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Odor perception phenotypes: multiple, specific hyperosmias to musks.

Olfactory detection thresholds for 11 structurally diverse musk odorants and one non-musk odorant were obtained from 32 subjects. Hierarchical cluster analysis produced four groups of subjects. One group (n = 12) was uniformly sensitive to all musks; another (n = 16) was uniformly insensitive. Two groups of subjects contained otherwise insensitive individuals who were exceptionally sensitive to cyclopentadecanone and musk xylol (n = 2) and to delta9-hexadecenolactone and tonalid (n = 2) respectively. We propose that the latter two groups are odor perception phenotypes (MSHM1 and MSHM2) that consist of multiple, specific hyperosmias to musk odorants.

Adult↗

Pharmacokinetic studies of the fragrance compound 1,8-cineol in humans during inhalation.

The present study was undertaken to investigate the pharmacokinetics of 1,8-cineol in human subjects during prolonged inhalation. The results showed that 1,8-cineol is well absorbed from breathing air, with a peak plasma concentration after approximately 18 min. The elimination of this fragrance compound from the blood is biphasic, with a mean distribution half-life of 6.7 min and an elimination half-life of 104.6 min.

Administration, Inhalation↗

Effects of chiral fragrances on human autonomic nervous system parameters and self-evaluation.

The effects of chiral fragrances (enantiomers of limonene and carvone) on the human autonomic nervous system (ANS) and on self-evaluation were studied in 20 healthy volunteers. Each fragrance was administered to each subject by inhalation using an A-A-B design. Individuals were tested in four separate sessions; in one session one fragrance was administered. ANS parameters recorded were skin temperature, skin conductance, breathing rate, pulse rate, blood oxygen saturation and systolic as well as diastolic blood pressure. Subjective experience was assessed in terms of mood, calmness and alertness on visual analog scales. In addition, fragrances were rated in terms of pleasantness, intensity and stimulating property. Inhalation of (+)-limonene led to increased systolic blood pressure, subjective alertness and restlessness. Inhalation of (-)-limonene caused an increase in systolic blood pressure but had no effects on psychological parameters. Inhalation of (-)-carvone caused increases in pulse rate, diastolic blood pressure and subjective restlessness. After inhalation of (+)-carvone increased levels of systolic as well as diastolic blood pressure were observed. Correlational analyses revealed that changes in both ANS parameters and self-evaluation were in part related to subjective evaluation of the odor and suggest that both pharmacological and psychological mechanisms are involved in the observed effects. In conclusion, the present study indicates that: (i) prolonged inhalation of fragrances influences ANS parameters as well as mental and emotional conditions; (ii) effects of fragrances are in part based on subjective evaluation of odor; (iii) chirality of odor molecules seems to be a central factor with respect to the biological activity of fragrances.

Adolescent↗

Life span changes in the verbal categorization of odors.

An odor description task was used to explore age-related change in odor perception based on 1.19 million U.S. and Canadian respondents (ages 10-90 years) to the National Geographic Smell Survey. Respondents sampled six microencapsulated odorants and selected 1 of 11 descriptors to characterize each smell. Four odors were characterized by strong consensus endorsement of a single descriptor. This consensus weakened with advancing age, and nonmodal descriptors were endorsed more frequently. Nonmodal responses were neither randomly selected, nor systematically biased across odors. Rather, they showed odor-specific patterns of change. Together, these results suggest a marked change in odor categorization across the life span. Odor descriptor profiles were used to generate age-specific multidimensional scaling maps. Stimulus configurations were stable from the third through fifth decades. Those from the sixth through ninth decades showed major displacements for two odors, and suggest that the sweet dimension of odor quality may be particularly variable with maturation.

Adolescent↗

Simultaneous congener-specific determination of selected organochlorine compounds and nitro musks in human whole blood samples by solid-phase extraction and capillary gas chromatography with electron capture detection.

Chlororganic compounds like pesticides or polychlorinated biphenyls (PCB) and nitro musks are environmental contaminants, which remain public health concerns because of their persistence in humans and their toxicological properties. Many of these substances are associated with endocrine dysfunction or with carcinogenicity. Therefore, a simple method using solid-phase extraction followed by capillary gas chromatography with electron capture detection for the simultaneous determination of both organochlorines and nitro musks in human whole blood samples has been developed. Recovery rates of 13 PCB congeners and of 7 pesticides ranged from 67.5% to 100.4% and from 81.1% to 110.5%, respectively. Recoveries of the 5 nitro musks were consistent and ranged from 90.2% to 98.8%. The accuracy for organochlorines and nitro musks varied from 6.3% to 8.6%. Method detection limits ranged from 0.02 microg/L to 0.11 microg/L for the organochlorines and from 0.04 microg/L to 0.08 microg/L for the nitro musks. The method has a high sensitivity with a low detection limit even in slightly contaminated human blood samples. The time and technical effort is small, so the method is feasible for epidemiological studies with regard to the impact of organochlorines and nitro musks on certain diseases.

Chromatography, Gas↗

Fragrance as an occupational allergen.

Sensitization to fragrance is believed to occur mainly outside the workplace. This study addresses the frequency of fragrance allergy in patch test patients of differing occupations during a 15 year period. The occupation most strongly associated with fragrance allergy in both sexes was health care work (positive tests in 11.7% of males and 10.4% of females). Retired individuals also had high rates of fragrance allergy (11.6% of males and 14.5% of females), and the prevalence of sensitization increased with advancing age. Health care workers and metal workers had statistically significantly higher rates of allergy to eugenol than did workers in other occupations. Food handlers had significantly higher rates of allergy to cinnamal and cinnamic alcohol. These findings suggest that sensitization to fragrance occurs more frequently in an occupational setting than is generally understood and could have implications for preventive measures.

Adult↗

Interaction of polycyclic musks and UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR) in reporter gene bioassays.

Two important ingredients of personal care products, namely polycyclic musk fragrances and UV filters, can be found in the environment and in humans. In previous studies, several compounds of both classes have been tested for their interaction with the estrogen receptor. Two polycyclic musk fragrances, namely AHTN and HHCB, turned out to be anti-estrogenic both in vitro and in vivo in a transgenic zebrafish assay. Several UV filters have been shown to exert estrogenic effects in vitro and in some in vivo studies. Here, we assessed the interaction of five polycyclic musk compounds and seven UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone (PR) receptor, using sensitive and specific reporter gene cell lines. Four polycyclic musks (AHTN, HHCB, AETT, and AHMI) were found to be antagonists toward the ERbeta, AR and PR. The UV filters that showed estrogenic effects (benzophenone-3, Bp-3; 3-benzylidene camphor, 3-BC; homosalate, HMS; and 4-methylbenzylidene camphor, 4-MBC) were found to be antagonists toward the AR and PR. The ERalpha agonistic UV filter octyl-dimethyl-p-aminobenzoic acid (OD-PABA) did not show activity toward the AR and PR. Octyl methoxy cinnamate (OMC) showed weak ERalpha agonism, but potent PR antagonism. Butyl methoxydibenzoylmethane (B-MDM) only showed weak ERalpha agonism and weak AR antagonism. Most effects were observed at relatively high concentrations (above 1 muM); however, the anti-progestagenic effects of the polycyclic musks AHMI and AHTN were detected at concentrations as low as 0.01 muM. The activity of anti-progestagenic xenobiotics at low concentrations indicates the need to undertake more research to find out about the potential endocrine disrupting effects of these compounds in vivo.

Benzopyrans↗

Rose scent: genomics approach to discovering novel floral fragrance-related genes.

For centuries, rose has been the most important crop in the floriculture industry; its economic importance also lies in the use of its petals as a source of natural fragrances. Here, we used genomics approaches to identify novel scent-related genes, using rose flowers from tetraploid scented and nonscented cultivars. An annotated petal EST database of approximately 2100 unique genes from both cultivars was created, and DNA chips were prepared and used for expression analyses of selected clones. Detailed chemical analysis of volatile composition in the two cultivars, together with the identification of secondary metabolism-related genes whose expression coincides with scent production, led to the discovery of several novel flower scent-related candidate genes. The function of some of these genes, including a germacrene D synthase, was biochemically determined using an Escherichia coli expression system. This work demonstrates the advantages of using the high-throughput approaches of genomics to detail traits of interest expressed in a cultivar-specific manner in nonmodel plants. EST sequences were submitted to the GenBank database (accession numbers BQ 103855 to BQ 106728).

Alkyl and Aryl Transferases↗

Identification of topical photosensitizing agents in humans.

A method is described for the detection of topical photosensitizers in humans. Test agents were applied to the untanned midback under an occlusive dressing for 6 hr and then exposed to broad-spectrum radiation containing UV-A and visible wavelengths from a Xenon arc source. Well-known topical photosensitizers were readily identified. It was found that with certain poorly-penetrating substances, such as water-soluble dyes, applications to scarified skin were necessary to reveal phototoxic activity. In addition, these dyes were activated by wavelengths in the visible region of the spectrum.

Administration, Topical↗

Assay of contact photosensitivity to musk ambrette in guinea pigs.

This study reports the induction of contact photodermatitis to musk ambrette, 2-methoxy-3,5-dinitro-4-methyl-t-butylbenzene, in guinea pigs. Photoallergic contact dermatitis was assayed using 2 alternative induction methods. Successful photosensitization was achieved only when the nuchal skin was stripped with scotch tape before application of musk ambrette and ultraviolet radiation. Induction methods utilizing nonstripped nuchal skin which induce photosensitivity to potent photoallergens were ineffective for musk ambrette. Phtotoxicity tests to musk ambrette at concentrations between 1 and 50% and a dose of 10.2 joules/cm2 from "Black Light" fluorescent tubes were all negative. Under identical irradiation conditions, anthracene at 0.9% and 8-methoxypsoralen at 1% were consistently positive. The mechanism of photosensitivity to musk ambrette appears to be photoallergic rather than phototoxic. The requirement for skin abrasion to induce photosensitization parallels the clinical reports of photosensitivity to musk ambrette in man.

Allergens↗

Patch testing with oxidized R-(+)-limonene and its hydroperoxide fraction.

R-(+)-Limonene is an ubiquitous allergen in our environment. It is one of the most widely used fragrance materials not only in fine fragrances but also most often incorporated in domestic and occupational products. Although the non-oxidized R-(+)-limonene itself is not allergenic, it easily forms allergenic products due to autoxidation during handling and storage. 2273 patients at 4 dermatological clinics in Europe were patch tested between 1997 and 1999 in 2 steps. First, the oxidation mixture of R-(+)-limonene and 1 selected allergen fraction of the mixture, the limonene hydroperoxides, were tested in 2 different vehicles in consecutive patients. A diverging frequency of positive patch test reactions was observed in the 4 clinics. 3.8% of the consecutive patients tested reacted to oxidized R-(+)-limonene in 2 clinics, 6.5% in the 3rd, whereas 0.3% in the 4th clinic. In 2 of the centres, different but significant concomitant positive response rates to other allergens were observed; e.g. to fragrance materials and to colophonium. However, in the total test population, 57% of the limonene-allergic subjects did not react to any of the fragrance allergy markers used in the standard series. In the 2nd step, patients showing positive reactions were retested, also including additional separate allergens of the limonene oxidation mixture (carvone and limonene oxide). 60% of the limonene-allergic patients showed positive results at retesting. The limonene hydroperoxide fraction was proved to be the most important allergen of the oxidation mixture, showing positive reactions in around 60% of the limonene-allergic patients at both test sessions. Testing limonene oxide and carvone separately resulted in very few positive reactions. 3% oxidized R-(+)-limonene in non-stabilized petrolatum is most suitable when using only 1 test preparation for diagnosis of contact allergy to oxidized limonene. Our data give clinical support to the European classification of R-(+)-limonene, containing oxidation products, as a skin sensitizer.

Cyclohexenes↗

Citral a fragrance allergen and irritant.

Citral is a well known contact allergen and a contact irritant. Routine patch testing in the past may have been restricted because of possible irritant (IR) patch test responses. 586 consecutive patients, with hand eczema, were patch tested with a selection of fragrances including citral 2% petrolatum and the European standard series. 28 of the patients showed a positive patch test reaction (+ to +++) to citral and 82 at least 1 IR patch test reaction and no positive patch test reaction to citral. A statistically significant association between a positive patch test reaction to citral and positive patch test reactions to other fragrances compared with IR reactions (n = 82) was established. The difference regarding fragrance history found between those with IR and positive reactions to citral was not significant. Citral could be an allergen and/or irritant, worthy of further more extensive studies.

Acyclic Monoterpenes↗

Patch-test reaction patterns in patients with a predisposition to atopic dermatitis.

Patients with a predisposition to atopic dermatitis often need to be patch tested in order to detect possible contact sensitization. However, it is unknown whether immunologic or other peculiarities of atopic skin are related to altered patch-test reaction patterns. Our study was aimed at answering this question, because patch-test reaction patterns are of considerable practical importance in the reading and interpretation of patch tests. Therefore, we compared patterns of patch-test reactions in patients with a predisposition to atopic dermatitis and in control patients matched for sex, age, reason for testing and test centre. Patch-test results from 9 centres (2322 patients with a disposition to atopic dermatitis and 2126 matched controls) were evaluated retrospectively. All patients were tested with nickel sulfate, fragrance mix, potassium dichromate, lanolin alcohol, formaldehyde and mercury ammonium chloride. Patch tests applied for 1 day with readings on days 1, 2 and 3 were evaluated in order to cover the early phase of the reactions. Not unexpectedly, we found that, compared to the matched controls, patients with a predisposition to atopic dermatitis tended to have more doubtful and irritant reactions on day 1. As a new observation, it turned out that they had less reactions of crescendo pattern and more strong reactions on day 3. All these differences were slight/insignificant. A higher skin irritability in patients with a predisposition to atopic dermatitis is a likely explanation. In conclusion, standard methods for patch testing can be applied in patients with a predisposition to atopic dermatitis, but minor differences in reaction patterns should be considered.

Adult↗

Patch testing with fine fragrances: comparison with fragrance mix, balsam of Peru and a fragrance series.

High frequencies of contact allergy to fragrance ingredients have been reported in recent years. Only approximately 70-80% are detected by fragrance allergens in the standard patch test series. This investigation compares the patch test reactions to fine fragrances with reactions to fragrance mix (FM), balsam of Peru (BP) (Myroxylon pereirae resin) and a fragrance series. 641 consecutive patients with eczema were patch tested with the European standard series and with selected fine fragrances. Those who were positive to 1 of the fine fragrances or the FM or BP were also tested with the fragrance series. 95 (14.8%) patients were found to have a positive patch test reaction to FM or BP; 41 (6.4%) had positive results to fragrance no. 1 and 29 (4.5%) to no. 2. 9 (9.5% of the 95 positive patients) had a positive reaction to fine fragrances and a negative reaction to all other fragrance allergens in the standard series. These findings indicate that testing with fine fragrances can add to our evaluation of fragrance-sensitive patients.

Adolescent↗

Further evaluation of quantitative structure--activity relationship models for the prediction of the skin sensitization potency of selected fragrance allergens.

Fragrance substances represent a very diverse group of chemicals; a proportion of them are associated with the ability to cause allergic reactions in the skin. Efforts to find substitute materials are hindered by the need to undertake animal testing for determining both skin sensitization hazard and potency. One strategy to avoid such testing is through an understanding of the relationships between chemical structure and skin sensitization, so-called structure-activity relationships. In recent work, we evaluated 2 groups of fragrance chemicals -- saturated aldehydes and alpha,beta-unsaturated aldehydes. Simple quantitative structure-activity relationship (QSAR) models relating the EC3 values [derived from the local lymph node assay (LLNA)] to physicochemical properties were developed for both sets of aldehydes. In the current study, we evaluated an additional group of carbonyl-containing compounds to test the predictive power of the developed QSARs and to extend their scope. The QSAR models were used to predict EC3 values of 10 newly selected compounds. Local lymph node assay data generated for these compounds demonstrated that the original QSARs were fairly accurate, but still required improvement. Development of these QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes, and hence how to avoid or limit allergy. Knowledge generated from this work is being incorporated into new/improved rules for sensitization in the expert toxicity prediction system, deductive estimation of risk from existing knowledge (DEREK).

Aldehydes↗