Arch Dermatol Res (1999) 291 : 425–431
© Springer-Verlag 1999
O R I G I N A L PA P E R
Lars P. Christensen · Henrik B. Jakobsen · Evy Paulsen · Lene Hodal · Klaus E. Andersen
Airborne Compositae dermatitis: monoterpenes and no parthenolide are released from flowering Tanacetum parthenium (feverfew) plants
Abstract The air around intact feverfew (Tanacetum parthenium) plants was examined for the presence of airborne parthenolide and other potential allergens using a high-volume air sampler and a dynamic headspace technique. No particle-bound parthenolide was detected in the former. Among volatiles emitted from the aerial parts of feverfew plants and collected by the dynamic headspace technique a total of 41 compounds, mainly monoterpenes, were identified and quantified by GC and GC-MS. α-Pinene, camphene, limonene, γ-terpinene, (E)-β-ocimene, linalool, p-cymene, (E)-chrysanthenol, camphor and (E)-chrysanthenyl acetate were the predominant monoterpenes accounting for nearly 88% of the total volatiles emitted. The average total yield of volatiles emitted over 24 h was 18,160 ng/g fresh weight of leaves and flowers, corresponding to the emission of approximately 8 mg volatiles per day from one fullgrown feverfew plant. No parthenolide or other sesquiterpene lactones were detected. The present investigation does not support the theory of airborne sesquiterpene lactone-containing plant parts or of direct release of sesquiterpene lactones from living plants as the only explanations for airborne Compositae dermatitis. Potential allergens were found among the emitted monoterpenes and their importance in airborne Compositae dermatitis is discussed.
L. P. Christensen · H. B. Jakobsen Department of Fruit, Vegetable and Food Science, Danish Institute of Agricultural Sciences, Kirstinebjergvej 10, DK-5792 Aarslev, Denmark E. Paulsen · K. E. Andersen (쾷) Department of Dermatology, Odense University Hospital, DK-5000 Odense, Denmark e-mail:
[email protected], Tel. +45 65412700, Fax +45 66123819 L. Hodal The Danish Asthma and Allergy Association, Hovedvejen 9 C, DK-2600 Glostrup, Denmark
Key words Allergic contact dermatitis · Dynamic headspace · High-volume air sampler · Volatiles
Introduction Compositae dermatitis is most often an allergic contact dermatitis with a chronic and relapsing course triggered by plants of the Compositae (Asteraceae) family. The main allergens are the lipophilic sesquiterpene lactones (SLs) present in the lipid-soluble part (oleoresin fraction) of the plant [27, 29]. The SLs are produced in trichomes (glandular hairs) on the surface of some Compositae species [18]. More than 1350 SLs have been isolated from Compositae and several hundred of them are potential contact allergens. The diagnosis of Compositae allergy was previously based on clinical suspicion and patch testing with plant material or extracts. However, the development of the SL mix patch test material (containing equimolar concentrations of alantolactone, costunolide and dehydrocostus lactone) has made routine testing of eczema patients possible [6], and the mix is now included in the European standard patch test series [4]. The frequency of Compositae allergy varies from country to country depending on various factors such as geographically determined variation in the flora, the frequency of gardening as a hobby and floristry as a trade. High figures have been reported on routine testing with the SL mix in Amsterdam (the Netherlands) and Odense (Denmark) [32], both centres for the pot plant and cut flower industries. The clinical aspects of Compositae dermatitis with widespread dermatitis affecting light- and air-exposed skin of the hands, arms, neck and face suggest that, besides direct and indirect contact with parts of the plants, contact with airborne allergens is a possible source of exposure [20, 30]. This is also supported by the finding that many patients improve when they move from rural to urban areas [12]. Since air drying of plant material does not change the SL content [18], airborne dust particles containing allergens have been suspected as a cause of Com-
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positae dermatitis [27, 33]. SLs in dust particles around dead and dry material of Compositae plants have been reported [13], whereas airborne SLs around living plants, which are also suspected to cause airborne Compositae dermatitis, have so far not been detected. Clinically, Compositae-sensitive patients are affected from early spring to late autumn. The plants are not withered in the spring and additionally patients often experience flares in summer when they are near flowering plants. Feverfew (Tanacetum parthenium) has been considered as a cause of airborne Compositae dermatitis and seems to be a common sensitizer, and the major allergen in feverfew is parthenolide (PHL) [7, 16, 17, 27]. Based on the above-mentioned clinical observations and the lack of proof of the airborne dust theory, the aim of the present study was to test both the last-mentioned theory and alternative ways of exposure to PHL and other potential allergens from living feverfew plants. We used a high-volume air sampler and dynamic headspace analysis to collect particles and volatiles, respectively, around the plants.
Materials and methods
leaves, the inflorescence was guided through the socket at an early development stage and allowed to develop above the inverted lid for 1 week before sampling [23]. The space between the stem and stopper was sealed with vaseline. Headspace samples from the empty reaction vessel containing vaseline as sealing material were collected to test for impurities. The air flow in the glass bulb was 400 ml/min and was achieved by a Miniport N 75 KN18 vacuum pump (KNF Neuberger, Freiburg, Germany). Contaminating volatiles were removed from the incoming air by passing it through a cylindrical steel container containing 250 ml activated charcoal granules (ML Gas Puritube, Mikrolab, Aarhus, Denmark). The air temperature in the glass bulb was kept at 20 °C by passing water through the double-walled reaction vessel. The cooling water was supplied from a thermostated waterbath. The relative humidity was kept at 60% with an accuracy of ± 10% and the light intensity was 250 µmol quanta/m2 per s2. Volatiles were collected in glass tubes (4 mm i.d., length 18 cm) equipped with 200 mg Porapak Q 50–80 mesh (Waters, Milford, Mass.) inserted between two silane-treated glass-wool plugs. A six-channel clock controlling six magnetic valves inserted between the glass bulb and the pump allowed automatic collection on six columns mounted parallel in the flow path using Omnifit Teflon fittings. The collection time on each column was 4 h and in that period of time no ‘breakthrough’ of volatiles could be detected. The volatiles were collected over a 24-h period starting at 8 a.m. Volatiles were eluted from the Porapak columns with 2 ml redistilled CH2Cl2. For quantification, (E)-2-octenal (3400 ng in 20 µl CH2Cl2) was added to the headspace samples prior to evaporation of excess solvent under a nitrogen flow to a final volume of 50 µl.
Analysis for parthenolide in high-volume air sampler filters A high-volume air sampler was placed in a garden 1 m from a group of flowering feverfew plants. The sampler was mounted with glass fibre filters capturing particles down to 0.01 µm in size. The air sampler collected airborne particles 24 h a day for 22 days in September-October 1993, and for 20 days in July-August 1994. The filters were changed once a day and kept in a freezer until analysis. The filters were extracted with ether or chloroform and the eluate was analysed by gas chromatography-mass spectrometry (GCMS) for PHL and other SLs. GC-MS analyses were performed on a Varian gas chromatograph, interfaced with an SSQ 710 Finnigan MAT single quadrupole mass spectrometer operated at 70 eV. GC separation of PHL was performed on a 30 m OV-101 capillary column. The oven temperature was programmed to be isothermal for 5 min at 80 °C and to increase from 80 °C to 250 °C at a rate of 8 °C/min. Helium carrier gas was used at a flow rate of 1 ml/min. The retention time for PHL was 21.10 min and the detection limit approximately 0.2 ng PHL/µl. Plant material for headspace experiments Three specimens of T. parthenium (L.) Schultz Bip. (syn. Chrysanthemum parthenium (L.) Bernh.) were grown in a greenhouse at 17–23 °C in 20-l pots and watered daily. One week before sampling the plants were subjected to a 16-h photoperiod starting at 8 a.m. Artificial light was supplied by a Philips HPI-T 400-W lamp to ensure a sufficient light intensity in the photoperiod. Since humans are exposed to feverfew volatiles from all parts of the plants, the volatile compounds emitted from the entire aerial section of living feverfew plants were examined. Collection of volatiles Volatiles emitted from T. parthenium were collected by a dynamic headspace technique as described by Jakobsen [22] and Jakobsen and Olsen [23], with a few alterations. One inflorescence with 15–20 flowers was measured in each trial and was guided into a double-walled 5-l reaction vessel through a 34/35 mm socket in the inverted lid. In order to prevent damage to the flowers and
Analysis of volatiles A Hewlett-Packard 5890 gas chromatograph (Hewlett-Packard, Avondale, Pa.) equipped with a flame ionization detector (FID) was used. Volatiles were separated on a 50 m × 0.25 mm (i.d.) CBWax 52 CB column (df = 0.20 µm; Chrompack cat no. 7723) or on a 60 m × 0.25 mm (i.d.) HP-Innowax column (df = 0.25 µm; HP part no. 19091N-136). The oven temperature was programmed to be isothermal for 1.5 min at 32 °C, then increase from 32 °C to 40 °C at a rate of 2.7 °C/min, then isothermal at 40 °C for 10 min, then increase from 40 °C to 200 °C at a rate of 3 °C/min, then increase from 200 °C to 220 °C at a rate of 10 °C/min, and then finally isothermal at 220 °C for 12 min. Helium carrier gas was used at a flow rate of 1 ml/min with a splitless purge time of 75 s. The injection temperature was 200 °C and the FID temperature 230 °C. Yields of individual volatiles in the Porapak eluates were estimated from FID peak areas of components and the standard, (E)-2octenal, used in the GC analyses. The response factor was set to 1 for all compounds. Several compounds which occurred in all the entrained samples and controls were not quantified as they were probably artifacts originating from the breakdown of sample tube adsorbant. These included benzene, toluene, dimethylbenzene, styrene, trimethylbenzene and other non identified compounds. GC retention indices (Kovats indices) were determined externally with a series of n-alkanes (C9–C25) [8, 38] on a 60 m × 0.25 mm (i.d.) HP-Innowax column. The GC conditions were the same as described above with the exception of the oven temperature which was approximately linearly programmed: 32 °C (1 min isothermal) to 220 °C at 2 °C/min, and finally isothermal at 220 °C for 40 min. A Varian Saturn 2000 ion trap mass spectrometer operated at 70 eV and interfaced to a Varian Star 3400 CX gas chromatograph equipped with a 60 m × 0.25 mm (i.d.) HP-Innowax column was used for GC-MS analysis of volatiles. The GC conditions were the same as described above for the quantification of volatiles or the determination of the GC retention indices. Compounds were identified from the GC retention data and by comparing the mass spectra of the entrained compounds with those of standard materials (Table 1), unless otherwise noted. Authentic compounds were supplied by Aldrich (Germany), Fluka Chemie AG (Switzerland), and TCI Tokyo Organic Chemicals (Japan).
427 Table 1 Volatiles emitted from Tanacetum parthenium (L.) Schulz Bip. in situ Peak no.
Compounda
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Tricyclene α-Pinene Camphene β-Pinene Sabinene 3-Carene α-Phellandrene β-Myrcene α-Terpinene Limonene β-Phellandrene (Z)-β-Ocimene γ-Terpinene (E)-β-Ocimene p-Cymene 2-Methyl-6-methylene-1,7octadien-2-onee (Z)-3-Hexenyl acetate 6-Methyl-5-hepten-2-one (Z)-3-Hexenol (E)-Chrysanthenole (Z)-Chrysanthenole α-Copaene Camphor (E)-Chrysanthenyl acetate Unidentified monoterpene Linalool Bornyl acetate (E)-β-Caryophyllene Terpinene-4-ol Unidentified monoterpene α-Humulene β-Farnesene Borneol Unidentified sesquiterpene Benzyl acetate α-Farnesene Bornyl isovaleratee Methyl salicylate Phenethyl acetate Benzyl alcohol Phenethyl alcohol Caryophyllene epoxide Eugenol methyl ether Eugenol Indol
17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
Total a Identification
Yield (ng)b
Rt (min)c
KIc
Mass spectral ions (m/z)d
9.1 235.8 803.4 54.9 34.5 12.2 71.3 44.1 7.0 114.3 9.4 43.7 244.7 659.6 797.9 6.4
10.48 11.17 13.29 15.53 16.50 18.13 19.20 19.47 20.15 21.37 21.91 24.16 24.58 25.27 26.35 29.03
1008 1023 1065 1103 1121 1149 1165 1170 1180 1197 1206 1242 1248 1259 1274 1313
93, 91, 77, 79, 121, 39, 105, 136 93, 91, 77, 79, 39, 105, 121, 136 93, 121, 91, 79, 77, 67, 107, 39, 136 93, 91, 77, 39. 79, 41, 121, 136, 107 93, 91, 77, 79, 39, 136, 41, 121, 107 93, 91, 77, 79, 121, 39, 105, 136 91, 93, 77, 39, 67, 136, 107, 121 93, 41, 39, 91, 69, 77, 121, 107, 136 121, 93, 91, 136, 77, 105, 39 67, 93, 79, 91, 39, 77, 107, 121, 136 93, 91, 77, 79, 39, 136, 121 93, 91, 77, 79, 39, 105, 121, 136 93, 91, 77, 136, 121, 79, 105, 39, 65 93, 91, 79, 77, 39, 105, 121, 136 119, 91, 134, 117, 77 69, 41, 39, 135, 107, 121, 150
56.7 ± 33.4 54.7 ± 5.4 103.1 ± 58.4 1299.4 ± 947.8 45.0 ± 16.1 84.7 ± 69.4 4845.5 ± 2716.9 2856.2 ± 1712.6 54.3 ± 25.1 211.7 ± 139.9 91.6 ± 38.7 281.4 ± 123.5 54.3 ± 29.9 85.6 ± 51.6 15.7 ± 3.1 319.5 ± 176.1 6.6 ± 5.2 Tracef Trace 251.6 ± 140.0 102.8 ± 84.3 16.6 ± 4.4 23.5 ± 6.6 Trace 13.5 ± 8.9 12.4 ± 6.4 9.9 ± 3.3 Trace Trace
29.87 31.15 34.47 39.56 40.16 40.75 42.58 43.54 44.96 45.13 46.74 47.44 48.29 50.37 51.86 52.07 54.27 55.62 56.10 56.90 57.12 58.65 60.95 64.45 66.24 69.42 71.61 79.33 92.13
1326 1345 1393 1472 1481 1489 1518 1534 1557 1559 1584 1595 1609 1645 1669 1673 1709 1733 1742 1756 1759 1786 1827 1890 1924 1985 2028 2184 2465
67, 43, 82, 142 43, 108, 41, 69, 55, 111, 126 67, 39, 41, 82, 55 81, 121, 67, 109, 95, 91, 39, 137, 152 81, 121, 109, 67, 39, 137, 152 161, 119, 105, 91, 77, 133, 39, 204, 189 95, 108, 81, 152, 39, 55, 67, 137, 123 119, 93, 43, 134, 91, 81, 109, 194 43, 93, 109, 121, 136, 154 (?) 43, 93, 71, 55, 121, 109, 136 95, 93, 121, 136, 43, 67, 108, 154, 196 91, 133, 105, 39, 79, 67, 119, 161, 147, 189, 175, 204 71, 93, 43, 111, 67, 55, 136, 154 43, 134, 109, 91. 151, 119, 81, 67 93, 91, 147, 121, 79, 67, 105, 204, 161, 189, 133 69, 41, 93, 133, 120, 161, 79, 105, 147, 204, 189 95, 67, 39, 55, 121, 109, 136 119, 91, 39, 77, 105, 161, 189, 204 108, 91, 150, 79, 43, 77, 65 93, 91, 123, 107, 41, 77, 119, 105, 69, 133, 161, 189, 204 95, 136, 93, 57, 121, 41, 109, 67, 154, 238 120, 92, 152, 65 104, 43, 91, 65, 77 79, 77, 108, 107, 51, 91, 63, 65 91, 92, 65, 122, 51 91, 79, 39, 67, 107, 121, 55, 135, 149, 161, 177, 187, 205, 220 178, 163, 107, 147, 91 164, 149, 131, 103, 77, 137, 91, 121 117, 90, 89, 63
124.2 ± 680.6 ± 2149.2 ± 133.0 ± 91.7 ± 31.8 ± 87.0 ± 61.2 ± 10.6 ± 314.7 ± 33.8 ± 61.8 ± 280.9 ± 941.9 ± 2247.9 ± 13.4 ±
18160
± 9254
based on comparison of mass spectral data and GC data from plant components with those from authentic compounds unless otherwise noted b Yield of volatiles emitted in 24 h in ng/g fresh weight of leaves and flowers (means ± SD, n = 3) c Retention time (R ) and Kovats index (KI) determined on a 60 m × t 0.25 mm HP-Innowax column (see Materials and methods)
d Fragmentation ions, base peak and characteristic ions in decreasing order of relative abundance. Molecular ion boldfaced e No standards available. Compound’s mass spectrum consistent with published spectrum given in the NIST/EPA/NIH mass spectral database (version 4.0, 1992) and/or in reference [9] f Trace = integrated but less than 5 ng/g fresh weight of leaves and flowers
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Fig. 1 GC-MS chromatogram of the volatiles entrained from aerial parts of Tanacetum parthenium in situ. Peak numbers refer to those in Table 1 and ISD to the internal standard, (E)-2-octenal. Peaks labelled B refer to background contaminants. For chromatographic conditions see Materials and methods (determination of GC retention indices)
Analysis for parthenolide in headspace samples Headspace samples with 100 mg PHL in the glass bulb were collected at 20 °C and 25 °C. The collecting time on each column varied from 4 to 36 h. All the other parameters were the same as those described above (see Collection of volatiles). The headspace samples were analysed by GC-MS on a 30 m × 0.25 mm (i.d.) Restek RTX/5 (df = 0.25 mm) column. The oven temperature was programmed to be isothermal for 1 min at 32 °C, then increase from 32 °C to 260 °C at a rate of 10 °C/min, and finally isothermal at 260 °C for 20 min. Under these conditions the retention time for PHL was 24.85 min.
Results The concentration of PHL in the aerial parts of the investigated feverfew plants was c. 0.15% of dry weight as determined by GC and analytical reversed-phase HPLC, using acetonitrile-water as mobile phase [1, 19]. PHL was extracted with ether or water from unchopped leaves and
isolated by preparative thin-layer chromatography [15] and identified by GC-MS, electron ionization mass spectrometry, and 1H-NMR. All 42 filters from the high-volume air sampler were analysed for PHL by GC-MS. However, no particlebound PHL was detected in the filters. Further, PHL could not be detected in the headspace samples with pure PHL present in the vessel or in the samples collected from the living plant, although the lower detection threshold was c. 0.02 ng PHL/µl on the GC and GC-MS apparatus used. Some samples from the headspace analysis gave a minute peak in the GC chromatograms with a retention time corresponding to PHL. However, the presence of PHL could not be confirmed by GC-MS. The possibility that other allergenic compounds might be responsible for airborne Compositae dermatitis was therefore investigated by analysing the volatile compounds emitted from feverfew plants. A typical GC-MS chromatogram of a headspace sample collected over 24 h revealed the presence of over 120 different compounds (Fig. 1). However, since it was possible that a number of these compounds originated from sources other than the plant, headspace samples were collected when no plant was present. The contaminants included aliphatic and aromatic hydrocarbons and aldehydes of which some originated from the breakdown of sample tube adsorbant. Other contaminants from the analyti-
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day. The total emission of volatiles was normally highest at noon, i.e. between 12 a.m. and 4 p.m., and for α-pinene, camphene, and camphor the emission was over three times higher than the emission at the time of day with the lowest emission (Fig. 2).
Discussion
Fig. 2 Rhythmic emission of the monoterpenes α-pinene (첸), camphene (쑗) and camphor (왕) during 24 h. Each value represents the amount collected in 4 h. The rhythm was repeated three times with a standard deviation of approximately 30% for all compounds
cal process included siloxanes originating from the chromatographic column. When the presence of the above mentioned artifacts was taken into consideration it was found that feverfew emitted a total of 45 compounds of which 41 were identified. The GC-MS data of the four non-identified compounds indicated that they were of terpenoid origin. The characteristic mass spectral ions and retention indices of the emitted volatiles are shown in Table 1. Both qualitatively and quantitatively the monoterpenes dominated in the headspace. The predominant monoterpenes were α-pinene (3.8%), camphene (11.8%), limonene (1.7%), γ-terpinene (1.5%), (E)-β-ocimene (5.2%), linalool (1.4%), p-cymene (12.4%), (E)-chrysanthenol (7.2%), camphor (26.7%) and (E)-chrysanthenyl acetate (15.7%). When these emissions were combined they constituted nearly 88% of the total volatiles emitted from feverfew. Sesquiterpenes were also found and accounted for 3.8% of the volatiles. The most abundant sesquiterpenes were α-farnesene, β-farnesene and (E)-βcaryophyllene. Another class of emitted compounds comprised wellknown aromatics such as benzyl alcohol, phenethyl alcohol and eugenol. The aromatics were, however, only present in minute amounts in the headspace (Table 1). Finally, fatty acid derivatives comprising (Z)-3-hexenol and (Z)-3-hexenyl acetate constituted only 0.9% of the total volatiles (Table 1). The average total yield of volatiles emitted from feverfew plants at 20 °C with a 16-h photoperiod starting at 8 a.m. were about 18,160 ng/g fresh weight of flowers and leaves over 24 h (Table 1), i.e. one natural growing feverfew plant (fresh weight of leaves and flowers c. 400 g) in a typical Danish summer would emit c. 8 mg volatiles per
The common perennial herb fewerfew (Tanacetum parthenium) has been the subject of much interest because of its sesquiterpene constituents [1, 3, 11, 28, 35]. Some of the detected SLs are known to exhibit cytotoxic, antimicrobial and plant growth inhibitory activities, and to be responsible for allergic contact dermatitis in humans [34]. The germacranolide PHL is the predominant SL found in Northern- and Central European-grown feverfews [1, 3, 15, 19], whereas Yugoslavian- and Mexicangrown feverfews contain eudesmanolides and guaianolides, but no PHL [35, 36]. In the Northern and Central European feverfews the content of PHL varies considerably in leaves from 0.05% to 0.9% of dry weight [1, 3, 15, 19]. For comparison the aerial parts of Danish fewerfew contained 0.15% of dry weight. Feverfew may cause severe allergic contact dermatitis and it has been shown that PHL is the major sensitizer [14]. Feverfew has also been considered responsible for some cases of airborne Compositae dermatitis and the source of this contact allergy has been claimed to be dried airborne plant particles containing PHL [27]. However, the present investigation does not support the theory that airborne SLs are solely responsible for the “airborne type” of Compositae dermatitis. The headspace analysis showed that PHL and other SLs are not directly emitted from feverfew e.g. through sublimation or via pollen. Secondly the negative results obtained by the high-volume air sampler also indicate that plant particles containing SLs are not directly released from the plants, although the results do not exclude the possibility that plant parts containing SLs can be released under extremely windy and dry conditions. The terpenes emitted from Danish feverfew have previously been found in the essential oils of other European feverfews [2, 5] and/or in the essential oils of related Tanacetum (Chrysanthemum) species [5, 9, 26] and the majority of these compounds may therefore be regarded as widely distributed in these Compositae plants. The amount of the different terpenes appears to vary considerably between or even within Tanacetum species. It is for example well known that T. vulgare produces different chemotypes, named according to their main volatile components [9]. In contrast, Danish feverfew contains the same pattern of major volatile terpenes as that found in feverfew grown in Belgium [5] and England [2], although some quantitative and qualitative differences are apparent. The differences may be due to growing conditions, plant material and not least the different methods used for collecting the volatiles. The essential feverfew oils were obtained from ‘dead’ plant material, whereas we studied the volatiles emitted from living plants.
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Among the volatiles emitted from feverfew, several are potential or precursors of contact allergens, including the monoterpenes α-terpinene, limonene, β-myrcene and linalool [7]. With regard to allergic reactions it is not only important to determine the compounds emitted directly from the plant, but also to consider their stability and products of biodegradation in the air. For example, the maximum life of terpenes in air is suggested to be 10 h and may be influenced by ozone levels [24]. Myrcene has been reported to break down to acetaldehyde, formaldehyde and acetone under certain conditions [10] and limonene is easily oxidized to carvone, limone epoxides, hydroperoxides and other monoterpenes when released in the air [21, 25]. Regarding carvone, we have previously reported a strongly significant relationship between the occurrence of positive patch tests to carvone and Compositae allergy [31]. Although the results could not be reproduced on retesting, the possibility of true cross reactions between distantly related terpenes cannot be ruled out [37]. We conclude that release of SLs through plant particles or direct emission is not the only explanation for the airborne pattern of feverfew dermatitis. The possible role of the emitted monoterpenes and their oxidation and breakdown products needs further clinical investigations. Acknowledgement The authors thank the Danish Medical Research Council (Grant No. 9602213) for financial support.
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