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.

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.

[Induction of occupational leucoderma and vitiligo. Can butylated hydroxytoluene induce vitiligo similarly to p-tert-butylphenol?]. / Beruflich bedingte Leukoderme und Vitiligo. Kann Butylhydroxytoluol ähnlich dem p-tert.-Butylphenol eine Vitiligo auslösen?

BACKGROUND: While vitiligo is usually idiopathic, some cases are caused by chemicals. If occupational exposure to p-tert-butylphenol (ptBP) leads to vitiligo, the legal requirements for occupational disease Nr. 1314 can be fulfilled in Germany. Chemicals of similar structure can induce local and more widespread symmetrical depigmentation with genital involvement, making the differential diagnosis more complicated. Occupationally caused depigmentation from other chemicals can also be treated according to § 9 sec. 2 of the occupational disease regulations. MATERIALS AND METHODS: Some substances can cause leukoderma only in animals; others in animals and humans; in some cases systemic vitiligo-like changes develop. The effects on human skin cannot always be predicted from the structural analogies of the involved chemicals. RESULTS: Based on a case of occupational exposure to butyl hydroxytoluene with possible induction of vitiligo, a careful updated literature analysis of substances inducing depigmentation is presented. CONCLUSION: The literature contains discrepancies in the evidence for the ability of some substances-especially BHT-to cause vitiligo. A more exact analysis indicates that BHT does not cause vitiligo or leukoderma.

Modular chemistry with aluminum phosphanides: cluster formation of (AlP)n (n=3,6,7), Al4P3, and Al4Li4P6 frameworks.

The Al3P3 heterocycle 1 is formed in 94% yield by the reaction of the primary silylphosphane 6a with Me3Al in toluene at 70 degrees C. While 1 crystallizes in an isomerically pure form, in which the six-membered Al3P3 ring prefers the chair conformation and the P-H hydrogen atoms adopt exo positions, it isomerizes in solution to give different diastereomers as shown by 1H and 31P NMR spectroscopy. Intermolecular cyclocondensation of 1 at 110 degrees C in toluene leads, under liberation of methane, to the distorted hexameric-prismatic (AlP)6 cluster 2 in 98% yield. The capability of 1 to function as a building block was further used for the synthesis of the solvent-separated ion pair [Li(thf)2]+ [(Me2Al)4(PR)3]- (3) which was prepared by a one-pot reaction of 1 with nBuLi and Me2AlCl in 15% yield. The structure of 3 was established by an X-ray diffraction analysis. Double deprotonation at phosphorus in 1 with RPLi2 (R = iPr3Si) (molar ratio 1:2), and subsequent transformation of the reaction mixture with Me3Al afforded the novel donor-solvent-free cluster 4 in 62% yield. The latter consists of a rhombododecahedral Al4Li4P6 framework, in which the Li centers are three-coordinate. The reaction of the silylphosphane 6b with the trimethylamine adduct of alane furnishes not only the hexamer (RPAIH)6 (R = (iPrMe2C)-Me2Si) but also the corresponding heptamer 5, which has a nonregular polyhedral (AIP)7 framework and represents the first cluster of this type.