulses (greater than 10 s). Threshold pulse duration for the lowest detectable concentration ranged from 1324 to 3840 ms, depending on the subject (average = 2691 ms). In log-log coordinates, linear functions accounted for 8696% (mean = 91%) of the variance in thresholds. Geometric mean slope (calculated across subjects using absolute values) equaled 1.30 (95% confidence interval from 1.03 to 1.64). Averaged across subjects, it required an increase in duration of about
2.5-fold to compensate for a 2-fold decrease in concentration.
Discussion
We note three main features of the data. First, the finding that subjects could lateralize increasingly weaker pulses as duration increased demonstrates that the nasal trigeminal system can integrate NH3 over time at threshold level. Second, the finding that linear functions described time-concentration trading reasonably well suggests that lateralization is related in some simple way to total mass delivered to the nose; i.e., that some form of simple integrator model can describe the data, at least over the range of concentrations studied (but see below). Finally, the finding that slopes of linear functions were, on average, less than 1 suggests that an imperfect mass-integrator model is appropriate. All three findings are in qualitative agreement with both lateralization of carbon dioxide (Wise et al., 2004) and supra-threshold ratings of irritation from NH3 (Cometto-Muñiz and Cain, 1984
).
With the current method and stimulus, lateralization failed below about 37 ppm, even for pulses as long as 10 s. Based on the threshold pulse durations for the weakest stimuli that subjects could lateralize, the limit of temporal integration may be about 2.7 s. This agrees well with threshold pulse durations for the weakest concentration of CO2 that subjects could lateralize, 2.5 s (Wise et al., 2004
). In both cases, one cannot rule out the possibility that less complete integration occurs after about 3 s, such that subjects could lateralize weaker concentrations with much longer pulses. Regardless, it is interesting that the apparent limit of short-term integration seems to coincide with the duration of a single, natural inspiration. Whether this observation has basic significance is unclear.
Considering the data in Figure 2, one might also wonder whether integration begins to break down even sooner than 2.7 s. Linear functions (simple integration model) fit reasonably well. However, long-duration thresholds might deviate from the trend. If thresholds longer than 2000 ms are excluded (dropping the leftmost point for subjects 2, 3, 5, and 6), linear fits accounted for an average of 95% of variance in ratings, as opposed to 91% with all data included. Further, average slope fell to 1.01 (95% CI .88 to 1.13), suggesting perfect (99%) integration for short-duration (or high-concentration) stimuli. Admittedly, there is no clear justification for excluding the data points in question. However, the possibility that perfect integration occurs over some range for lateralization of NH3 remains open. Denser sampling of low concentrations could help settle the matter.
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EXPERIMENT 2 |
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Materials and Methods
Subjects.
Approval came from the IRB of the University of Pennsylvania. Subjects provided written, informed consent prior to any manipulations. Participants included 7 men and 13 women, 21 to 54 years of age. One subject (female) failed to complete the study because of time constraints. Her data were excluded. Author P.W. served as one subject. He was blind to the order of conditions. Analyses with and without P.W.'s data supported the same conclusions. Others were paid volunteers.
Olfactometer.
The olfactometer and most details of stimulus presentation matched those used in Experiment 1. The olfactometer was modified to present more than one concentration within a session. This was done by adding more odorant solutions with solenoid valves to select which concentration joined the humid air stream. Flow through all channels was constant, and solutions were replaced after every run to reduce depletion.
Presentation was bi-rhinal, i.e., identical concentrations of NH3 were delivered to both nostrils. The results of Experiment 1 were also based on both nostrils, but only one nostril received NH3 in a given trial. Ideally, Experiment 2 would also include single-nostril presentations, with a balanced number of trials for left and right nostrils. However, this method would have required a larger number of trials per condition. Because some supra-threshold stimuli are painful, it seemed desirable to minimize the number of presentations. Further, because perceived irritation from bi-rhinal stimulation is a simple ratio transform of irritation from mono-rhinal stimulation (Garcia-Medina and Cain, 1982), the effects of simultaneous presentation would not influence the analyses of integration used below.
Procedure.
Subjects rated the strength of sensations via magnitude estimation. Subjects received standard instructions that highlighted the need to make ratio judgments, i.e., to assign a number twice as high to a sensation twice as strong (Stevens, 1975). Subjects demonstrated understanding by rating the length of lines. An experimenter verified that ratings were proportional to line length. Subjects were told to rate nasal irritation, i.e., burning, stinging, or tingling, and ignore odor. Most subjects were experienced volunteers who understood the difference between odor and irritation. Nevertheless, experimenters discussed the difference with subjects, using examples.
Subjects received the following stimuli: 165 ppm NH3 presented for 1000, 1587, 2520, and 4000 ms; 304 ppm for 400, 660, 1090, and 1800 ms; and 478 ppm for 250, 376, 565, and 850 ms. According to pilot work, these durations gave rise to comparable ranges of perceived irritation across concentrations. Subjects received each stimulus three times for a total of 36 trials. Subjects completed the 36 trials in two 18-trial sessions. Trials occurred in random order.
One duration of each concentration served as a modulus: 2276 ms of 165 ppm for six subjects, 988 ms of 304 ppm for six subjects, and 510 ms of 478 ppm for seven subjects. According to pilot work, these stimuli roughly matched in intensity and fell close to the middle of the intensity range for all stimuli in the study. Subjects were randomly assigned to a modulus, with the constraint of approximately equal numbers in each group. At the beginning of each session, subjects received the modulus with the instruction to assign a rating of 100 to the irritation it caused. The modulus helped ensure that subjects used comparable ratings for a given intensity in the two sessions. At least 1 min elapsed between the modulus and the first trial of the session. Thereafter, 45 s separated successive trials (more than 55 s between stimulus presentations). Most subjects completed the two sessions on successive days. For four subjects, 23 days elapsed between sessions.
Data analysis.
The arithmetic mean summarized replicate ratings within subjects. The geometric mean summarized data across subjects (Stevens, 1975). Next, experimenters fit linear functions, via least squares regression, to plots of log rated intensity versus log stimulus duration. Good linear fits would indicate simple integration, i.e., increasing stimulus duration by a fixed factor would increase intensity by a fixed factor. Unit slope would indicate perfect integration, whereas a shallower slope, i.e., less than 1, would indicate imperfect integration (N.B. this is opposite to the analysis in Experiment 1). This analysis assumes that ratings are perfectly proportional to perceived intensity.
A second analysis assumed only that equal magnitude estimates across two conditions indicated equal perceived intensity (Cometto-Muñiz and Cain, 1984). Experimenters calculated the stimulus durations for each concentration needed to achieve fixed levels of perceived intensity. The second analysis is more comparable to that of Experiment 1, where duration and concentration traded to maintain a fixed level of detection. If one plots log stimulus duration versus log concentration, a slope of 1 indicates perfect integration and a slope less than 1 indicates imperfect integration.
Results
We note three main features of the data in Figure 3. First, rated intensity increased with duration for each concentration. Second, linear functions (in log-log coordinates) described the relationship between duration and rated intensity quite well, accounting for 97.599.9% of the variance in ratings. To a first approximation, a fixed-ratio increase in stimulus duration at a given concentration produced a fixed-ratio increase in rated irritation. Finally, slopes (with 95% confidence intervals based on regression) were 0.57 (0.290.85) for 165 ppm, 0.77 (0.680.85) for 304 ppm, and 0.82 (0.621.02) for 478 ppm. Geometric mean slope, across concentrations, was 0.71 (0.560.91). Averaged across concentrations, doubling duration at fixed concentration increased intensity by a factor of 1.65.
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Inspection of Figure 3 reveals another point of agreement between the results of Experiment 2 and those of Cometto-Muñiz and Cain (1984). In both experiments, slopes of intensity versus stimulus-duration functions went up as concentration increased. All in all, qualitative agreement among the studies is striking.
The results of Experiment 2 disagree with those of Cometto-Muñiz and Cain (1984) in degree of integration. Experiment 2 suggests that a 3.1-fold increase in duration is required to compensate for a 2-fold decrease in concentration to maintain a fixed level of perceived intensity, whereas the older study suggested that a 2.1-fold increase in duration would suffice. Accordingly, the two supra-threshold studies of irritation from NH3 disagree with each other about as strongly as the findings of Cometto-Muñiz and Cain (1984)
disagree with the Wise et al. (2004)
results on lateralization of CO2 (which suggested that a 3.4-fold increase in concentration is required to compensate for a 2-fold decrease in concentration). This finding strongly suggests that differences between the two older studies are not exclusively stimulus driven. If the differences between the older studies were instead driven largely by differences between threshold and supra-threshold integration, then one would expect better integration in Experiment 2 than in Experiment 1. In other words, given the same stimulus and similar methods, we would expect supra-threshold integration to be more perfect than threshold-level integration. Results of Experiment 1, which suggested that a 2.5-fold increase in duration is needed to compensate for a 2-fold decrease in concentration, actually came closer to perfect integration than did those of Experiment 2. In short, the results suggest that neither differences between NH3 and CO2 nor differences between threshold-level and supra-threshold level integration can completely account for differences in degree of integration seen in previous studies.
Some disagreement probably comes from methodological differences. In the present experiments, subjects received passive injection of stimuli, whereas in the older study subjects sniffed. Differences in patterns of flow through the nose almost certainly occurred. Furthermore, the current studies used a humidified stimulus, whereas the older study did not. In addition, the current study used a warmed stimulus, whereas the older study did not. Because chemical stimuli activate some nociceptors at lower concentrations as temperature increases (Caterina and Julius, 2001; Tominaga et al., 1998
), temperature could indeed prove to be important. Future studies should systematically investigate these and other methodological differences. For now, the basic qualitative agreement among experiments seems more striking than the quantitative differences.
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GENERAL DISCUSSION |
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Limitations
The simple integration model is of the black-box type, and it includes all events from entry of the stimulus into the nostril to execution of the response. Dynamics of the generated stimulus will strongly influence dynamics of concentration in the peri-receptor environment, i.e., in epithelial or sub-epithelial layers of the mucosa (Finger et al., 1990). However, patterns of flow and diffusion through the nasal cavity and subsequent diffusion into the tissue will also influence dynamics of peri-receptor concentration. Online tracking of peri-receptor concentration, perhaps through a pH meter (Shusterman and Avila, 2003
) or pH-sensitive dye, may help elucidate this component of the black box (see Wise et al., 2004
, for more discussion). Psychophysiology, e.g., combinations of psychophysics and measurement of mucosal or cortical evoked potentials (Hummel, 2000
; Hummel et al., 2003
), may help elucidate other components of the black box.
Another limitation is instrumental, because the olfactometer could not reliably produce pulses briefer than about 100 ms. Perhaps integration would behave differently for very brief stimuli. The visual system, for example, displays perfect integration up to about 100 ms (200 ms for rod vision), and imperfect integration up to as long as 3 s (Baumgardt, 1972).
Finally, the stimulation technique, i.e., passive injection of vapor into the nose during velopharyngeal closure, is un-physiological. To elucidate basic response properties of the sensory system, the rigorous experimental control of the method has advantages. However, experimental conditions differed from natural breathing. For example, experimental flow rates fell below those of normal breathing. Further, stimulus flow was probably confined mostly to the nose itself, rather than being distributed throughout the nasal cavity. Even within the nose, patterns of flow almost certainly differed from those associated with natural breathing. Given the considerable body of literature which suggests that rates and patterns of flow strongly influence deposition and absorption of volatile compounds in the nasal cavity (e.g., Frederick et al., 1994, 1998
; Kurtz et al., 2004
; Morris, 2001
), one should exercise caution in generalizing the results of the current studies to more natural conditions. Additional studies using natural breathing techniques would be useful in this regard.
Basic Significance
Simple but imperfect integration is potentially consistent with a variety of mechanisms (Cain, 1990; Wise et al., 2004
). For example, integration may come from a build-up of stimulus molecules in the mucosa over time, but the build-up could be undermined by continual clearance or breakdown of molecules. Adaptation could also undermine perfect integration. Further, both unmyelinated C-fibers and thinly myelinated A
-fibers in the nose can respond to chemical irritants (see Bryant and Silver, 2000
). The two types of fibers have different temporal response properties and may give rise to different sensations, i.e., burning versus stinging (see Hummel, 2000
). Some effects of varying stimulus duration could come from sequential stimulation of the two populations of fibers.
As suggested above under Limitations, it will require more than psychophysics to relate patterns of perception to specific mechanisms. However, to understand the relationship between physiology and sensation, it is necessary to measure sensation. The psychophysical models described above, or extensions thereof, can guide biophysicists, molecular biologists, and physiologists in the quest to elucidate the mechanisms of perceived irritation.
Practical Significance
Short-term integration, i.e., integration that might occur within the duration of a single, natural inspiration, may have limited applicability to integration in natural settings. However, increased understanding of short-term integration can have immediate implications for how data are collected and interpreted in the laboratory. In the laboratory, investigations of sensitivity to irritants, both for patients and for normal controls, are often based on presentations that last between.25 and 3 s (Hummel, 2000; Hummel et al., 2003
; Shusterman, 2002
). Often, subjects simply sniff from bottles, and duration is uncontrolled. As a result of integration, individual differences in sniff duration can become confounded with differences in sensitivity. One can control stimulus duration through olfactometery. Still, because of individual differences in slopes of integration functions (see Wise et al., 2004
, and Figure 1 above), stimuli of different lengths may provide very different pictures of individual differences. Furthermore, much of the growing body of literature on the how irritant potency is related to molecular parameters is based on brief exposures in the laboratory (e.g., Abraham et al., 1998
, 2003
). If compounds differ in the slopes of their integration functions, sampling at a fixed duration will provide at best an incomplete picture of differences among compounds. Simple models that allow researchers to characterize entire time-concentration trading functions by measuring a few carefully selected points can be powerful tools that give researchers a better understanding of their data.
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NOTES |
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ACKNOWLEDGMENTS |
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REFERENCES |
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Abraham, M. H., Kumarsingh, R., Cometto-Muñiz, J. E., and Cain, W. S. (1998). An algorithm for nasal pungency thresholds in man. Arch. Toxicol. 72, 227232.[CrossRef][ISI][Medline]
Anton, F., Euchner, I., and Handwerker, H. O., (1992). Psychophysical examination of pain induced by defined CO2 pulses applied to the nasal mucosa. Pain 49, 5360.[CrossRef][ISI][Medline]
Baumgardt, E. (1972). Threshold quantal problems. In Visual Psychophysics (D. Jameson and J. Hurvich, Eds.), pp 2955. Springer-Verlag, New York.
Bliss, C. I. (1940). The relation between exposure time, concentration and toxicity in experiments on insecticides. Ann. Entomol. Soc. Am. 33, 721766.
Bryant, B. P., and Silver, W. L. (2000). Chemesthesis: The common chemical sense. In The Neurobiology of Taste and Smell (T. E. Finger, W. L. Silver, and D. Restrepo, Eds.), 2nd ed., pp. 73100. Wiley-Liss, New York.
Cain, W. S. (1996). Overview: Odors and irritation in indoor pollution. In Indoor Air and Human Health (R. B. Gammage and B. A. Berven, Eds.), 2nd ed., pp. 2330. Lewis, Boca Raton, FL.
Cain, W. S. (1990). Perceptual characteristics of nasal irritation. In Chemical Senses (Vol. 2): Irritation (B.G. Green, J. R. Mason, and M. R. Kare, Eds.), pp. 4358. Marcel Dekker, New York.
Cain, W. S., See, L. C., and Tosun, T. (1986). Irritation and odor from formaldehyde: Chamber studies. In IAQ '86: Managing the Indoor Air for Health and Energy Conservation, pp. 126137. American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE), Atlanta.
Caterina, M. J., and Julius, D. (2001). The vanilloid receptor: A molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487517.[CrossRef][ISI][Medline]
Cometto-Muñiz, J. E., and Cain, W. S. (1984). Temporal integration of pungency. Chem. Senses 8, 315327.[ISI]
Doty, R. L., and Cometto-Muñiz, J. E. (2003). Trigeminal chemosensation. In Handbook of Olfaction and Gustation (R. L. Doty, Ed.), 2nd Ed., pp. 981999. Marcel Dekker, New York.
Doty, R. L., Cometto-Muniz, J. E., Jalowayski, A. A., Dalton, P., Kendal-Reed, M., and Hodgson, M. (2004). Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans. Crit. Rev. Toxicol. 34, 85142.[CrossRef][ISI][Medline]
Finger, T. E., Getchell, M. L., Getchell, T. V., and Kinnamon, J. C. (1990). Affector and effector functions of peptidergic innervation of the nasal cavity. In Chemical Senses (Vol. 2): Irritation (B. G. Green, J. R. Mason, and M. R. Kare, Eds.), pp. 120. Marcel Dekker, New York.
Frasnelli, J., Lötsch, J., and Hummel, T. (2003). Event-related potentials to intranasal trigeminal stimuli change in relation to stimulus concentration and stimulus duration. J. Clin. Neurophysiol. 20, 8086.[ISI][Medline]
Frederick, C. B., Bush, M. L., Lomax, L. G., Black, K. A., Finch, L., Kimbell, J. S., Morgan, K. T., Subramaniam, R. P., Morris, J. B., and Ultman, J. S. (1998). Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways. Toxicol. Appl. Pharmacol. 152, 211231.[CrossRef][ISI][Medline]
Frederick, C. B., Morris, J. B., Kimbell, J. S., Morgan, K. T., and Scherer, P. T. (1994). Comparison of four biologically based dosimetry models for the deposition of rapidly metabolized vapors in the rodent nasal cavity. Inhal. Toxicol. 6(Suppl.), 135157.[ISI]
Garcia-Medina, M. R., and Cain, W. S. (1982). Bilateral integration in the common chemical sense. Physiol. Behav. 29, 349353.[CrossRef][ISI][Medline]
Garner, W. R., and Miller, G. A. (1947). The masked threshold of pure tones as a function of duration. J. Exp. Psychol. 37, 293305.[ISI]
Hempel-Jorgensen, A., Kjaergaard, S. K., Molhave, L., and Hudnell, H. K. (1999). Time course of sensory eye irritation in humans exposed to N-butanol and 1-octene. Arch. Environ. Health 54, 8694.[ISI][Medline]
Hummel, T. (2000). Assessment of intranasal trigeminal function. Int. J. Psychophysiol. 36, 147155.[CrossRef][ISI][Medline]
Hummel, T., Mohammadian, P., Marchl, R., Kobal, G., and Lötsch, J. (2003). Irritation of the nasal mucosa using short- and long-lasting painful stimuli. Int. J. Psychophysiol. 47, 147158.[CrossRef][ISI][Medline]
Kobal, G., and Hummel, T. (1991). Olfactory evoked potentials in humans. In Smell and Taste in Health and Disease (T. V. Getchell, R. L. Doty, L. M. Bartoshuck, and J. B. Snow, Eds.), pp. 255275. Raven Press, New York.
Kobal, G., Van Toller, S., and Hummel, T. (1989). Is there directional smelling?. Experientia 45, 130132.[CrossRef][ISI][Medline]
Korhonen, K., Liukkonen, T., Ahrens, W., Astrakianakis, G., Boffetta, P., Burdorf, A., Heederik, D., Kauppinen, T., Kogevinas, M., Osvoll, P., et al. (2004). Occupational exposure to chemical agents in the paper industry. Int. Arch. Occup. Environ. Health 77, 451460.[CrossRef][ISI][Medline]
Kurtz, D. B., Zhao, K., Hornung, D. E., and Scherer, P. (2004). Experimental and numerical determination of odorant solubility in nasal and olfactory mucosa. Chem. Senses 29, 763773.
Miller, F. J., Schlosser, P. M., and Janszen, D. B. (2000). Haber's rule: A special case in a family of curves relating concentration and duration of exposure to a fixed level of response for a given endpoint. Toxicology 149, 2134.[CrossRef][ISI][Medline]
Morris, J. B. (2001). Overview of upper respiratory tract vapor uptake studies. Inhal. Toxicol. 13, 335345.[ISI][Medline]
NIOSH (National Institute for Occupational Safety and Health). (1994). NIOSH Pocket Guide to Chemical Hazards (Publication No. 94116). National Institute for Occupational Safety and Health, Cincinnati.
Omland, O. (2002). Exposure and respiratory health in farming in temperate zonesA review of the literature. Ann. Agr. Environ. Med. 9, 119136.[ISI]
Proctor, N. H., Hughes, J. P., and Fischman, M. L. (1988). Chemical Hazards of the Workplace. J. B. Lippincott, Philadelphia.
Shusterman, D. (2002). Individual factors in nasal chemesthesis. Chem. Senses 27, 551564.
Shusterman, D., and Avila, P. C. (2003). Real-time monitoring of nasal mucosal pH during carbon dioxide stimulation: Implications for stimulus dynamics. Chem. Senses 28, 595601.
Stevens, S. S. (1975). Psychophysics: Introduction to Its Perceptual, Neural, and Social Prospects. Wiley, New York.
Tarun, A., Bryant, B., Zhai, W., Soloman, C., and Shusterman, D. (2003). Gene expression for carbonic anhydrase isoenzymes in human nasal mucosa. Chem. Senses 28, 621629.
Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum, A. I., and Julius, D. (1998). The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21, 531543.[CrossRef][ISI][Medline]
Wetherill, G., and Levitt, H. (1965). Sequential estimation of points on a psychometric function. Br. J. Math. Stat. Psychol. 18, 110.[ISI][Medline]
Wise, P. M., Radil., T., and Wysocki, C. J. (2004). Temporal integration in nasal lateralization and nasal detection of carbon dioxide. Chem. Senses 29, 137142.
Wise, P. M., Wysocki, C. J., and Radil T. (2003). Timeintensity ratings of nasal irritation from carbon dioxide. Chem. Senses 28, 751760.
Wysocki, C. J., and Wise, P. (2003). Methods, approaches, and caveats for functionally evaluating olfaction and chemesthesis. In Handbook of Flavor Characterization: Sensory, Chemical and Physiological (K. Deibler and J. F. Delwiche, Eds.), pp 140. Marcel Dekker, New York.