Irritation Thresholds Research Articles

Assessment of pyrethroid-induced paraesthesias: comparison of animal model and human data

The quantification of upper respiratory tract (URT) sensory irritation is considered to be important in rodent inhalation studies, since it may be also used as an endpoint mimicking trigeminal paraesthesias observed in humans. URT sensory irritation is known to be associated with rodent-specific secondary physiological effects such as depression of body temperature and changes in heart rate. In acutely exposed rats, these endpoints have been addressed by telemetrical measurements. The analysis of the ventilation pattern during acute inhalation studies of rats exposed to the α-cyano-pyrethroid cyfluthrin demonstrates that concentration-dependent URT sensory irritation was associated with a hypothermic response. The no-effect levels (NO(A)EL) based on the URT sensory irritation endpoint following acute inhalation exposure for 1 h and following a repeated 4-week or 13-week inhalation exposure for 6 h/day on 5 days/week were virtually identical (≈0.1 mg/m 3 air). An additional objective was to examine whether human volunteers experience comparable signs when acutely exposed for 1 h to airborne concentrations slightly above or in the range of the NO(A)EL. In human volunteers there were no clinically significant or pyrethroid related abnormalities in vital signs, ECG’s or in any clinical laboratory tests after either exposure, although transient effects related to URT (sensory) irritation were reported. In conclusion, an initial actual exposure concentration of ≈0.1 mg cyfluthrin/m 3 air appears to be in the range of the sensory irritant threshold concentration for both rats and humans. Thus, with regard to physiological afferent portal-of-entry effects, the interspecies response was consistent.

Trigeminal and Olfactory Chemosensory Impact of Selected Terpenes

COMETTO-MUÑIZ, J. E., W. S. CAIN, M. H. ABRAHAM AND R. KUMARSINGH. Trigeminal and olfactory chemosensory impact of selected terpenes. PHARMACOL BIOCHEM BEHAV 60(3) 765–770, 1998.—In Experiment 1, four normosmics and four anosmics (three congenital, one idiopathic) provided odor and nasal pungency thresholds, respectively, for the following terpenes: Δ 3-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 thresholds. 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: α- and γ-terpinene, α- and β-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 α-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.

Acute irritation thresholds in subjects with type I--type VI skin.

It has long been recognized that human skin can be subdivided into simple categories based on their sensitivity to sunlight--from Type I, never tans, always burns, to Type VI, marked constitutive pigmentation. There is also evidence that the more readily sunburnt type of skin is also more susceptible to the effect of irritants. In the present work, the irritancy threshold for sodium lauryl sulfate (SLS) has been assessed using a recently described 4-h acute skin irritation patch test. A total of 110 subjects covering all 6 skin types were examined and their threshold for acute irritancy defined as the lowest concentration of SLS, applied under 4-h occlusion, which would induce a clinically detectable irritant response. The SLS dose response generated using a range of concentrations (0.1%-20%) demonstrated that there was no significant difference between the groups under these test conditions. Even for Type VI skin (n = 25), the dose-response curve fell within the general pattern. These results reinforce the general applicability of predictions of acute irritant potential made in groups of human volunteers.

Acetone odor and irritation thresholds obtained from acetone-exposed factory workers and from control (occupationally unexposed) subjects.

Sensitivity of olfaction (smell) and chemesthesis (irritation) was evaluated for 2-propanone (acetone) and 1-butanol in acetone-exposed workers (AEW; N = 32) during a workday and unexposed subjects (microES; N = 32). Irritation sensitivity was assessed using a method that relies on the ability of individuals to localize irritants on the body. When a volatile compound is inhaled into one nostril and air into the other, the stimulated side can be determined (lateralized) only after the concentration reaches a level that stimulates the trigeminal nerve (irritation); compounds stimulating olfaction alone cannot be lateralized. Intranasal lateralization thresholds offer an objective measure of sensory irritation elicited by volatile compounds. Test results indicated that neither olfactory nor lateralization thresholds for butanol differed between AEW and microES. Olfactory thresholds to acetone in AEW (855 ppm) were elevated relative to those of microES (41 ppm), as were lateralization thresholds (36,669 ppm and 15,758 ppm, respectively). Within AEW, level of occupational exposure was not correlated with thresholds. Other measures revealed that microES used more irritation descriptors than did AEW on trials where the acetone concentration was below the lateralization threshold. This is noteworthy because microES received lower concentrations of acetone to evaluate than did AEW. These results suggest that exposures to acetone induce changes in acetone sensitivity that are specific to acetone. The acetone concentrations eliciting sensory irritation using the lateralization technique were all well above current occupational exposure standards. The current study indicates that acetone is a weak sensory irritant and that sensory adaptation is an important factor affecting its overall irritancy.

Acetone Odor and Irritation Thresholds Obtained From Acetone-Exposed Factory Workers and From Control (Occupationally Unexposed) Subjects

Sensitivity of olfaction (smell) and chemesthesis (irritation) was evaluated for 2-propanone (acetone) and 1-butanol in acetone-exposed workers (AEW; N = 32) during a workday and unexposed subjects (μES; N = 32). Irritation sensitivity was assessed using a method that relies on the ability of individuals to localize irritants on the body. When a volatile compound is inhaled into one nostril and air into the other, the stimulated side can be determined (lateralized) only after the concentration reaches a level that stimulates the trigeminal nerve (irritation); compounds stimulating olfaction alone cannot be lateralized. Intranasal lateralization thresholds offer an objective measure of sensory irritation elicited by volatile compounds. Test results indicated that neither olfactory nor lateralization thresholds for butanol differed between AEW and μES. Olfactory thresholds to acetone in AEW (855 ppm) were elevated relative to those of μES (41 ppm), as were lateralization thresholds (36,669 ppm and 15,758 ppm, respectively). Within AEW, level of occupational exposure was not correlated with thresholds. Other measures revealed that μES used more irritation descriptors than did AEW on trials where the acetone concentration was below the lateralization threshold. This is noteworthy because μES received lower concentrations of acetone to evaluate than did AEW. These results suggest that exposures to acetone induce changes in acetone sensitivity that are specific to acetone. The acetone concentrations eliciting sensory irritation using the lateralization technique were all well above current occupational exposure standards. The current study indicates that acetone is a weak sensory irritant and that sensory adaptation is an important factor affecting its overall irritancy.

Evaluation of the HET-CAM-TSA method as an alternative to the draize eye irritation test

The Hen's Egg Test-Chorioallantoic Membrane (HET-CAM) method was modified in our laboratory by means of microscopic evaluation, a clear description of the three in vitro endpoints (haemorrhage, lysis and coagulation) and the use of a test substance applicator (TSA). A previous study on 46 chemicals demonstrated the usage of the HET-CAM-TSA assay as a screening test for eye irritancy. In order to extend our database and to come to a more reliable conclusion concerning the use of the HET-CAM-TSA method, a second set of 60 test substances was tested. The in vitro irritation scores (IS) were compared with the in vivo modified maximum average scores (MMAS) calculated 24 hr after instillation. The MMAS irritancy threshold was set at 15.0. The results were analysed according to the Cooper's parameters (specificity, sensitivity and concordance with the Draize test) and the Pearson's correlation coefficient. It was concluded that the HET-CAM-TSA test was a valuable screening test. To compensate for the misclassifications generated, it was also concluded that the HET-CAM-TSA method should be considered as a part of a test battery, together with the Bovine Corneal Opacity-Permeability (BCOP) assay.

Chemical and Biological Evaluation of Building Material Emissions. I. A Screening Procedure based on a Closed Emission System*

Abstract The impact on air quality of the emission of pollutants from freshly conditioned sealant and waterborne paint, and a new carpet was investigated by means of a closed emission system and a high loading factor, i.e. “maximized” test conditions. VOCs were measured. Speciated TVOC values obtained by summation of single VOCs and TVOC (cyclohexane equivalents) values determined by IR spectroscopy were of the same order of magnitude for the carpet and for the sealant. Biological evaluation of the effects of the VOCs was undertaken from the concentrations and the odour and irritation thresholds of each substance. The overall agreements and the mutual supplementation of the results from the TVOC and biological evaluations were apparent, suggesting that both approaches should be part of the evaluation of emissions from building materials. Also the mouse bioassay (ASTM, 1984) was used for evaluation of the irritants emitted. Chemical emission testing and the use of established lists of irritation thresholds appear to be more cost-effective, due to the low sensitivity of the bioassay. This approach was demonstrated with 2-butanone oxime (emitted from the sealant). The same type of approach may be used in relation to odour and hazard identification. However, human and animal tests are necessary in cases where biological data are lacking or where the chemical emission is unknown.

Risk assessment of pyrethroids following indoor use

One notable form of toxicity associated with exposure to high concentrations of synthetic pyrethroids has been a cutaneous paresthesia. This strong excitatory action on the sense organs in the vertebrate skin and upper respiratory tract is characteristic of synthetic pyrethroids, whereas the cyano pyrethroids evoke more intense neuroexcitatory activities than the noncyano pyrethroids. Such facial sensations and irritative symptoms appear to be produced by direct stimulation of peripheral sensory nerve endings rather than by inflammatory mechanisms. Effects related to sensory irritation can be evoked by a wide variety of substances occurring in the indoor environment, and analysis of the etiopathological relationships presents difficult and complex medical and scientific issues. For the appropriate assessment of pyrethroids in the indoor environment, it would be helpful to have an objective laboratory assay to confirm and quantitate the degree of sensory irritation evoked by airborne pyrethroids. A bioassay was established using the nociceptive system of mice and rats to assess the extent of pyrethroid-related sensory irritation to the respiratory tract. For analysis, aerosolized Cyfluthrin was selected due to the greater potency of the α-cyano pyrethroids to evoke sensory irritation. Additionally, this pyrethroid was tested in a carpet-model to assess the extent to which pyrethroid-laden dust from carpets is likely to become airborne following continuous brushing. Comparative evaluations of the sensory irritation potential of aerosolized Cyfluthrin in mice and rats revealed that for assessment of the sensory irritant threshold concentration, rats appeared to be more susceptible than mice. Measurements performed repeatedly during subacute exposure to the pyrethroid (6 h/day, 5 days/week for 4 consecutive weeks) did not indicate any alteration in responsiveness, and the magnitude of changes in breathing patterns was similar to those observed following acute 1-h exposure. These findings confirm the conclusion that α-cyano-pyrethroids appear to act as “pure” sensory irritants and that the effects observed are non-cumulative and transient in nature. Concomitant respiratory tract inflammation and ensuing changes in susceptibility—common findings in chemical sensory irritants—did not occur. From the studies addressing the dislodgeability of pyrethroid containing dust from carpets, it is apparent that measurement of deposited dust is a poor substitute for airborne dust. Even under worst-case testing conditions (continuous brushing of the carpet for approximately 19 h in a bias-flow compartment), only a very small fraction of the pyrethroid laden dust particles charged to the carpet could be recovered airborne (0.04%/m 2 per h). Thus, experimental findings support the conclusion that such agents cannot be dislodged from carpets to an extent that lexicologically significant airborne concentrations are attained. Therefore, assessment of health hazards in the indoor environment based solely on “vacuum cleaner” sampling is prone to a high level of errors and misjudgment.

A new approach for indoor climate labeling of building materials—emission testing, modeling, and comfort evaluation

A labeling system for building materials' primary emission of volatile organic compounds (VOCs) according to their impact on comfort and health has been developed and introduced in Denmark. The system unifies chemical emission testing over time (months), modeling (including a standard room and mathematical modeling of the emission profile, when necessary), and health evaluation. As a first step, the Danish system focuses on comfort, i.e. odor annoyance and mucous membrane irritation, because of their preponderance in the sick building syndrome reporting and the absence of other relevant data on indoor air related health effects. Two design criteria have been set: the labeling system shall be easily comprehensible and at the same time operational and dynamic. The principle is to determine the time value, t( C m), required to reach the relevant indoor air value, C m (presently, based on odor and mucous membrane irritation thresholds), in a standard room. Odor thresholds are used because they generally are at least one order of magnitude lower than mucous membrane irritation thresholds. t( C m) is a measure of the period of time during which a new building material may cause indoor air quality problems, unless special precautions are made. The system may also be used for singular VOCs of which a specific health endpoint has been reported. The Danish labeling system is illustrated with the emission testing and comfort evaluation of two sealants using the Field and Laboratory Emission Cell (FLEC)

An Analysis of Nasal Irritation Thresholds Using a New Solvation Equation

In the present paper we have developed a quantitative structure–activity relationship (QSAR) equation for nasal pungency caused by nonreactive volatile organic compounds (VOCs). Our QSAR was developed upon previously published nasal pungency thresholds in anosmics, i.e., patients lacking a sense of smell and thus responding only to sensory irritation evoked by trigeminal nerve stimulation. The reported solvation equation, which fits the data with considerable precision, describes sensory potency in terms of interaction via electron pairs, dipolarity/polarizability, hydrogen bond acidity and basicity, and hydrophobicity. It correspondingly suggests relevant physicochemical properties of the biophase where the sensory response is brought about. The equation implies that in the range of molecular size where nonreactive VOCs can produce any pungency, transport from the air to the biophase strictly determines potency. In this respect, the potency of nasal pungency shares characteristics with the ability of VOCs to cause narcosis and anesthesia.

Regional and Individual Differences in Cutaneous Sensitivity to Chemical Irritants: Capsaicin and Menthol

Regional and individual differences in sensory irritation produced by capsaicin and l-menthol were assessed in two experiments. Thresholds for irritation were measured on the forearm and cheek using a psychophysical method that combines a bilateral, forced-choice detection task with an intensity scaling task. Experiment 1 showed that thresholds on the cheek were higher than on the forearm for both chemicals; on average, thresholds were much lower for capsaicin than for menthol; there were large individual differences in thresholds for both chemicals on both sites; and capsaicin and menthol produced different qualities of sensation. In contrast to earlier findings, capsaicin failed to produce itching on either site. Experiment 2 showed that itching could be evoked on the forearm, but not the face, when capsaicin was applied in a single dose rather than in an ascending concentrations series, as it had been in experiment 1. It was hypothesized that the absence of itching in experiment 1 was due to a more rapid desensitization for itching compared to burning and stinging, and that the lack of itching on the cheek may reflect different chemosensory innervation on facial and forearm skin. Overall, the results demonstrate that psychophysical measurements can provide information about regional and individual differences in the susceptibility to sensory irritation from contact with environmental chemicals.

An Analysis of Nasal Irritation Thresholds Using a New Solvation Equation

An Analysis of Nasal Irritation Thresholds Using a New Solvation Equation

Propylene glycol dermatitis: re-evaluation of an old problem.

Evaluation of dermatitis associated with propylene glycol application or ingestion remains a challenge. The research dealing with skin reactions to propylene glycol is revisited and new aspects for future research are outlined. Based on literature review and our own observations, we propose classifying skin reactions to propylene glycol into 4 mechanisms: (a) irritant contact dermatitis, (b) allergic contact dermatitis, (c) non-immunologic contact urticaria, and (d) subjective or sensory irritation. This concept allows a partial explanation of effects observed by different authors. Despite attempts to define objective criteria, biologically, histopathologically, or clinically, the distinction between irritant and allergic reactions remains unclear. Furthermore, the irritation threshold of propylene glycol, and likewise the optimal standard concentration in patch tests, is sub judice. Future studies on propylene glycol dermatitis should include repeated patch tests with serial dose dilutions, repeated open application tests/provocative use tests, oral challenge tests, and biopsies for a more complete evaluation of mechanisms and clinical significance.

Perception of Odor and Nasal Pungency from Homologous Series of Volatile Organic Compounds

We tested nasal detection thresholds for airborne chemicals in a group of anosmics (i.e., subjects lacking a functional sense of smell) and in a group of age-, gender-, and smoking-status-matched normosmics (i.e., subjects with normal olfaction). Anosmics provided odor unbiased nasal pungency (irritation) thresholds. Normosmics provided odor thresholds. Homologous series of alcohols, acetates, and ketones served as stimuli. Eye irritation thresholds were also measured for selected acetates. Most substances evoked pungency (i.e., were detected by the anosmics). All sensory thresholds decreased systematically with carbon chain length. The gap between pungency and odor grew larger with increasing carbon chain length. Pungency thresholds — but not odor thresholds — showed a uniform linear relationship of slope close to unity with saturated vapor concentration, irrespective of chemical functionality or carbon chain length. This suggests that pungency from nonreactive airborne chemicals rests heavily on a relatively unspecific physical interaction with a susceptible biophase. Of relevance to indoor environments, such an interaction opens the possibility for a high degree of sensory addition of pungency from individual components of complex mixtures resulting in noticeable irritation even when each component is at a level well below threshold.

Assessment of respiratory hypersensitivity in guinea-pigs sensitized to diphenylmethane-4,4′-diisocyanate (MDI) and challenged with MDI, acetylcholine or MDI-albumin conjugate

Guinea-pigs were sensitized to monomeric diphenylmethane-4,4′-diisocyanate (MDI) by two intradermal injections (1–10% MDI, injection volumes of 50–100 μl/day, on days 0, 2 and 4) or by a single brief high-concentration inhalation exposure (135 or 360 mg/m 3, 15 min). Starting with day 21 following sensitization the animals were subjected to inhalation-challenge exposures (30 min) with non-irritating and irritating concentrations of the hapten (MDI). MDI-challenge concentrations ranged from 3.4 ± 0.9 to 60 ± 14.3 mg/m 3 air. In some groups guinea-pigs were also challenged with acetylcholine (ACh) aerosol or the MDI-guinea pig serum albumin (GPSA) conjugate. Experimental findings indicated that from intradermally sensitized animals an immediate onset respiratory hypersensitivity response could only be elicited with concentrations exceeding the irritant threshold concentration for MDI, i.e. with concentrations greater than ∼20 mg/m 3 air. Guinea-pigs challenged with the MDI-GPSA conjugate (35.3 ± 2.8 mg/m 3 air) also experienced a weak immediate-type respiratory hypersensitivity response. An increased non-specific airway hyper-responsiveness following ACh-challenge was only observed from animals challenged with approximately 60 mg MDI/m 3 air. The histopathological evaluation of lungs and lung-associated lymph nodes revealed an association of the increase in eosinophilic granulocytes and concentration of MDI used for challenge exposures. It appeared, in most instances, that this influx was more pronounced in animals sensitized with MDI as compared with concurrent controls challenged with the same MDI concentration. Guinea-pigs sensitized by a single 15-min inhalation exposure to either 135 or 360 mg MDI/m 3 air were challenged sequentially with 12 ± 2.1 mg MDI/m 3 air, ACh and MDI-GPSA conjugate. Following the inhalation-induction, an airway hyper-responsiveness was elicited both after challenge with MDI and with the MDI-GPSA conjugate. The influx of eosinophilic granulocytes was more pronounced from animals sensitized by inhalation when compared with guinea-pigs sensitized intradermally and challenged with the same concentration of MDI. Thus, experimental findings suggest that elicitation of respiratory hypersensitivity is concentration-dependent and that challenge concentrations should slightly exceed the threshold concentration for irritation (∼20 mg/m 3). Sensitization by inhalation increased the susceptibility to irritant stimuli and thus confounds the selection of the most appropriate concentration for challenge. However, the combined assessment of specific pathologic features such as airway eosinophilia and the evaluation of several breathing parameters during hapten- and ACh-challenge make it easier to distinguish effects caused by irritation and respiratory hypersensitivity. It would also appear that the intradermal-induction inhalation-challenge protocol is less susceptible to influences pertinent to irritation-induced airway hyper-reactivity than the inhalation-induction inhalation-challenge protocol.

Effect of age and sex on the elicitation of irritant contact dermatitis

Irritant contact dermatitis causes significant disability to numerous consumers and individuals in industry. Knowledge of the prevalence of this disease remains inadequate. Irritant contact dermatitis occurs in workers engaged in occupations where the subjects are exposed to different types and doses of irritants. The intensity of the reaction depends on the quality and the quantity of exposure. Irritant thresholds and dose responses depend on many different factors. This article reviews the clinical and physiological parameters that affect the age and sex related differences in irritant contact dermatitis.

Sensitivity of the eyes to airborne irritant stimuli: influence of individual characteristics.

The purpose of this study was to measure trigeminal sensitivity of the eyes to irritative exposures and to examine the influence of individual characteristics, e.g., gender, age, and smoking, on this sensitivity. During an experimental study, 158 of 2,025 randomly selected volunteers were examined for sensory irritation threshold in the eyes to carbon dioxide (CO2). Eyes were exposed to progressive concentrations of CO2 (10, 20, 40, 80, and 160 ml/l), until the subject claimed a distinct irritation. Each exposure level lasted 2 min. A special exposure mask system was used for eyes-only exposure. No significant dependence of gender or smoking was found, but subjects who were less than 40 y of age were more sensitive than were the elderly subjects. Subjects who reported frequent "sick building syndrome" irritation symptoms had lower thresholds (i.e., higher sensitivity). The CO2 threshold was related to skin irritation sensitivity, i.e., response to lactic acid smeared on the cheek, and there were indications that occupational stress was associated with low thresholds. Studies of irritation to n-decane indicate that the CO2 threshold may be an important factor in the prediction of individual sensitivity to irritation from airborne pollutants. The CO2 threshold of the eyes may be of value in the evaluation of hypersensitivity to indoor air pollution. Furthermore, the threshold may be used to assess important relationships between the different trigeminal innervated areas, e.g., skin and eyes. Finally, the method has the advantage of avoiding interference from olfactory stimulation.

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.

Irritant and sensitizing potential of copper, mercury and tin salts in experimental contact stomatitis of rat oral mucosa

HgCl2, CuSO4, SnCl2, SnCl4 or sodium lauryl sulphate (SLS) were openly applied to rat oral mucosa for 1 min, followed 6 h later by histologic examination of the tissue response. Granulocytes were the predominant inflammatory cells and no lymphocytic infiltration could be seen with any of the substances tested. Irritant threshold levels were defined histologically for each of the substances. CuSO4 was found to be non-irritant at all concentrations. The addition of non-irritant concentrations of SLS lowered the threshold levels for HgCl2 and SnCl2, but CuSO4/SLS was non-irritant at all concentrations tested. Preapplication to the mucosa of SLS at non-irritant concentrations gave results with HgCl2, SnCl2 and CuSO4 similar to those with SLS added to the metal salt solutions. Lesions of allergic contact type could not be induced in the oral mucosa to any of the metal salt preparations.

Cutaneous nickel sensitivity in Toronto, Canada

Patch tests were administered to 1074 subjects with suspected contact dermatitis by the method recommended by the International Contact Dermatitis Research Group. Of 629 subjects tested with 5% nickel sulfate in petrolatum, 10.5% had positive reactions (males, 5.1%; females, 16.7%). Of 447 subjects tested with 2.5% nickel sulfate in petrolatum, 11.9% reacted (males, 7.7%; females, 16.9%). In 447 subjects in whom the relationship between clinical findings and the patch test response was evaluated (i.e., relevance), more than 90% of the responses could be related to a past or present problem with contact dermatitis. The sites of involvement were not different between nickel-sensitive subjects and the overall population tested, except in the case of foot involvement, which was underrepresented in the nickel-sensitive group. Patients who had positive responses to nickel reacted more frequently to marginal irritants such as formaldehyde and benzoyl peroxide. This finding may suggest a reduction in the irritancy threshold in nickel-sensitive subjects. In most instances, domestic rather than occupational exposure was thought to account for the induction of nickel allergy.