Irritation Thresholds Research Articles

Determination of threshold concentrations of plant pollens in intradermal testing using fluorescein in clinically healthy nonallergic cats.

Currently the same allergen concentrations for canine intradermal testing (IDT) are recommended for feline IDT. Feline skin reactions are subtle and more difficult to read than canine reactions. This difference may be due to suboptimal allergen concentrations used for IDT in cats. To determine the irritant threshold concentration (ITC) of 16 pollen allergens using serial dilutions of allergen and intravenous fluorescein. The hypothesis tested was that feline IDT currently is performed at suboptimal allergen concentrations for pollens. Twenty privately owned healthy clinically nonallergic cats. IDT was performed in duplicate using 16 pollen allergens (weeds, grasses and trees) at a dilution of 8000 PNU/mL. Two blinded investigators graded the test reactions independently using subjective and objective criteria. Intravenous fluorescein was then administered and the test reactions were re-evaluated. IDT was repeated for any allergen that was positive, using serial dilutions of allergen at a concentration of 6000 and 4000 PNU/mL. The ITC for 2 of 16 of the allergens was determined. The ITC of Cynodon dactylon (Bermuda grass) and Schinus spp. (Peppercorn) was determined to be between 6000 and 8000 PNU/mL. The ITC of all other allergens tested in this study was >8000 PNU/mL. This study confirms that suboptimal allergen concentrations currently are used for feline IDT as the ITC is >8000 PNU/mL for 14 of 16 of the grass, weed and tree pollens evaluated. The ITC of Cynodon dactylon and Schinus spp. was determined to be between 6000 and 8000 PNU/mL.

Symptoms from masked acrolein exposure suggest altered trigeminal reactivity in chemical intolerance

BackgroundChemical intolerance (CI) is a widespread occupational and public health problem characterized by symptoms that reportedly result from low-levels of chemical exposure. The mechanisms behind CI are unknown, however modifications of the chemical senses (rather than toxic processes) have been suggested as key components. The aim of this study was to investigate whether individuals with self-reported CI report more sensory irritation during masked acrolein exposure compared to controls without CI. MethodsIndividuals with CI (n=18) and controls without CI (n=19) were exposed in an exposure chamber. Each participant took part in two exposure conditions – one with heptane (the masking compound), and one with heptane and acrolein at a dose below previously reported sensory irritation thresholds. The exposures lasted for 60min. Symptoms and confidence ratings were measured continuously throughout the exposure as were measurements of electrodermal activity and self-reported tear-film break-up time. Participants were blind to exposure condition. ResultsIndividuals with CI, compared with controls reported greater sensory irritation in the eyes, nose and throat when exposed to acrolein masked with heptane. There was no difference during exposure to heptane. ConclusionsMasked exposure to acrolein at a concentration below the previously reported detection threshold is perceived as more irritating by individuals with CI compared with controls. The results indicate that there is altered trigeminal reactivity in those with CI compared to controls.

Correlation of volatile carbonyl yields emitted by e-cigarettes with the temperature of the heating coil and the perceived sensorial quality of the generated vapours.

E-liquids generally contain four main components: nicotine, flavours, water and carrier liquids. The carrier liquid dissolves flavours and nicotine and vaporises at a certain temperature on the atomizer of the e-cigarette. Propylene glycol and glycerol, the principal carriers used in e-liquids, undergo decomposition in contact with the atomizer heating-coil forming volatile carbonyls. Some of these, such as formaldehyde, acetaldehyde and acrolein, are of concern due to their adverse impact on human health when inhaled at sufficient concentrations. The aim of this study was to correlate the yield of volatile carbonyls emitted by e-cigarettes with the temperature of the heating coil. For this purpose, a popular commercial e-liquid was machine-vaped on a third generation e-cigarette which allowed the variation of the output wattage (5-25W) and therefore the heat generated on the atomizer heating-coil. The temperature of the heating-coil was determined by infrared thermography and the vapour generated at each temperature underwent subjective sensorial quality evaluation by an experienced vaper. A steep increase in the generated carbonyls was observed when applying a battery-output of at least 15W corresponding to 200-250°C on the heating coil. However, when considering concentrations in each inhaled puff, the short-term indoor air guideline value for formaldehyde was already exceeded at the lowest wattage of 5W, which is the wattage applied in most 2nd generation e-cigarettes. Concentrations of acetaldehyde in each puff were several times below the short-term irritation threshold value for humans. Acrolein was only detected from 20W upwards. The negative sensorial quality evaluation by the volunteering vaper of the vapour generated at 20W demonstrated the unlikelihood that such a wattage would be realistically set by a vaper. This study highlights the importance to develop standardised testing methods for the assessment of carbonyl-emissions and emissions of other potentially harmful compounds from e-cigarettes. The wide variety and variability of products available on the market make the development of such methods and the associated standardised testing conditions particularly demanding.

The Influence of Humidity on Assessing Irritation Threshold of Ammonia.

A large number of occupational exposure limit values (OELs) are based on avoiding of sensory irritation of the eyes and the upper respiratory tract. In order to investigate the chemosensory effect range of a chemical, odor and sensory irritation thresholds (lateralization thresholds, LTs) can be assessed. Humidity affects olfactory function and thus influences odor thresholds; however, a similar effect has not been shown for sensory irritation thresholds. The purpose of the present study was to explore whether LTs for ammonia vapor vary depending on the water vapor content of the inspired stimulus. Eight healthy nonsmoking volunteers were simultaneously exposed to ammonia vapor through one nostril and clean air through the other and were asked to determine which nostril received the chemical. Within experimental runs, ascending ammonia concentrations (60–350 ppm) that were either dry or humidified were administered at fixed time intervals. Geometric mean LTs obtained at wet (181 ppm) or dry (172 ppm) conditions did not differ significantly (P = 0.19) and were within the range of those reported by previous studies. These results suggest that humidity is not a critical factor in determining sensory irritation thresholds for ammonia, and future studies will examine if these findings are transferable to sensory irritation thresholds for other chemicals.

Physiological mechanisms of plasticity of central and peripheral links of neuromotor system as a result of adaptation to increased activity of skeletal muscles

Sport activities associated with basketball and field athletics run at various distances contribute significantly to the excitability of the cervical spinal motoneuron pools, motor axons, and muscle fibers which is proved to be less typical of powerlifting. At the same time the research indicated an increased level of reflex excitability of α-motoneurons of muscles of the hip and shin, a significant lowering of the threshold of irritation of the correspondent afferent and efferent nerve fibers, and an increase in the quantity and synchronization of activity of motor elements of the lower limb proximal and distal muscles in basketball players and runners as compared with powerlifters. Refs 27. Tables 4.

Acute effects of acrolein in human volunteers during controlled exposure

Context: Acrolein is a reactive aldehyde mainly formed by combustion. The critical effect is considered to be irritation of the eyes and airways; however, the scarce data available make it difficult to assess effect levels.Objective: The aim of the study was to determine thresholds for acute irritation for acrolein.Methods: Nine healthy volunteers of each sex were exposed at six occasions for 2 h at rest to: clean air, 15 ppm ethyl acetate (EA), and 0.05 ppm and 0.1 ppm acrolein with and without EA (15 ppm) to mask the potential influence of odor. Symptoms related to irritation and central nervous system effects were rated on 100-mm Visual Analogue Scales.Results: The ratings of eye irritation were slightly but significantly increased during exposure to acrolein in a dose-dependent manner (p < 0.001, Friedman test) with a median rating of 8 mm (corresponding to “hardly at all”) at the 0.1 ppm condition and with no influence from EA. No significant exposure-related effects were found for pulmonary function, or nasal swelling, nor for markers of inflammation and coagulation in blood (IL-6, C-reactive protein, serum amyloid A, fibrinogen, factor VIII, von Willebrand factor, and Clara cell protein) or induced sputum (cell count, differential cell count, IL-6 and IL-8). Blink frequency recorded by electromyography was increased during exposure to 0.1 ppm acrolein alone but not during any of the other five exposure conditions.Conclusion: Based on subjective ratings, the present study showed minor eye irritation by exposure to 0.1 ppm acrolein.

The Past and Future of Occupational Exposure Limits

The Past and Future of Occupational Exposure Limits

An assessment of air quality reflecting the chemosensory irritation impact of mixtures of volatile organic compounds

We present a method to assess the air quality of an environment based on the chemosensory irritation impact of mixtures of volatile organic compounds (VOCs) present in such environment. We begin by approximating the sigmoid function that characterizes psychometric plots of probability of irritation detection (Q) versus VOC vapor concentration to a linear function. First, we apply an established equation that correlates and predicts human sensory irritation thresholds (SIT) (i.e., nasal and eye irritation) based on the transfer of the VOC from the gas phase to biophases, e.g., nasal mucus and tear film. Second, we expand the equation to include other biological data (e.g., odor detection thresholds) and to include further VOCs that act mainly by “specific” effects rather than by transfer (i.e., “physical”) effects as defined in the article. Then we show that, for 72 VOCs in common, Q values based on our calculated SITs are consistent with the Threshold Limit Values (TLVs) listed for those same VOCs on the basis of sensory irritation by the American Conference of Governmental Industrial Hygienists (ACGIH). Third, we set two equations to calculate the probability (Qmix) that a given air sample containing a number of VOCs could elicit chemosensory irritation: one equation based on response addition (Qmix scale: 0.00 to 1.00) and the other based on dose addition (1000*Qmix scale: 0 to 2000). We further validate the applicability of our air quality assessment method by showing that both Qmix scales provide values consistent with the expected sensory irritation burden from VOC mixtures present in a wide variety of indoor and outdoor environments as reported on field studies in the literature. These scales take into account both the concentration of VOCs at a particular site and the propensity of the VOCs to evoke sensory irritation.

Analysis of the interrelationship of the pulmonary irritation and elicitation thresholds in rats sensitized with 1,6-hexamethylene diisocyanate (HDI)

This paper summarizes a range of experimental data central for developing a science-based approach for hazard identification of monomeric and polymeric aliphatic 1,6-hexamethylene diisocyanate (HDI). The dose–response curve of HDI-induced pulmonary responses in naïve or dermally sensitized rats after one or several inhalation priming exposures was examined in the Brown Norway (BN) rat asthma model. Emphasis was directed to demonstrate the need and the difficulty in selecting an appropriate pulmonary dose when much of the inhaled chemically reactive vapor may concentration dependently be retained in the upper airways of obligate nose-breathing rats. The course taken acknowledges the experimental challenges in identifying an elicitation threshold for HDI-monomer near or above the saturated vapor concentration or in the presence of a HDI-polymer aerosol. The inhalation threshold dose on elicitation was determined based on a fixed concentration (C) × variable exposure duration (t) protocol for improving inhalation dosimetry of the lower airways. Neutrophilic granulocytes (PMN) in bronchoalveolar lavage (BAL) fluid in equally inhalation primed naïve and dermally sensitized rats were used to define the inhalation elicitation threshold C × t. Sensitized rats elaborated markedly increased PMN challenged sensitized rats relative to equally challenged naïve rats at 5625 mg HDI/m3 × min (75 mg/m3 for 75 min). PMN were essentially indistinguishable at 900 mg HDI/m3 × min. By applying adjustment factors accounting for both inter-species differences in inhalation dosimetry and intra-species susceptibility, the workplace human-equivalent threshold C × t was estimated to be in the range of the current ACGIH TLV® of HDI. Thus, this rat “asthma” model was suitable to demonstrate elicitation thresholds for HDI-vapor after one or several inhalation priming exposures and seems to be suitable to derive occupational exposure values (OELs) for diisocyanates in general.

ELECTRIC PULP TEST OF TEETH WITH PERIODONTAL DISEASE

SUMMARY: Purpose: The aim of the research is to investigate the change in pulp vitality of teeth with periodontal disease using electric pulp tester (EPT). Methods: Subjected to observation were 108 patients with chronic periodontitis. Vitality of 805 teeth with periodontal pocket depth greater than 4 mm was studied by EPT. The research was conducted with EPT “Yonovit “. Results: The highest percentage of surveyed teeth (68.4%) respond to the norm when they are tested with EPT – values between 3 µA and 10 µA . Teeth that respond to EPT with values below 3 µA and between 35-100 µA are relatively equal - respectively 4.3% and 3.3%. With increased threshold of irritation – 10-35 µA react 23.4% of teeth. Small number of teeth have threshold of irritation over 100 µA - 0.6%. Conclusion: The value of EPT among periodontal damaged teeth depends on many factors - patient’s age, extent of periodontal affect, group affiliation of teeth, etc.

Development of a respiratory sensitization/elicitation protocol of toluene diisocyanate (TDI) in Brown Norway rats to derive an elicitation-based occupational exposure level

Toluene diisocyanate (TDI), a known human asthmagen, was investigated in skin-sensitized Brown Norway rats for its concentration×time (C×t)-response relationship on elicitation-based endpoints. The major goal of study was to determine the elicitation inhalation threshold dose in sensitized, re-challenged Brown Norway rats, including the associated variables affecting the dosimetry of inhaled TDI-vapor in rats and as to how these differences can be translated to humans. Attempts were made to duplicate at least some traits of human asthma by using skin-sensitized rats which were subjected to single or multiple inhalation-escalation challenge exposures. Two types of dose-escalation protocols were used to determine the elicitation-threshold C×t; one used a variable C (Cvar) and constant t (tconst), the other a constant C (Cconst) and variable t (tvar). The selection of the “minimal irritant" C was based an ancillary pre-studies. Neutrophilic granulocytes (PMNs) in bronchoalveolar lavage fluid (BAL) were considered as the endpoint of choice to integrate the allergic pulmonary inflammation. These were supplemented by physiological measurements characterizing nocturnal asthma-like responses and increased nitric oxide in exhaled breath (eNO). The Cconst×tvar regimen yielded the most conclusive dose–response relationship as long C was high enough to overcome the scrubbing capacity of the upper airways. Based on ancillary pre-studies in naïve rats, the related human-equivalent respiratory tract irritant threshold concentration was estimated to be 0.09ppm. The respective 8-h time-adjusted asthma-related human-equivalent threshold C×t-product (dose), in ‘asthmatic’ rats, was estimated to be 0.003ppm. Both thresholds are in agreement of the current ACGIH TLV® of TDI and published human evidence. In summary, the findings from this animal model suggest that TDI-induced respiratory allergy is likely to be contingent on two interlinked, sequentially occurring mechanisms: first, dermal sensitizing encounters high enough to cause systemic sensitization. Second, when followed by inhalation exposure(s) high enough to initiate and amplify an allergic airway inflammation, then a progression into asthma may occur. This bioassay requires an in-depth knowledge on respiratory tract dosimetry and irritation of the involved test substance to clearly understand the dosimetry causing C- and/or C×t-dependent respiratory tract irritation and eventually asthma.

Acute irritant threshold correlates with barrier function, skin hydration and contact hypersensitivity in atopic dermatitis and rosacea

The aim of the study was to disclose interactions between epidermal barrier, skin irritation and sensitization in healthy and diseased skin. Transepidermal water loss (TEWL) and stratum corneum hydration (SCH) were assessed in adult patients with atopic dermatitis (AD), rosacea and healthy controls. A 4-h patch test with seven concentrations of sodium lauryl sulphate was performed to determine the irritant threshold (IT). Contact sensitization pattern was revealed by patch testing with European baseline series. Subjects with a lower IT had higher TEWL values and lower SCH. Subjects with positive allergic reactions had significantly lower IT. In AD, epidermal barrier deterioration was detected on both volar forearm and nasolabial fold, while in rosacea, impeded skin physiology parameters were observed on the facial skin only, suggesting that barrier impediment is restricted to the face in rosacea, in contrast with AD where the abnormal skin physiology is generalized.

Winter Season, Frequent Hand Washing, and Irritant Patch Test Reactions to Detergents Are Associated With Hand Dermatitis in Health Care Workers

Irritant hand dermatitis (IHD) is common in health care workers. We studied endogenous irritant contact dermatitis threshold by patch testing and exogenous factors such as season and hand washing for their association with IHD in health care workers. Irritant patch testing with sodium lauryl sulfate (SLS), sodium hydroxide, and benzalkonium chloride at varying concentrations was measured in 113 health care workers. Examination for hand dermatitis occurred at 1-month intervals for a period of 6 months in the Midwestern United States. Positive patch testing to low-concentration SLS was associated with IHD (P = 0.0310) after adjusting for age, sex, ethnicity, season, history of childhood flexural dermatitis, mean indoor relative humidity, and glove and hand sanitizer usage. Subjects with a positive patch test to SLS were 78% more likely to have occurrence of IHD (incidence rate ratio [IRR] = 1.78; 95% confidence interval [CI], 0.92-3.45). Hand washing frequency (≥10 times a day; IRR = 1.55; 95% CI, 1.01-2.39) and cold season (IRR = 2.76; 95% CI, 1.35-5.65) were associated with IHD. No association was found between history of childhood flexural dermatitis and IHD in this population. Both genetic and environmental factors are important in the etiology of IHD and should be considered in designing strategies to protect, educate, and treat susceptible individuals.

Occupational asthma and rhinitis caused by cyanoacrylate-based eyelash extension glues

Eyelash extensions are applied on top of customers' lashes using instant glue containing cyano acrylate, known to cause occupational rhinitis (OR) and occupational asthma (OA). The number of beauty professionals applying these extensions is increasing due to their popularity. To report on a case of OA with OR and a case of OR attributable to lash extension glue and to evaluate respiratory exposure in lash extension work. Two beauty professionals with suspected OA and/or OR underwent inhalation challenge, including both control challenge and work-mimicking challenges using the lash extension glue, each with a 24-h follow-up. Volatile organic compounds (VOCs) present were assessed during the lash extension glue challenge. The glues were analysed for their (meth)acrylate content. Both beauty professionals (case 1 and case 2) applied lash extensions regularly for several hours per day as part of their work and had work-related rhinitis. Case 1 had a longer history of lash extension work and also had asthmatic symptoms. The first lash extension glue challenge was negative in both cases, but positive OR reactions were detected in the second test. Case 1 also had a late asthmatic reaction. During the lash extension glue challenge, VOC were present in total concentrations below the irritant threshold and ethylcyanoacrylate (ECA) was detected in a concentration of 0.4mg/m(3). Chemical analysis of the glues revealed ECA was the major component. Application of eyelash extensions using small amounts of cyanoacrylate-based glues can cause OA and OR.

Indoor air pollutants in office environments: Assessment of comfort, health, and performance

Concentrations of volatile organic compounds (VOCs) in office environments are generally too low to cause sensory irritation in the eyes and airways on the basis of estimated thresholds for sensory irritation. Furthermore, effects in the lungs, e.g. inflammatory effects, have not been substantiated at indoor relevant concentrations. Some VOCs, including formaldehyde, in combination may under certain environmental and occupational conditions result in reported sensory irritation. The odour thresholds of several VOCs are low enough to influence the perceived air quality that result in a number of acute effects from reported sensory irritation in eyes and airways and deterioration of performance. The odour perception (air quality) depends on a number of factors that may influence the odour impact. There is neither clear indication that office dust particles may cause sensory effects, even not particles spiked with glucans, aldehydes or phthalates, nor lung effects; some inflammatory effects may be observed among asthmatics. Ozone-initiated terpene reaction products may be of concern in ozone-enriched environments (≥0.1mg/m(3)) and elevated limonene concentrations, partly due to the production of formaldehyde. Ambient particles may cause cardio-pulmonary effects, especially in susceptible people (e.g. elderly and sick people); even, short-term effects, e.g. from traffic emission and candle smoke may possibly have modulating and delayed effects on the heart, but otherwise adverse effects in the airways and lung functions have not been observed. Secondary organic aerosols generated in indoor ozone-initiated terpene reactions appear not to cause adverse effects in the airways; rather the gaseous products are relevant. Combined exposure to particles and ozone may evoke effects in subgroups of asthmatics. Based on an analysis of thresholds for odour and sensory irritation selected compounds are recommended for measurements to assess the indoor air quality and to minimize reports of irritation symptoms, deteriorated performance, and cardiovascular and pulmonary effects.

Impaired Cough Sensitivity in Children of Smokers

Exposure to environmental tobacco smoke puts children at greater risk for respiratory tract infection and other illnesses and increases the risk that children later become habitual smokers. Because cough sensitivity may relate to both illness and smoking initiation, we determined whether this vital reflex is impaired in children living with smokers. METHODS A single-inhalation capsaicin challenge was administered to 2 groups of healthy children (16 females, 22 males; 10-17 years old) and parents (25 mothers, 1 father): exposed children (n = 17) and parents (n = 13) who smoked ~10 cigarettes/day; and age-matched children (n = 21) never exposed to smoke at home and parents who never smoked in their lifetimes (n = 13). The lowest capsaicin concentrations that triggered (a) sensations of tingle, sting, or burn (irritation threshold) and (b) at least two coughs (cough threshold) were determined. RESULTS Cough thresholds were 2 times as high in exposed children (15.00 µM; 95% confidence interval (CI): 9.98-22.55 µM) as in non-ETS-exposed children (7.31 µM; CI: 5.25-10.19 µM, p = .003). Smoking parents also had higher cough thresholds than never-smoker parents (p = .009). Throat irritation was reported at concentrations below cough threshold for both children and parents. Irritation thresholds did not differ significantly between the two groups of children but were higher for smoking parents than for never-smokers (p = .027). CONCLUSIONS We provide the first evidence that the cough reflex is impaired in seemingly healthy children who live with smokers. The 2-fold difference in cough threshold is comparable in magnitude to the change that occurs with acute respiratory tract infection.

Determination of descriptors for fragrance compounds by gas chromatography and liquid–liquid partition

Retention factors on a minimum of eight stationary phases at various temperatures by gas–liquid chromatography and liquid–liquid partition coefficients for five totally organic biphasic systems were combined to estimate descriptors for 28 fragrance compounds with an emphasis on compounds that are known or potential allergens. The descriptors facilitated the estimation of several properties of biological and environmental interest (sensory irritation threshold, odor detection threshold, nasal pungency threshold, skin permeability from water, skin–water partition coefficients, octanol–water partition coefficients, absorption by air particles, adsorption by diesel soot particles, air–water partition coefficients, and adsorption by film water). The descriptors are suitable for use in the solvation parameter model and facilitate the estimation of a wide range of physicochemical, chromatographic, biological, and environmental properties using existing models.

A Bisensory Method for Odor and Irritation Detection of Formaldehyde and Pyridine

A bisensory method was developed for determining the psychometric functions and absolute thresholds for odor and sensory irritation of two odorous irritants. Individual and group thresholds for formaldehyde or pyridine were measured for 31 age-matched subjects (18–35 years old). P 50 absolute thresholds were for formaldehyde odor 110 ppb (range 23–505), for pyridine odor 77 ppb (range 20–613), and for pyridine irritation 620 ppb (range 90–3,656); too few subjects’ formaldehyde irritation thresholds were possible to determine (human exposures limited to 1 ppm). In spite of large interindividual differences, all thresholds for irritation were higher than for odor. The average slopes of the 62 psychometric functions for odor and the 32 possible for sensory irritation were highest for formaldehyde odor (83% per log ppb) and equal for pyridine odor and irritation (68% per log ppb). The bisensory method for measuring odor and sensory irritation jointly produced detection functions and absolute thresholds compatible with those earlier published; however, a steeper slope for sensory irritation than odor was expected for pyridine. The bisensory method is intended for measuring odor and sensory irritation to broadband mixtures and dynamic exposures, like indoor air.

Interrelating the acute and chronic mode of action of inhaled methylenediphenyl diisocyanate (MDI) in rats assisted by computational toxicology

Polymeric methylenediphenyl diisocyanate (MDI) is a high production volume chemical intermediate consisting of monomeric 4,4′-MDI, its 2,2′- and 2,4′-isomers, and higher oligomeric homologues. The toxicity of pMDI has systematically been investigated in previous regulatory and mechanistic studies. One cornerstone of toxicological risk assessment is to understand the critical Mode of Action (MoA) of inhaled MDI aerosol. This paper compares the no-observed-adverse effect levels (NOAELs) in rats from two published whole-body exposure chronic inhalation bioassays with the lung irritation-based point of departures (PODs) from acute and subacute nose-only inhalation studies. Acute irritation was related to elevated concentrations of protein in bronchoalveolar lavage fluid (short-term studies), whilst the chronic events were characterized by histopathology. In the chronic bioassay the exposure duration was either 6 or 18h/day while in all other studies a 6h/day regimens were applied. The major objective of this paper is to analyze the interrelationship of acute pulmonary irritation and the acute-on-chronic manifestations of pulmonary disease following recurrent chronic inhalation exposure. This included considerations on the most critical metrics of exposure with regard to the acute concentration×exposure duration per day (C×Tday) and the chronic cumulative dose metrics. In summary, this analysis supports the conclusion that the C×Tday relative to the acute pulmonary irritation threshold is more decisive for the chronic outcome than the concentration per se or the time-adjusted cumulative dose. For MDI aerosols, the acute threshold C×Tday was remarkably close to the NOAELs of the chronic inhalation studies, independent on their differing exposure mode and regimens. This evidence is supportive of a simple, direct MoA at the site of initial deposition of aerosol. Accordingly, for chemicals reactive to the endogenous nucleophilic agents contained in the lining fluid of the lung, one unifying essential prerequisite for pulmonary injury appears to be a C×Tday that exhausts the homeostatic pool of MDI-scavenging agents. In the case that threshold is exceeded, the secondary compensatory chronic response may then cause additional superimposed types of chronic pathologies.

The Effect of Menthol Vapor on Nasal Sensitivity to Chemical Irritation

Among other effects, menthol added to cigarettes may modulate sensory response to cigarette smoke either by masking "harshness" or contributing to a desirable "impact." However, harshness and impact have been imprecisely defined and assessed using subjective measures. Thus, the current experiments used an objective measure of sensitivity to chemical irritation in the nose to test the hypothesis that menthol vapor modulates sensitivity to chemical irritation in the airways. Nasal irritation thresholds were measured for 2 model compounds (acetic acid and allyl isothiocyanate) using nasal lateralization. In this technique, participants simultaneously sniff clean air in one nostril and chemical vapor in the other and attempt to identify the stimulated nostril. People cannot lateralize based on smell alone but can do so when chemicals are strong enough to feel. In one condition, participants were pretreated by sniffing menthol vapor. In a control condition, participants were pretreated by sniffing an odorless blank (within-subjects design). Pretreatment with menthol vapor decreased sensitivity to nasal irritation from acetic acid (participants required higher concentrations to lateralize) but increased sensitivity to allyl isothiocyanate (lower concentrations were required). The current experiments provide objective evidence that menthol vapor can modulate sensitivity to chemical irritation in the upper airways in humans. Cigarette smoke is a complex mixture of chemicals and particulates, and further work will be needed to determine exactly how menthol modulates smoking sensation. A better understanding could lead to treatments tailored to help menthol smokers quit by replacing the sensation of mentholated cigarettes.