Elberling, J, Duus Johansen, J, Dirksen, A, Mosbech, H Exposure of eyes to perfume: a double-blind, placebo-controlled experiment. Indoor Air 2006 16(4):276-281.

Abstract: Environmental perfume exposure can elicit bothersome respiratory symptoms. Symptoms are induced at exposure levels which most people find tolerable, and the mechanisms are unclear. The aim of the study was to investigate patients with eye and respiratory symptoms related to environmental perfume, by exposing the eyes to perfume in a double-blind, placebo-controlled study. Twenty-one eczema patients with respiratory symptoms elicited by perfume were compared with 21 healthy volunteers in a sex- and age-matched case-control study. The participants completed a symptom questionnaire, and underwent a double-blind, placebo-controlled exposure to perfume. Of the 42 individuals tested, 10 had more eye symptoms (irritation, itching, and tears) during perfume exposure than during placebo exposures, and eight of these individuals (P = 0.07, Fisher's exact test) belonged to the patient group. A true positive eye reaction to perfume was significantly associated with identification of perfume as an active exposure (P < 0.05). In this study, vapor of perfume elicited irritation in the eyes independently of olfaction, but the relative importance of ocular chemoperception in relation to elicitation of respiratory symptoms from common environmental exposures to perfume remains unclear. Practical Implications: Vapors of perfume provoked symptoms in the relevant eye in some patients and healthy control persons, but under our exposure conditions, ocular chemesthesis failed to elicit respiratory symptoms. Elberling J, Linneberg A, Dirksen J. D. Johansen L, Frlund F, Madsen N, Nielsen H, Mosbech, H Mucosal symptoms elicited by fragrance products in a populationbased sample in relation to atopy and bronchial hyper-reactivity. Clinical and Experimental Allergy 2005 35(1), 75-81. Abstract: To investigate both the localization and character of symptoms from the eyes and airways elicited by fragrance products, and the associations between such symptoms and skin prick test reactivity (atopy), methacholine bronchial hyper-reactivity (BHR), allergic rhinitis and asthma. Methods A questionnaire on mucosal symptoms elicited by fragrance products was posted to 1189 persons who had participated in a Danish population-based study of allergic diseases in 1997/1998. The study included measurement of BHR, atopy, forced expiratory volume in 1 s (FEV1), and serum eosinophilic cationic protein (serum ECP). Results The response rate was 79.6%. Symptoms from the eyes or airways elicited by fragrance products were reported by 42%. BHR (adjusted odds ratio 2.3, 95% confidence interval 1.53.5) was independently associated with symptoms from the eyes and airways elicited by fragrance products. There were no significant associations between these symptoms and atopy, FEV1 or serum ECP. Conclusions Mucosal symptoms from the eyes and airways were common in this population. BHR was a significant and independent predictor of these symptoms. The lack of association with atopy suggested that IgE-mediated allergic mechanisms do not play a major role in the development of these symptoms.

Su HJ, Chao CJ, Chang HY, Wu, PC The effects of evaporating essential oils on indoor air quality. Atmospheric Environment 2007 41(6), 1230-1236 Abstract: Essential oils, predominantly comprised of a group of aromatic chemicals, have attracted increasing attention as they are introduced into indoor environments through various forms of consumer products via different venues. Our study aimed to characterize the profiles and concentrations of emitted volatile organic compounds (VOCs) when evaporating essential oils indoors. Three popular essential oils in the market, lavender, eucalyptus, and tea tree, based on a nation-wide questionnaire survey, were tested. Specific aromatic compounds of interest were sampled during evaporating the essential oils, and analyzed by GC-MS. Indoor carbon monoxide (CO), carbon dioxide (CO2), total volatile organic compounds (TVOCs), and particulate matters (PM10) were measured by real-time, continuous monitors, and duplicate samples for airborne fungi and bacteria were collected in different periods of the evaporation. Indoor CO (average concentration 1.48 vs. 0.47 ppm at test vs. background), CO2 (543.21 vs. 435.47 ppm), and TVOCs (0.74 vs. 0.48 ppm) levels have increased significantly after evaporating essential oils, but not the PM10 (2.45 vs. 2.42 ppm). The antimicrobial activity on airborne microbes, an effect claimed by the use of many essential oils, could only be found at the first 3060 min after the evaporation began as the highest levels of volatile components in these essential oils appeared to emit into the air, especially in the case of tea tree oil. High emissions of linalool (0.0920.787 mg m3), eucalyptol (0.0070.856 mg m3), d-limonene (0.0040.153 mg m3), -cymene (0.0190.141 mg m3), and terpinene-4-ol-1 (0.0290.978 mg m3), all from the family of terpenes, were observed, and warranted for further examination for their health implications, especially for their potential contribution to the increasing indoor levels of secondary pollutants such as formaldehyde and secondary organic aerosols (SOAs) in the presence of ozone. Caress SM, Steinemann AC Prevalence of fragrance sensitivity in the American population. J Env Health 2009 71(7) 46-50. Comment in: J Environ Health. 2009 May;71(9):51-2; author reply 52. This study determined the percentages of individuals who report adverse effects from exposure to fragranced products in the U.S. population and in subpopulations of those with asthma or chemical sensitivity. Data were collected through telephone interviews from two geographically weighted, random samples of the continental U.S. in two surveys during 2002-2003 and 2005-2006 (1,057 and 1,058 cases, respectively). Respondents were asked if they find being next to someone wearing a scented product irritating or appealing; if they have headaches, breathing difficulties, or other problems when exposed to air fresheners or deodorizers; and if they are irritated by the scent from laundry products, fabric softeners, or dryer sheets that are vented outside. Results aggregated from both surveys found that 30.5% of the general population reported scented products on others irritating, 19% reported adverse health effects from air fresheners, and 10.9% reported irritation by scented laundry products vented outside. This study reveals that a considerable percentage of the U.S. population

reports adverse health effects or irritation from fragranced products, with higher percentages among those with asthma and chemical sensitivity.

Elberling, J, Linneberg A, Mosbech H, Dirksen A, Frolund L, Madsen F, Nielsen, NH Johansen JD A link between skin and airways regarding sensitivity to fragrance products? British Journal of Dermatology. 151(6):1197-1203, December 2004. Abstract: To investigate if eye and airway symptoms elicited by fragrance products are associated with perfume contact allergy or hand eczema in a population-based sample. Methods: A questionnaire on eye and airway symptoms elicited by fragrance products was mailed to 1189 individuals who had recently participated in a Danish population-based study of allergic diseases. Results from the questionnaire about localization and character of the symptoms were compared with data on patch testing and 1-year prevalence of hand eczema collected during the health examination. Results: Positive, independent and significant (P < 0.05) associations were found between eye and airway symptoms elicited by fragrance products and perfume contact allergy (adjusted odds ratios 2.0-3.7) and hand eczema (adjusted odds ratios 1.6-2.6). In further analysis, similar and consistent results were found regarding severity of the symptoms. No associations were found between nickel contact allergy and the symptoms. Female sex and psychological vulnerability were independently associated with eye and airway symptoms elicited by fragrance products, but adjustment in multivariate analysis did not change the results regarding perfume contact allergy and hand eczema. Conclusions: Individuals with perfume contact allergy and/or hand eczema, as opposed to those without, have more frequent and more severe eye or airway symptoms after exposure to volatile fragrance products. Having hand eczema has the greatest impact on reporting eye and airway symptoms elicited by fragrance products. Elberling J, Skov PS, Mosbech H, Holst, H, Dirksen A, Johansen JD Increased release of histamine in patients with respiratory symptoms related to perfume. Clinical and Experimental Allergy 2007, 37(11), 1676-1680. ABSTRACT The study aimed to investigate whether basophils from patients with respiratory symptoms related to perfume released more histamine in the presence of perfume as compared with healthy volunteers. Methods Histamine release was measured by the glass fibre method. Blood was obtained from healthy volunteers (n=20) and patients with respiratory symptoms related to perfume (n=17) attending a dermatological outpatient clinic for patch testing. The effect of an international brand perfume was investigated using the basophil histamine release test with perfume. Furthermore, basophils from a healthy non-atopic donor were incubated with participant's sera and histamine release induced by perfume was measured. Results In both groups, incremental perfume concentrations showed a positive and significant (P<0.001) dose-response effect on the release of histamine. At the highest perfume concentration, the basophils released significantly (P<0.05) more histamine in patients as compared with healthy volunteers. No difference was found between the

groups when sera were incubated with basophils from a healthy non-atopic donor. Conclusion Perfume induces a dose-dependent non-IgE-mediated release of histamine from human peripheral blood basophils. Increased basophil reactivity to perfume was found in patients with respiratory symptoms related to perfume.

Curtis, L Letter to the Editor: Toxicity of fragrances EHP 2004 112(8) A461
Anderson R, Anderson J. 1998. Acute toxic effects of fragrance products. Arch Environ Health 53(2):138146. Ashford N, Miller C. 1991. Chemical Exposures: Low Levels and High Stakes. New York: Von Nostrand Reinold. Kumar P, Caradonna-Graham VM, Gupta S, Cai X, Rao PN, Thompson J. Inhalation challenge effects of perfume scent strips in patients with asthma. 1995. Annals Allergy 75(5):429433. Millqvist E, Lowhagen O. 1996. Placebo controlled challenges with perfume in patients with asthma-like symptoms. Allergy 51(6):434439. Shim C, Williams MH. 1986. Effect of odors in asthma. Am J Med 80(1):1822. Spencer PS, Bischoff-Fenton MC, Moreno OM, Opdyke DL, Ford RA. 1984. Neurotoxic properties of musk ambrette. Toxicol Appl Pharmacol 75(3):571575.

Steinemann, AC Fragranced consumer products and undisclosed ingredients. Environmental Impact Assessment Review 2009, 29(1): 32-38 Abstract Fragranced consumer productssuch as air fresheners, laundry supplies, personal care products, and cleanersare widely used in homes, businesses, institutions, and public places. While prevalent, these products can contain chemicals that are not disclosed to the public through product labels or material safety data sheets (MSDSs). What are some of these chemicals and what limits their disclosure? This article investigates these questions, and brings new pieces of evidence to the science, health, and policy puzzle. Results from a regulatory analysis, coupled with a chemical analysis of six best-selling products (three air fresheners and three laundry supplies), provide several findings. First, no law in the U.S. requires disclosure of all chemical ingredients in consumer products or in fragrances. Second, in these six products, nearly 100 volatile organic compounds (VOCs) were identified, but none of the VOCs were listed on any product label, and one was listed on one MSDS. Third, of these identified VOCs, ten are regulated as toxic or hazardous under federal laws, with three (acetaldehyde, chloromethane, and 1,4-dioxane) classified as Hazardous Air Pollutants (HAPs). Results point to a need for improved understanding of product constituents and mechanisms between exposures and effects.

Thyssen J P, Menne T, Linneberg A, Johansen, J D Contact sensitization to fragrances in the general population: a Koch's approach may reveal the burden of disease. British Journal of Dermatology 2009 160(4):729-735. Abstract: Background: Contact sensitization to fragrance mix (FM) I and Myroxylon pereirae (MP) is common among European patients with dermatitis. Recently, FM II was included in the European baseline series as an additional marker of fragrance

sensitization. Objectives: This literature review aims to assess the prevalence of fragrance sensitization in the general population, and to suggest how future populationbased studies and questionnaires should be constructed, better to assess the prevalence and burden of fragrance sensitization. This is of relevance as it is often difficult to establish causality in biological systems. Methods: A systematic review of the literature was carried out by searching Pubmed-Medline, Biosis and contact dermatitis textbooks. Results: Nineteen studies were identified, of which 13 were performed among adults. Sample sizes varied between 82 and 2545 tested subjects, and 11,648 subjects were tested in total. The median prevalence of FM and MP sensitization among adults was 2.3% (women, 1.7%; men, 1.3%) and 1.% (women, 1.4%; men, 0%), respectively. Conclusions: Based on the reliability of patch test data from the general population and exposure data obtained from patients with dermatitis, the prevalence and burden of fragrance sensitization in the general population is significant. Ezendam J et al Immune effects of respiratory exposure to fragrance chemicals (the Netherlands). RIVM Reports 2007 http://hdl.handle.net/10029/16464 Result: Inhalation of the fragrance chemicals, isoeugenol and cinnamal, by mice resulted in immune reactions in the respiratory tract. RIVM investigated the effects of inhalation of isoeugenol and cinnamal, fragrance chemicals that can cause skin allergy. Mice were exposed to the fragrance chemicals via inhalation. Effects on the immune system were measured using a respiratory lymph node assay, which measures cell proliferation in lymph nodes of the respiratory tract. Inhalation of both isoeugenol and cinnamal resulted in stimulation of the immune system of the respiratory tract. The effects of isoeugenol were more pronounced than those of cinnamal. To obtain more insight into the hazards of fragrance chemicals used in scented products, RIVM is advising assessment of more fragrance chemicals in the respiratory lymph node assay. Luckenbach, T & Epel, D Nitromusk and Polycyclic Musk Compounds as Long-Term Inhibitors of Cellular Xenobiotic Defense Systems Mediated by Multidrug Transporters. EHP 2005 113(1):1724. Response from Salvito, D, Synthetic Musk Compounds and Effects on Human Health? Fragrance industrys response Letter to the Editor EHP (2005) 113,(12) A802-A803.

28. Herbert M, Glick R, Black H. Olfactory precipitants of bronchial asthma. J Psychosomat Res 11:195202 (1967). 29. Shim C, Williams MH. Effect of odors in asthma. Am J Med 80:1822 (1986). 30. Kumar P, Caradonna-Graham VM, Gupta S, Cai X, Rao PN Thompson J. Inhalation challenge effects of perfume scent strips in patients with asthma. Ann Allergy Asthma Immunol 75:429433 (1995). 31. Anderson RC, Anderson JH. Toxic effects of air freshener emissions. Arch Environ Health 52(6):433441 (1997). 32. Anderson RC, Anderson JH. Acute toxic effects of fragrance products. Arch Environ Health 53(2):138146 (1998). 33. Anderson RC, Anderson JH. Respiratory toxicity in mice exposed to mattress covers. Arch Environ Health 54(3):202209 (1999). 34. Anderson RC, Anderson JH. Acute respiratory effects of diaper emissions. Arch Environ Health 54(5):353358 (1999).

35. Shusterman D, Balmes J, Cone J. Behavioral sensitization to irritants/odorants after acute overexposures. J Occup Med 30:565567 (1988).

Report on the project at http://archive.leg.state.mn.us/docs/2008/mandated/080128.pdf