Experimental inhalation of fragrance allergens in predisposed subjects: effects on skin and airways.

BACKGROUND: Exposure to fragrances is increasingly encountered in the environment. Some fragrances are known to be important skin and potential airway sensitizers. OBJECTIVES: We investigated whether patients with contact allergy to isoeugenol (ISO) or hydroxyisohexyl-3-carboxaldehyde (HICC) would react to inhalation exposure at the level of the airways and skin. METHODS: Eleven patients sensitized to ISO and 10 patients sensitized to HICC were exposed for 60 min to 1000 microg m(-3) of these compounds in an exposure chamber at rest, and to geraniol 1000 microg m(-3) as a control. Patients wore protective clothing to prevent skin exposure. Assessments were performed prior to exposure, and immediately, 2, 5, 24 and 72 h afterwards. RESULTS: There were no significant changes in lung function but a tendency towards an increased bronchial hyper-responsiveness after exposure to any of the compounds. Laboratory parameters of inflammation did not indicate responses. Single patients reported respiratory symptoms unrelated to objective measures. In contrast, the observed skin symptoms corresponded to the patients' specific sensitization. Four patients reported symptoms compatible with delayed-type hypersensitivity, and two demonstrated a flare after ISO. On re-exposure they did not respond to a lower, more realistic level of ISO. CONCLUSION: Inhalation of high concentrations of fragrance contact allergens apparently poses a risk for some patients of developing manifest haematogenic contact dermatitis, while the changes in the respiratory tract are limited to symptoms in some subjects without objective changes.

Field intercomparison of diffusive samplers for measuring ammonia.

Agricultural production systems are recognised as a major source of atmospheric ammonia. Deposition of ammonia and ammonium may contribute to undesired changes in oligotrophic ecosystems. The continuous measurement of atmospheric ammonia requires expensive and sophisticated techniques and is performed only in a very restrict number of ambient air stations in Europe. Therefore, the application of passive samplers, which have the advantage of being easy to handle and cost-efficient, is useful. In the past the comparability of different passive samplers must be considered as rather scarce. In a joint European project under the leadership of the GSF-Forschungszentrum für Umwelt und Gesundheit, Neuherberg, in 1997 a comparison of different passive ammonia monitoring methods was carried out in a prealpine rural site near Garmisch-Partenkirchen. It was considered valuable to include not only well established systems but also methods still being developed. For the comparative test ten working groups with different methods took part. A wet annular denuder system, which has been developed by the Netherlands Energy Research Foundation for on-line measurement of atmospheric ammonia, served as reference of passive methods. The experiment, which started in June and finished in December, showed that most of the passive samplers fulfil the requirements and can be recommended for further measurements. Additional measurements of meteorological parameters were performed to check the influences of different weather conditions on passive sampling.

Biological monitoring of hospital pharmacy personnel occupationally exposed to cytostatic drugs: urinary excretion and cytogenetics studies.

For evaluation of the risk borne by hospital pharmacy personnel exposed to antineoplastic agents, the incorporation of cyclophosphamide, ifosfamide, and platinum-containing drugs was quantified by the determination of urinary concentrations. In addition, the induction of micronuclei (MN) and sister-chromatid-exchange (SCE) rates in peripheral blood lymphocytes were studied for correlation with the urinary excretion of cytostatic drugs. Cyclophosphamide and ifosfamide were determined in 24-h urine samples using gas chromatography with electron capture (detection limit 2.5 micrograms/l). Voltammetric analysis enabled the determination of platinum concentrations of 4 ng/l. Heparinized blood (20 ml) was drawn and lymphocytes were cultured for MN and SCE studies. In all, 13 hospital pharmacists and pharmacy technicians regularly involved in the preparation of cytostatic drugs participated in this investigation (7 persons represent a follow-up group). All subjects applied standard safety precautions, including the use of a vertical laminar air-flow hood, protective gowns, and latex gloves. On the day of urine sampling an average of 4,870 mg cyclophosphamide, 5,580 mg ifosfamide, and 504 mg platinum-containing drugs were handled. The excretion of 5 and 9 micrograms cyclophosphamide/l urine was measured in two samples, respectively. An elevated level of urinary platinum was found in one pharmacist (22.3 ng/g creatinine) in comparison with a nonexposed control group. Mean frequencies of MN and SCE did not differ significantly between the drug exposed group and control group. The employees who had incorporated chemotherapeutic agents were part of the follow-up group and, thus, particularly cautious and sensitive to a possible hazard. The results emphasize the necessity of improving personal protection of hospital pharmacy personnel occupationally exposed to cytostatic drugs and support the importance of biological monitoring. In an ongoing project in our department the sources of contamination are being investigated parallel to biological monitoring so as to determine critical situations and improve personal protection.

Biological monitoring of cyclophosphamide and ifosfamide in urine of hospital personnel occupationally exposed to cytostatic drugs.

The occupational exposure of 21 nurses and pharmacy personnel from eight hospitals to cyclophosphamide and ifosfamide was determined by quantifying the amount of the drugs handled and by measuring the urinary excretion of the unmetabolised substances. Preparing antineoplastic drugs for intravenous treatment was the major task of all study participants. Twenty four hour urine was collected on days when cyclophosphamide and/or ifosfamide were mixed, on average 3900 mg cyclophosphamide and/or 5900 mg ifosfamide. The analyses were performed by gas chromatography with electron capture, detection limit 2.5 micrograms/24 hour urine. Despite standard safety precautions, including a vertical laminar air flow safety cabinet and gloves, cyclophosphamide was detected in 12 of 31 and ifosfamide in four of 21 urine samples on days when the drugs were handled. Excretion of cyclophosphamide ranged from 3.5 to 38 micrograms/24 h (mean 11.4 micrograms/24 h) urine, ifosfamide from 5 to 12.7 micrograms/24 h (mean 9 micrograms/24 h) urine. Based on an excretion rate of 11.3% unmetabolised cyclophosphamide, the average amount excreted corresponded to an uptake of 101 micrograms cyclophosphamide. For ifosfamide the mean quantity incorporated was 20 micrograms assuming that 45% of the drug was excreted. Pertaining to the doses handled, the uptake of cyclophosphamide and ifosfamide was estimated to be approximately 0.0025% and 0.0004% respectively. Despite time-consuming purification procedures, gas chromatographic analysis is a suitable method for monitoring personnel occupationally exposed to cyclophosphamide and ifosfamide and is a major contribution to the evaluation of potential health risks of exposed personnel.

Alterations in lung function due to mixtures of organic solvents used in floor laying.

To determine the short-term and long-term effects of organic solvents on the respiratory tract, 26 male floorlayers exposed to organic solvents were compared with 36 persons unexposed to such substances. The investigation primarily included a detailed history, determination of solvent concentration in the air inhaled by the workers, long-term ECG during the entire shift and lung-function test (vital capacity, forced expiratory volume in one second, flow volume curve) as well as non-specific bronchial inhalation challenge using a 3% acetylcholine aerosol before and after the shift. The floorlayers were primarily subjected to inhalative exposure to adhesives containing mixtures of toluene, petroleum hydrocarbons, ethyl acetate, methanol and acetone or one of these substances alone. This frequently resulted in short-term value limit excesses, especially in the MAK value (standardised threshold concentration in Germany) for toluene, which is a prime component of neoprene glue. Of the 26 floorlayers, 6 complained of breathlessness and coughing, whereas 13 suffered from nasal discharge and blockage--symptoms closely related to work. The smokers in this group showed a decline in lung function during the shift--especially in the forced expiratory volume in 1 s (FEV1)--as compared with the non-smokers in this group and the persons in the control group. This probably due to the combination of noxious substances. A strong correlation between occupational age and changes in lung function was observed: the occupationally youngest workers demonstrated the highest decrease in values during the course of the shift. There was no evidence of either obstructive or restrictive respiratory disorders or of marked deviation from the European Community for Coal and Steel (ECCS) references.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnosis of irritative-toxic isocyanate asthma with the isocyanate exposure test]. / Diagnose des irritativ-toxischen Isozyanat-Asthmas mittels Isozyanat-Expositionstest.

We investigated 10 healthy control subjects, 15 asthmatics without occupational exposure to isocyanate, and 45 "isocyanate workers" with workplace-related respiratory symptoms. In none of the cases did the skin test or the IgE-RAST reveal a type I sensitisation to isocyanate. The investigation programme included a lung function test, provocation with metacholine or acetylcholine, and an isocyanate challenge test under controlled clinical conditions. A total of 17 "isocyanate workers", and 1 asthma patient with no occupational exposure to isocyanate revealed a positive bronchial obstructive reaction to the isocyanate challenge test. In 10 of the patients, the MCH (ACH) test was positive; 2 were chronically obstructive, but 6 patients showed no signs of bronchial hyperreactivity. No significant differences in the severity of the bronchial obstructive reaction induced by isocyanate exposure were observed between patients with and those without bronchial hyperreactivity. In the group of "isocyanate workers", the isocyanate challenge test was observed to be superior to the MCH (ACH) provocation test in terms of sensitivity (0.68 versus 0.62) and specificity (1.0 versus 0.61), this difference being more obvious in the overall group (sensitivity 0.71 versus 0.62; specificity 0.98 versus 0.49).

Determination of toluene diisocyanate in air by HPLC and band-tape monitors.

An improved HPLC method was developed for determining the atmospheric concentration of toluene diisocyanate (TDI). 1-(2-pyridyl)-piperazine in toluene was used as reagent absorber solution together with reversed phase chromatography and a simple efficient buffer system (0.1% trifluoroacetic acid--acetonitrile, 85:15%) in an isocratic elution mode. The values for atmospheric TDI concentration obtained with two continuous band-tape monitors were checked using the values from HPLC as reference. Under identical experimental conditions the two instruments (both model 7005) gave readings varying by more than 100%. At low humidity the band-tape values were considerably lower than the HPLC values. At an absolute humidity of 11.7 g H2O/m3 (58% relative humidity) the value from instrument 1, but not instrument 2, agreed with those from HPLC. The values obtained with band-tape devices in the continuous monitoring of TDI concentration in places of work, or epidemiological studies, should be assessed with caution. HPLC offers a useful reference method for monitoring the accuracy of such devices.

The pharmacokinetics of the bronchosecretolytic ozothin after intravenous injection.

Blood concentrations of the terpenes myrtenal, myrtenol, pionocarveol, verbenon and terbinhydrate in ozothin were investigated as a function of time after intravenous injection of 10 ml ozothin in 36 subjects. On each occasion 10 ml of the terpene mixture was injected into the inside right elbow. During the first 60 minutes after injection several 7 ml samples of citrate blood were withdrawn from the inside left elbow, immediately spun down and analysed by gas chromatography. Elimination of the terpenes from the blood during the first 10 minutes after injection appeared to follow a half-life time of three to four minutes with a second half-life time of 60 to 65 minutes. The concentration of these terpenes in expired air was determined in 27 subjects. Approximately 7% of the substances were eliminated via the lungs during the first 60 minutes. In a further series of experiments the concentration in subcutaneous fat during the first 24 hours after injection was studied. The whole terpenes concentrations range from 2.4 ng terpenes/g fat tissue to 0.8 ng terpenes/g fat at 24 hours.

Acute airway obstruction followed by hypersensitivity pneumonitis in an isocyanate (MDI) worker.

A rare combination of an acute asthmatic reaction followed by hypersensitivity pneumonitis after exposure to diphenylmethane diisocyanate (MDI) is described. The patient, who was nonatopic and did not show bronchial hyperreactivity to metacholine, was occasionally engaged at the workplace in spraying a mixture of MDI and polyol to produce a polyurethane foam for use as a packing material. Challenge testing by MDI resulted first in a significant immediate bronchial obstruction indicated by decreases in specific airway conductance and forced expiratory volume at 1 s, and then in a significant decrease in vital capacity and diffusing capacity, associated with systemic reactions such as anorexia, malaise, fever, and leukocytosis three to eight hours after challenge. Challenge testing by toluene diisocyanate produced a mild systemic reaction. This finding, as well as the detection of specific IgG antibodies to various isocyanate-human serum albumin conjugates, suggests immunologic cross-reactivity between different isocyanates. Neither skin testing nor the radioallergosorbent test indicated a type I sensitization. After contact with isocyanates was terminated, the disease did not recur.

[On the pathogenesis of isocyanate-induced asthma]. / On the pathogensis of isocyanate-induced asthma.

3 asthmatic patients, occupationally exposed to vapors of toluylene diisocyanate (TDI), responded with a moderate to strong elevation of airway resistance up to the 26th h after inhalation challenge by 0.006--0.02 ppm TDI. No changes in chest radiographs and in DLCO were found. In none of the patients' sera, isocyanate-specific antibodies could be detected by RAST and Ouchterlony test. Change of job resulted in one case in an immediate interruption of the asthmatic symptoms, whereas in 2 patients recovery was slow over a period of 3 to 8 months and not complete. Our investigations suggest a toxic effect of isocyanates, which depends on their concentrations, and an important pharmacological reaction; but, up to now, there were no signs of allergic mechanisms.