Discrimination Between Atopic, Allergic, and Asthmatic Volunteers for Human Exposure Studies on Sensory Irritation.

Atopic, allergic, and especially asthmatic subjects might be particularly susceptible to sensory irritation induced by airborne chemicals compared to healthy individuals. Therefore, a good characterization of subjects is essential in inhalation exposure studies on sensory irritants. A total of 105 volunteers, 87% of whom reported to be non-allergic, participated in a medical examination that included skin prick test (SPT), measurements of total IgE, specific IgE (sIgE) to an ubiquitous allergen mix (sx1), and fractionated exhaled nitric oxide (FeNO), as well as pulmonary function and methacholine test. The median value of sIgE to sx1 was 0.20 kU/L (0.07-91.3 kU/L) and correlated significantly with total IgE (28.8 kU/L (2-756 kU/L)) and FeNO (14 ppb (5-100 ppb)). Forty-three subjects (41%) had sIgE to sx1 ≥ 0.35 kU/L and were classified as atopic. Thirty-five subjects, all also sx1-positive, were positive in SPT. Obstruction, small airway disease, and/or bronchial hyperreactivity were diagnosed in 18 subjects. Receiver operating characteristics (ROC) were performed to check whether signs of sensitization are useful to discriminate subjects with and without airway diseases. However, sx1, total IgE, FeNO, and SPT reached only low areas under the curve (AUC: 0.57-0.66). Although predominantly young and, according to their own statements, mostly non-allergic subjects participated in the study, almost half of them were atopic, and 10% had airway disease or bronchial hyperreactivity. This indicates that the validity of self-reported data might be inaccurate. In summary, diversified investigations of the allergy-related health status appear necessary for a thorough characterization of subjects for exposure studies on sensory irritants.

How Healthy Is Healthy? Comparison Between Self-Reported Symptoms and Clinical Outcomes in Connection with the Enrollment of Volunteers for Human Exposure Studies on Sensory Irritation Effects.

Controlled human exposure studies on sensory irritation effects are usually performed with healthy volunteers. Therefore, in most studies pre-screening by a health questionnaire and a detailed medical examination are combined. The aim of this report is to investigate whether self-reported information about smoking and health status is sufficient or whether additional clinical tests are necessary for a successful and safe enrollment of healthy volunteers. There were 409 volunteers (55% female; 17-57 years; 79% non-smokers) who declared interest in participation in the study. However, 87 subjects failed to meet specific inclusion criteria, and further 138 had to be excluded due to the presence of chronic health problems. In effect, 184 subjects passed the initial questionnaire screening and proceed to further examination. Medical examination included electrocardiogram, blood and urine screening, and an olfactory function test. Atopy status was assessed by skin prick or specific IgE testing. Lung function and a methacholine challenge test were performed to assess respiratory health and bronchial hyperresponsiveness. Overall, only 107 non-smoking subjects (58% female; 19-40 years) who had no respiratory diseases, allergies, or chronic illnesses could be finally selected. Out of the 107 subjects, 8 were excluded due to positive cotinine tests, laboratory test results outside the reference range, or atypical ECGs. In another 12 subjects, obstruction or a bronchial hyperreactivity was diagnosed. Among the remaining 87 healthy subjects, 26 were classified as atopic and further two as hyposmic. In conclusion, although young and non-smoking volunteers considered themselves healthy by questionnaire, 20% showed signs of a heart, liver, or airway disease, and additional 24% were classified as atopics. This suggests that more detailed clinical testing may be necessary to safely exclude those who may adversely react to controlled exposure with sensory irritants.

Methodological Implications and Repeatability of Nasal Nitric Oxide: Relevance for Challenge Studies.

There is an interest in assessing changes in nasal NO (nNO) levels as an effect marker of upper airways. In this study, we examined methodologic influences on short and long term repeatability of nNO levels assessed by a portable electrochemical analyzer. Nine atopic and eighteen healthy subjects were exposed for 4 h to ethyl acrylate concentration of 0.05 ppm (sham) and mean concentrations of 5 ppm (either constant 5 ppm or variable 0 to 10 ppm). Sampling of nNO was performed by using passive aspiration during both breath-holding (634 ppb) or calm tidal breathing (364 ppb, p < 0.0001). The intra-session (between-session) repeatability in terms of coefficient of variation was 16.4% (18.5%) using the tidal-breathing and 8.6% (13.0%) using the breath-holding method, respectively. Atopic subjects demonstrated a significant increase in nNO (breath-holding mean 16%, tidal-breathing mean 32%) after applying a constant ethyl acrylate concentration (5 ppm). Our findings suggest that the less elaborate tidal-breathing method might be sufficient to detect significant changes at a group level. Given a lower coefficient of variation of breath-holding we assume there is an advantage of that approach at an individual level. Further research is needed to validate the usefulness of nNO in the evaluation of irritative, non-allergic responses.

Impact of Internal and External Factors on EBC-pH and FeNO Changes in Humans Following Challenge with Ethyl Acrylate.

Acute effects of ethyl acrylate exposure at 5 ppm for 4 h include changes of pH in exhaled breath condensate (EBC-pH) and exhaled nitric oxide (FeNO). So far, few data have been reported for atopic persons or the impact of the exposure conditions on biomarkers, e.g., constant versus variable application of irritants. Nine atopic and eighteen healthy volunteers without bronchial hyperresponsiveness were exposed for 4 h to ethyl acrylate concentrations of 0.05 ppm (sham), 5 ppm (constant concentration), and 0-10 ppm (variable, mean concentration of 5 ppm) in an exposure laboratory. A positive atopic status was defined according to specific IgE concentrations to common inhalant allergens (sx1 ≥ 0.35 kU/L). Biomarker levels were assessed before and after challenge and adjusted for levels after sham exposure (net response). Ethyl acrylate at constant, but not at variable concentrations induced a significant change in the net responses of EBC-pH and FeNO. Concerning FeNO, this could be observed only for atopic persons. The changes of biomarker levels were related to their baseline values. Biomarker responses to challenge with ethyl acrylate may be influenced by the patterns of application as well as baseline airway inflammation and atopic status of the volunteers.

Clinical Effects, Exhaled Breath Condensate pH and Exhaled Nitric Oxide in Humans After Ethyl Acrylate Exposure.

Ethyl acrylate is an irritant known to affect the upper airways and eyes. An increase of the eye blink frequency in humans was observed during exposure to 5 ppm. Studies on the lower airways are scant and our study objective was the evaluation of pH in exhaled breath condensate (EBC-pH) and nitric oxide in exhaled breath (FeNO) as markers of inflammation. Sixteen healthy volunteers were exposed for 4 h to ethyl acrylate at a concentration of 5 ppm and to sham (0.05 ppm) in an exposure laboratory. Clinical irritation symptoms, EBC-pH (at a pCO2 of 5.33 kPa) and FeNO were assessed before and after exposure. Differences after ethyl acrylate exposure were adjusted for those after sham exposure. 5 ppm ethyl acrylate induced clinical signs of local irritation in the nose and eyes, but not in lower airways. Exposure produced a subtle, but statistically significant, decrease in breathing frequency (1 breath/min; p = 0.017) and a lower EBC-pH (by 0.045 units; p = 0.037). Concerning FeNO, we did not observe significant changes compared to sham exposure. We conclude that local effects induced by 5 ppm ethyl acrylate consist of sensory irritation of eyes and nose. In addition, acute ethyl acrylate exposure to 5 ppm resulted in a net decrease of EBC-pH. Whether that can be interpreted in terms of additional lower airway irritation or already inflammatory alterations set in needs further investigations.

Methodological implications in pH standardization of exhaled breath condensate.

The variable amount of dissolved carbon dioxide is one of the main confounding factors of exhaled breath condensate (EBC) pH measurements. There have been many attempts at identifying the optimal approach to displace CO2 as a way to gain reproducible and valid pH values in EBC samples. The aim of the present study was to assess the correlation of pH and pCO2 in untreated, neat EBC samples and, after deaeration, to reevaluate the standardization of CO2 as a means to obtain valid pH values. A further aim was to evaluate the impact of deaeration on the acid-base balance in EBC samples. EBC was collected from seven female and 31 male subjects. The pH and pCO2 values immediately determined in untreated, neat EBC samples were strongly correlated (rp = -0.723, p < 0.0001). This correlation was not observed after deaeration with argon (rs = 0.264, p = 0.109). Based on a regression function for the pH/pCO2 relationship, the calculated pH at a pCO2 of 5.33 kPa was 6.07 (IQR 5.99, 6.20). No significant difference was observed between the pH measured in neat EBC samples and those calculated after deaeration with regression function and measured neat pCO2. Our data suggest that pCO2 is the most important confounder of pH measurement in EBC samples and, when adjusting for pCO2, the acid-base balance of EBC samples is not significantly influenced by the process of deaeration. Furthermore, measurement with a blood-gas analyzer and standardization of pH for pCO2 allows sensitive assaying of EBC samples. Therefore, this method provides a basis for detection of even small changes in airway pH due to inhalative exposure or respiratory disease.

Different Patterns in Changes of Exhaled Breath Condensate pH and Exhaled Nitric Oxide After Ozone Exposure.

Study objective was the evaluation of pH in exhaled breath condensate (EBC-pH) and nitric oxide in exhaled breath (FeNO) as biomarkers of ozone induced inflammation. We recently demonstrated that an ozone exposure of 240 ppb is sufficient to reduce lung function indices. We enrolled ten healthy subjects exposed in an intermittent exercise protocol to ozone concentrations of 240 ppb and 40 ppb (sham exposure). EBC-pH and FeNO were assessed before (pre), immediately post (post), and 16 h after exposure (16 h). Findings are that compared to baseline, EBC-pH was significantly higher immediately after sham and ozone exposures, but not 16 h later. There was a negative net change in EBC-pH after adjusting for effects after sham exposure (net-ΔpHpost -0.38%, net-ΔpH16h -0.23%). Concerning FeNO, we observed no changes of values after sham exposure compared to baseline, but measured a significant lower net response at the end of exposure (net-ΔFeNOpost -17.5%) which was transient within 16 h (net-ΔFeNO16h -9.4%). We conclude that exercise known to enhance EBC-pH may compensate for EBC acidification associated with inflammation resulting in diminished change of this biomarker. Ozone imposes an oxidative burden and reactions between reactive oxygen species and NO might be an explanation for reduced FeNO levels.

Evaluation of a 4-steps-1-day whole body challenge protocol for the diagnosis of occupational asthma due to diisocyanates.

Inhalative challenges are important in the diagnosis of occupational asthma due to diisocyanates. As existing protocols are time-consuming and costly, it was the aim of this study to develop a short duration whole body exposure protocol. Ninety three subjects with suspected occupational diisocyanate-induced asthma and verified current or previous occupational exposure to diisocyanates and ten control subjects without diisocyanate exposure but with bronchial hyperresponsiveness were investigated. After baseline examination on the first day, subjects underwent a standardized whole body multiple-steps-1-day challenge with exposures of up to four times 30 min to concentrations of 5, 10, 20, and 30 ppb of the dominant diisocyanate used at work on the second day. Common spirometric and body plethysmographic parameters were used as positivity criteria. Overall, 14 subjects demonstrated a positive diisocyanate challenge, 19 were considered doubtful, and 60 were negative. All controls had negative challenges. Positive reactions occurred during the challenge (n = 10) or during follow-up (n = 4). Eight subjects showed >40 % fall of FEV1. These severe reactions occurred after 5 ppb (n = 2) or 10 ppb (n = 3), while isolated late reactions after 2 h of follow-up were not observed. Multivariate analysis showed an association between a positive challenge and both the degree of previous occupational exposure and the presence of baseline bronchial hyperresponsiveness. In summary, the proposed 4-steps-1-day diisocyanate challenge protocol induced pronounced bronchial reactions in a small number of subjects. As these reactions were more likely to occur after low concentrations, it is recommended to shift the initial concentration/dose step to lower exposures.

Comparison of different non-invasive methods for detection of allergic asthma.

Non-invasive methods to assess inflammation of lower airways are induced sputum (IS), exhaled nitric oxide (eNO), and exhaled breath condensate (EBC). Here we focused on the assessment of airway inflammation with a panel of non-invasive methods in health care workers (HCWs) with suspected latex allergy with and without current allergic respiratory symptoms about 10 years after the latex ban in German health care facilities. Seventy-seven non-smoking subjects were examined by skin prick test and specific IgE measurements, eNO, IS, and EBC. Sensitivity, specificity, and positive and negative predicted values for relevant biomarkers were calculated using current asthma symptoms as the gold standard. Twenty-nine subjects (38%) reported ongoing asthmatic symptoms (AS). In these subjects the EBC concentrations of nitrogen oxides (NO(x); p=0.027) and leukotriene B(4) (p=0.025) were significantly higher than in subjects without AS. In addition, in the subjects with AS the numbers of eosinophils (p=0.015) and the concentrations of IL-5 (p= 0.021) in IS samples were significantly higher than in the subjects without AS. A good correlation between several inflammatory markers in IS was detected. The maximum Youden Index was reached for IS total eosinophils ≥3.5·10(4) with a test efficiency of 0.72. In conclusion, non-invasive inflammatory monitoring with EBC and IS may assist the diagnosis of allergic asthma. Self-reported current asthmatic symptoms were reflected by eosinophilic inflammation and the best parameter to support the asthma diagnosis is a total number of eosinophils ≥3.5·10(4) in IS.

The German experience 10 years after the latex allergy epidemic: need for further preventive measures in healthcare employees with latex allergy.

OBJECTIVES: Powdered latex gloves or latex gloves with high allergen content are forbidden in Germany since 1998. It was the aim of this study to test the hypothesis that nationwide preventive measures enable health care workers with latex allergy to work without health risks about 10 years afterwards. METHODS: Ninety-one health care workers who had been reported to the accident insurance between 1996 and 2004 for occupational latex allergy were examined in 2007. The survey included a questionnaire, a physical examination, spirometry, methacholine testing, skin prick testing and serum IgE measurements to latex and environmental allergens. RESULTS: Recent work-related possibly allergic symptoms were reported by 32 subjects (35%), among them 18 subjects (20%) with symptoms of the eyes, nose or airways. Current sensitization to latex was detected in 61 subjects (67%), and 60 subjects (66%) were atopic. Eleven subjects (12%) showed mild airway obstruction, and 27 subjects (30%) were considered hyperresponsive to methacholine. Whereas overall recent symptoms of the eyes, nose or airways were associated with current latex sensitization (OR 4.5; 95% CI 1.3-16.2), this was not the case for objective outcome parameters (spirometry, bronchial hyperresponsiveness). CONCLUSIONS: Although most subjects had only mild disease, ongoing work-related symptoms of the eyes, nose or airways in a substantial number of subjects with latex allergy suggest the need for further secondary preventive measures in German healthcare.

Review of adverse health effects of odours in field studies.

UNLABELLED: Exposure to environmental odours from industrial and agricultural premises, in addition to inducing annoyance responses in a dose-dependent manner, have been shown to be either directly associated with gastric symptoms as well as general health-related complaints under extreme exposure conditions, or indirectly mediated through odour annoyance under moderate odour exposure conditions. OBJECTIVE: In order to examine the influence of hedonic tone (pleasantness-unpleasantness) and perceived odour strength (intensity) on symptom reporting the results of two pertinent field studies were analysed. METHODS: In the vicinity of six industrial plants (sweets, rusk, textile, seed-oil, fat, cast iron) and eleven livestock operations (poultry, pig, cattle) assessment of odour exposure was done by means of systematic field inspections. Effect assessment was done by means of direct interviews (industrial: N=1456, agricultural: N=1053) using questionnaires covering odour annoyance, symptom reporting and relevant covariates. DATA ANALYSIS: Multiple logistic regression analysis was used to establish dose-response associations between odour frequency, intensity and hedonic tone as independent variables and symptom reporting as dependent variable. RESULTS: Exposure-symptom associations are strongly influenced by hedonic tone, whereas intensity has no additional predictive value. Adding odour annoyance to the regression model shows that symptom reporting is exclusively mediated by annoyance.

Dialogue procedures for the management of odour related community conflicts.

In the German Guideline on Odour in Ambient Air (GOAA) statements about the degree of residential odour annoyance are based on the frequency of recognisable odours and hedonic tone. The use of olfactory standards to adequately estimate the annoyance impact is limited if, for example, worry about adverse health outcomes significantly influences the annoyance response of the population. This report introduces dialogue procedures as complementary measures to consider the complainants' subjective perceptions and worries adequately. At first, it is illustrated that odour exposure and number of odour complaints are not necessarily correlated. Then the "interest analysis" and the five steps of a dialogue procedure are presented. A dialogue procedure can be initiated in "quiet times" - where the focus is on trust building and on the development of adequate communication strategies to promote realistic risk reception - as well as in order to establish a successful conflict resolution process if the issue is complex and emotionally discussed. After that, two examples of handling odour complaints are shown. Finally, considerations applying dialogue procedures as a tool to advance odour annoyance mitigation are outlined.

Odour intensity and hedonic tone--important parameters to describe odour annoyance to residents?

The Guideline on Odour in Ambient Air has been in use for many years for odour regulation in Germany. The main parameter that the odour regulation authority has to take into account is the odour frequency expressed as odour hours per year. In the guideline, limit values are given for the maximum odour frequency per year. These limit values are based on field investigations in which significant relationships between odour impact and odour annoyance was found. In these investigations, odour intensity did not yield a better description of the degree of annoyance caused to the residents. The hedonic tone was not mentioned. In a new research project finished in 2003, the influence of odour intensity and hedonic tone, in addition to odour frequency, has been assessed. Two installations emitting pleasant odours, two emitting neutral and two emitting unpleasant odours, have been selected. In each case grid field measurements by a panel were carried out, and the annoyance of the residents was assessed using a special questionnaire. The results of this project are: (1) A new method to measure odour intensity and hedonic tone in the field with data record forms was developed and validated. With this method, reliable and reproducible results are obtained. (2) The parameter odour frequency based on the system of "odour hours" is suitable and sufficient to predict the odour annoyance caused by unpleasant/neutral odours. (3) In the case of pleasant odours, hedonic tone has an abundantly clear effect on the dose-response relationship between odour frequency and annoyance. Pleasant odours have a significant lower annoyance potential than unpleasant/neutral odours. (4) The odour intensity has no additional influence on this relationship. If odours are recognisable then they can cause annoyance.

Adverse effects of environmental odours: reviewing studies on annoyance responses and symptom reporting.

Air pollution control authorities dealing with odourous emissions from industrial, municipal and agricultural activities are often faced with many complaints from the public. In Germany, the Directive on Odour in ambient air provides a regulation system for the abatement of odour annoyance. Ambient air quality standards have been established based on investigations of the relationship between ambient odour load and community annoyance reaction. This paper describes a tool for the assessment of annoyance reactions, whereby degree of annoyance is correlated with ambient odour load. Systematic exposure response relations have been established for odour annoyance responses and symptom reporting for a variety of industrial sources. However, the precision of annoyance prediction from odour exposure measures rarely exceeds r2 = 0.17 in such studies. This is partly due to the fact that person-related factors, such as age, perceived health or stress coping styles, modify exposure response relations. The contribution of intensity and unpleasantness (hedonic tone) of ambient odours as modifying the annoyance reaction is currently investigated.