Does usage of a room air freshener affect the nasal

mucosa?
Mehmet Akdag, M.D.,1 Salih Bakir, M.D.,1 Ulas Alabalik, M.D.,2 Fazl Emre Ozkurt, M.D.,1
and Ismail Topcu, M.D.1

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ABSTRACT

Background: Effects of chemicals emitted from the room air freshener sprays (RAFSs) on nasal mucosa are still unclear. The purpose of this study was to
investigate effects of RAFSs on the nasal mucosa of rats for different time intervals.
Methods: Twenty-eight rats were randomly divided into four experimental groups: group 1 (n 7) was the control group and not exposed to RAFS or
other chemicals, group 2 (n 7) was exposed to RAFS for 1 month, group 3 (n 7) was exposed to RAFS for 2 months, and group 4 (n 7) was exposed
to RAFS for 3 months. Samples from the nasal septum were stained using hematoxylin and eosin solution, examined by a pathologist using a light microscope,
and analyzed with Fishers exact test.
Results: We observed that distinct histopathological differences in the nasal mucosa of exposed rats depends on different time intervals (p 0.05).
Increased congestion was found after the 1st month of exposure (group 2). Although edema and mild inflammatory cell infiltration, including some
eosinophils, was seen after the 2nd month (group 3), squamous metaplasia, numerous eosinophils, and intense inflammatory cell infiltration began after
3 months of exposure (group 4).
Conclusion: Our results showed that continuous use of RAFS can cause inflammation and eosinophilic infiltration in rats, which begins after 2 months
of exposure and may lead to metaplasia after 3 months. Because of differences in body size, geometry, and physiological responses of rats, the extrapolation of
these results to humans is not straightforward. However, any such comparison should be made with caution. Finally, more performance is necessary to clarify
this subject.
(Am J Rhinol Allergy 28, e202e208, 2014; doi: 10.2500/ajra.2014.28.4105)

he nasal mucosa performs many important functions, such as

temperature regulation through the heating of air, olfaction,
respiration, and protection of the airway by filtering foreign bodies.1
Nasal mucosa, which is lined by respiratory epithelium, needs a
healthy mucociliary transport mechanism, cell structure, and anatomy to perform these functions. A problem with cell structure or
anatomy may disrupt the epithelial cells of the nasal mucosa and
cause different nasal diseases such as rhinitis. Rhinitis is an inflammatory condition of the nasal mucosa and can be caused by a variety
of different allergic and nonallergic (infectious, hormonal, drug induced, chemical agent induced, and occupational) conditions).2
Fragranced products including room air freshener sprays (RAFSs),
laundry supplies, and personal care products are commonly used in
daily life. Previous studies suggest that fragranced products can
create adverse health effects, especially in sensitive individuals such
as asthmatic patients.3 RAFSs are volatile organic compounds (VOCs)
composed of lowmolecular-weight compounds with lower and upper boiling points of 50100C and 240260C, respectively.4 All of
these solvents are liquid at room temperature and have lipophilic
properties. Common household products that contain VOCs include
air fresheners, insect sprays, cleaners, polishes, and personal care
products such as hair spray and deodorant.4 These chemical substances are normally considered tolerable, but these substances may
lead to multiple-chemical sensitivity, in which its symptoms include
respiratory problems such as rhinitis and anaphylaxis, as well as
neurological, musculoskeletal, dermatological, gastrointestinal, cardiac, and endocrine effects.5,6

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From the Departments of 1Otolaryngology and 2Pathology, Faculty of Medicine, Dicle

University, Diyarbakir, Turkey
Presented at the 11th International OtolaryngologyHead and Neck surgical scientific
meeting, April 1719, 2014, Ankara, Turkey
The authors have no conflicts of interest to declare pertaining to this article
Address correspondence to Mehmet Akdag, M.D, Department of Ear, Nose, and Throat
and Head and Neck Surgery, Faculty of Medicine, Dicle University, Diyarbakir,
Turkey
E-mail address: drmehmetakdag@hotmail.com
Published online August 12, 2014
Copyright 2014, OceanSide Publications, Inc., U.S.A.

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Different chemical agents are commonly used throughout our lives

and we are exposed to them via nasal inhalation. The nasal mucosa is
located at the airway entrance and changes to its functional structure
are likely responsible for the development of rhinitis. However, it is
unclear how these chemical agents lead to histopathological changes
within the nasal mucosa. Although the functional effects of RAFSs or
gases have been examined with allergy susceptibility testing in rats
and humans, histochemical changes have not been studied. Importantly, complete functional testing has not been conducted on the
airway of rats exposed to chemical agents.79
The aim of this study was to investigate the short-term histopathological effects that normal levels of air freshener sprays have on the
rat nasal mucosa.

MATERIALS AND METHODS

This study was approved by Dicle University Medical Institution
Ethical Committee (study number 2013/03) and was performed according to the Guide for the Care and Use of Laboratory Animals issued
by the National Institutes of Health, Commission on Life Sciences,
and the National Research Council.10

Experimental Design
Twenty-eight male adult Wistar albino rats weighing between 225
and 320 g were used in this study. Animal weights were measured at
the beginning and end of the study. The rats were housed in accordance with standard guidelines in cages maintained under standard
environmental conditions (room temperature between 22 and 24C,
50% relative humidity, and 12-hour light and dark cycles).11 The 28
rats were randomly divided into four groups: group 1/control (n 7)
was a control group not exposed to RAFSs or other chemicals, group
2/RAFS1 (n 7) was exposed to RAFSs for 1 month, group 3/RAFS2
(n 7) was exposed to RAFSs for 2 months, and group 4/RAFS3 (n
7) was exposed to RAFSs for 3 months. Animals underwent anterior
rhinoscopy with a pediatric speculum and rigid pediatric nasal endoscopy before the study began (1-mm; Karl Storz Hopkins AG,
Tuttlingen, Germany). Animals were housed in a room with a volume
of 30 m3 (3 2.5 4 m). There was 3 m of distance between the
animals and the RAFSs. The control group was placed in a room

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without RAFSs. The air exchange rate within the rooms was maintained at 0.670.1 air changes per hour, similar to typical residential air
exchange rates.

Exclusion Criteria

Table 1 Evaluation of nasal mucosa score count

Animals that showed signs of nasal disease were excluded. Other

exclusion criteria were as follows: (1) runny nose, (2) detectable
external nasal abnormalities on nasal endoscopy, and (3) signs of
nasal disease.

Score

Description

0
1

No alteration in mucosa
Slight edema, congestion, inflammation, and squamous
metaplasia
Moderate edema, congestion, inflammation, and squamous
metaplasia
Severe edema, congestion, inflammation, and squamous
metaplasia

2
3

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Drugs and Anesthesia

Table 2 Statistical results of group comparison (Fishers exact

2test)

Animals were anesthetized intraperitoneally with 30 mg/kg of

ketamine hydrochloride (Ketalar; Eczacibasi Ilac Sanayi ve Ticaret
A.S., Luleburgaz, Turkey) and 4 mg/kg of xylazine (Alfazyne 2%;
Alfasan International B.V., Woerden, The Netherlands). An automatic
pulse RAFS was used in this study, The RAFSs (Room Air Freshener;
Reckitt Benckiser, Lane, Derby, England). We analyzed gases using
the solid-phase microextraction technique with a gas chromatograph
mass spectrometer (GCMS-TQ8030 Triple Quadrupole; fiber, 75-m
Carboxen/Polydimethylsiloxane; extraction conditions, 50C, 15 minutes; volume, 50 m; Kyoto, Japan). There were 97 samples (Fig. 1),
and the majority of the chemical makeup included butane, isobutene,
propane, water, ethyl alcohol, sodium tetraborate dehydrate, perfume
(lavender shock), alpha methyl ionone, citral, citronerol, and limonene. The total RAFS volume was 250 mL with an injection volume of 0.1 mL. The spray was automatically injected every 33 minutes
in the experimental room.

Comparison of
Groups

Histopathological Examination
Tissue Preparation. All surgical procedures were performed under
clean but nonsterile conditions. Animals were decapitated under
anesthesia at the end of the 1st, 2nd, or 3rd month. The nose of each
rat was removed by microdissection and fixed in 10% formaldehyde
solution for 24 hours followed by decalcification in 10% ethylene
diamine tetraacetic acid solution for 3 weeks. Next, the nasal septa
with mucosa were carefully dissected using scissors. The nasal septa
were rinsed in tap water for 24 hours, dehydrated using a graded
alcohol series, rendered transparent, and blocked after infiltration
with paraffin. The paraffin-embedded samples were sliced with a
microtome (Microm HM 360; Charleston, Walldorf, Germany) to a
thickness of 5 m, and cross-sections were stained with hematoxylin
and eosin (H&E) before examination with a Nikon ECLIPSE 80i
microscope (Nikon Instruments, Amstelveen, The Netherlands). The
same pathologist, who was blinded to the study groups, evaluated all
stained specimens.
For morphological analysis, parameters such as congestion, edema,
inflammation, and squamous metaplasia were evaluated. These parameters were scored as 0 (none), 1 (slight), 2 (moderate), and 3
(severe; Table 1).

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Statistical Analysis

Statistical analysis of categorical data were performed using the

SPSS 15.0 software package for Windows (SPSS, Inc., Chicago, IL).
Because there were no severe histopathological scores, the slight and
moderate categories were combined. The categories were renamed
yes or no. Fishers exact test was used to analyze 2 2 crosstab
results. Two-tailed hypotheses were considered, and a value of p
0.05 was accepted as significant.

RESULTS
Hematoxylin and eosin staining showed distinctive differences in
the nasal mucosa of the control group and the groups exposed to
RAFSs. Significant differences between RAFS exposure times were
observed during histopathological examination including edema,
congestion, inflammation, and squamous metaplasia (p 0.05; Table

Edema
Control/RAFS1
Control/RAFS2
Control/RAFS3
RAFS1/RAFS2
RAFS1/RAFS3
RAFS2/RAFS3
Congestion
Control/RAFS1
Control/RAFS2
Control/RAFS3
RAFS1/RAFS2
RAFS1/RAFS3
RAFS2/RAFS3

p Value

Comparison of
Groups

p Value

Inflammation
Control/RAFS1
Control/RAFS2
Control/RAFS3
RAFS1/RAFS2
RAFS1/RAFS3
RAFS2/RAFS3
Squamous metaplasia
Control/RAFS1
Control/RAFS2
Control/RAFS3
RAFS1/RAFS2
RAFS1/RAFS3
RAFS2/RAFS3

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0.021
0.021
0.021
0.962
0.984
0.682
0.286
0.021
0.021
0.462
0.462
1.000

0.462
0.021
0.001
0.286
0.021
0.462
1.000
0.462
0.001
0.462
0.001
0.021

Distinct histopathological differences in the nasal mucosa of exposed rats

depends on different time intervals (p 0.05).
RAFS room air freshener spray.

2). The control group exhibited a normal nasal mucosal epithelium,

covered by cilia, and subepithelial tissue (Fig. 2). Increased congestion
was observed in the subepithelial tissue after the 1st month of RAFS
exposure (Fig. 3), and mild inflammatory cell infiltration, including
eosinophils, and edema were seen in the subepithelial tissue after the
2nd month of exposure (Fig. 4). Squamous metaplasia was observed
on the surface of the nasal mucosa after 3 months of RAFS exposure.
Also, inflammatory cell infiltration with numerous eosinophils began
in the subepithelial tissue at the end of the 3rd month of exposure
(Fig. 5). The rate of histopathological change by groups is shown in
Fig. 6. Also, Fig. 1 shows the analysis of 97 RAFS samples. The
histopathological parameters were compared between the groups and
the rate of histopathological change is detailed in Tables 2 and 3. The
measured volume of room spray was 0.145 cc/m3 in 24 hours. This
dosage is commonly used by consumers.

DISCUSSION
Recently, fragranced products such as RAFSs are frequently used in
modern societies. For instance, the use of RAFS was reported to be
30.5% in the United States.11 However, RAFSs contain many of
chemicals such as butane, isobutene, propane, water, ethyl alcohol,
sodium tetraborate dehydrate, perfume (lavender shock), alpha
methyl ionone, citral, citronerol, and limonene. As it is known, rhinitis, allergic rhinitis, and asthma may occur when toxic or allergenic
substances are inhaled.89 Carol et al.12 found that inhalant organic
gases have adverse effects on pulmonary function in allergic patients.
Therefore, this study was based on the widespread use of fragranced
products on nasal mucosa.
In this study, we showed that RAFS can cause deterioration of the
nasal mucosa after 3 months of exposure. Increased nonallergic in-

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flammation with metaplastic changes was observed because of continuous RAFS exposure. To the best of our knowledge, there have not
been any animal studies that have specifically investigated the effects
of RAFS on the nasal mucosa of rats. Therefore, we believe this study
is the first to investigate the histopathological effects of RAFSs on
nasal mucosa.
In this study, inflammation of the nasal mucosa was observed after
2 months of RAFS exposure. Gibson et al.8 reported that many chem-

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Figure 1. Different rate of histopathological change is shown according to groups.

icals, such as those found in RAFSs or inhaled gases, have a negative

effect on human health. These chemicals lead to the release of inflammatory cytokines within the nasal mucosa, which result in inflammation. However, the present study also found increased infiltration of
eosinophils that may mimic the pathology of nonallergic rhinitis.
These inflammatory findings were more pronounced in the 3rd
month of RAFS exposure. Anderson et al.9 investigated the functional
effects of many chemical agents, such as RAFS, on the respiratory

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Figure 1. Continued

systems of rats and found that chemical mixtures could cause sensory
irritation, pulmonary irritation, and airflow limitation. This report is
consistent with our result.
Volatile gases including butane, isobutane, limonene, and ethyl
alcohol are potentially toxic chemical substances. Many VOCs are
classified as known or possible carcinogens, irritants, and toxins.13 In
addition, limonene is classified as a cyclic terpene. Chin et al.14 reported that limonene-including VOCs within homes could pose a

health risk. The same study found that limonene was the most commonly used subgroup of VOCs in the home. In addition, Cooper et
al.15 analyzed 31 fragranced products including perfumes, deodorants, soaps, fabric softeners, and air fresheners and identified 150
unique VOCs. The most common VOCs, emitted from at least onehalf of the products, were ethanol, limonene, linalool, -phenethyl
alcohol, and -myrcene. Limonene and ethanol-containing VOCs are
considered dangerous air pollutants.16 These products may not be

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Figure 1. Continued

Figure 2. Group 1/control shows a normal appearance of the nasal mucosal

epithelium (arrows) and subepithelial tissue (stars; hematoxylin and eosin,
200).

Figure 3. Group 2/RAFS at 1 month shows nasal mucosal epithelium

(arrows) and moderate subepithelial edema (stars; hematoxylin and eosin,
200).

toxigenic in their primary form, but primary pollutants of fragrance

VOCs (e.g., limonene) can readily react with ozone to produce secondary pollutants such as formaldehyde, ultrafine particles, organic
aerosols, and hydroxyl radicals.17
We investigated the histopathological effects of RAFSs on the nasal
mucosa over time (3 months) and found significant (p 0.001)
histopathological changes in the nasal mucosa after the 1st, 2nd, and
3rd month of RAFS exposure (Figs. 25). These results are important
because they were determined by histopathological examination, a

definitive method. It is also important to note that the effects of RAFS

exposure changed as exposure time increased. The duration of RAFS
exposure may be a determinative factor in the formation of cellular
changes. In our study, cellular changes such as squamous metaplasia
began after 3 months of RAFS exposure (Fig. 5).
Metaplasia can be the result of stress and occurs when cells are
replaced by other cell types better equipped to survive in an adverse
environment. Metaplasia is reversible cell injury that can occur
through genetic reprogramming of stem cells rather than transdif-

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Table 3 Rate of histopathological change in score by group,

which found increased congestion after the 1st mo of exposure
Rate of Histopathological
Changes
Edema
Control
RAFS1
RAFS2
RAFS3
Congestion
Control
RAFS1
RAFS 2
RAFS 3

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28.6
71.4
100.0
100.0

Inflammation
Control
RAFS1
RAFS 2
RAFS 3
Squamous metaplasia
Control
RAFS1
RAFS 2
RAFS 3

0.0
28.6
71.4
100.0

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0.0
0.0
28.6
100.0

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The majority of studies related to toxic substances have been performed with function testing.79 Functional tests usually can not reveal any pathology. The present histopathological study observed
inflammatory changes including congestion and edema in the 1st and
2nd month of RAFS exposure, respectively.
VOCs in RAFS may be involved in the unknown etiology of rhinitis. There were inflammatory changes in all forms of rhinitis. Eosinophilic infiltration was found on histopathology in the present study.
This is an important pathological finding relevant to both allergic and
nonallergic rhinitis. However, we could not measure IgE in this study,
and these results may be related to nonallergic rhinitis. We observed
eosinophilic infiltration after 2 months of RAFS exposure. Xu et al.21
observed the same eosinophilic infiltration with inflammation in experimental allergy studies with ovalbumin. Also, Larsson et al.22
reported that fragranced substances such as perfume or RAFS could
cause 15% of rhinitis and asthma cases. In addition to cigarette
smoke, chemical substances may lead to rhinitis and asthma, consistent with our findings of eosinophilic infiltration with inflammation
in the subepithelial tissue after 3 months of RAFS exposure. Edema,
congestion, and inflammation mimic the histopathological view of
rhinosinusitis.23 Therefore, RAFSs may be predictive for rhinosinusitis.
The present study is novel and could be the precursor to long-term
molecular studies that analyze the effects of the various individual
chemicals in RAFSs. We are unable to compare histopathological
changes due to RAFSs between studies because there are no histopathological studies that have evaluated the effects of RAFSs on rat or
human nasal mucosa in the literature. Although we obtained important and useful findings, there is still much to learn and we did not
obtain these results by studying people. Because of differences in
body size, geometry, and physiological responses between rats and
humans, extrapolation of these results to humans is not straightforward and any such comparison should be made with caution.

ferentiation of already differentiated cells. If injured or damaged cells

are removed from harmful exposure in the early stages of metaplasia,
before severe membrane damage and nuclear dissolution, the effects
can be reversible. If chemical exposure continues, irreversible cell
damage such as necrosis or malignant transformation can occur.18 In
this study, metaplasia was observed in the nasal mucosa after 3
months of RAFS exposure. Shusterman et al.19 reported that a neutrophilic inflammatory response can occur after acute exposure to either
ozone or VOCs and that metaplastic mucosal changes may emerge
after prolonged exposure to photochemical mixed-air pollutants. This
study supports our results.
The presence of metaplastic changes in the nasal mucosa is critical.
Although inflammatory processes can elevate the risk of cancer,
prolonged exposure to chemicals can also be a risk factor for nasal
and nasopharyngeal cancer. For instance, Chung et al.20 reported an
association between allergic rhinitis and nasopharyngeal carcinoma.
The present study does not allow us to make any allegations about
malignancy, and multicenter double-blind, controlled, comparative,
long-term studies are needed to investigate the potential connection.

28.6
100.0
100.0
100.0

Rate of Histopathological
Changes

Although edema and mild inflammatory cell infiltration, including some

eosinophils, was seen after the 2nd mo, squamous metaplasia, numerous
eosinophils, and intense inflammatory cell infiltration began after 3 mo of
exposure.
RAFS room air freshener spray.

Figure 4. Group 3/RAFS at 2 months shows mild inflammatory cell infiltration, including some eosinophils, and congestion of the vessels in the
subepithelial region (hematoxylin and eosin, 200).

Figure 5. Group 4/RAFS at 3 months shows nasal mucosal epithelium

(arrows) covered by stratified squamous epithelium and numerous eosinophils. Intense inflammatory cell infiltration and mild congestion in the
vessels of the subepithelial region (hematoxylin and eosin, 200).

CONCLUSION
Our histopathological results show that continuous use of RAFSs
can cause nonallergic inflammation in rats, which begins after 2
months of exposure and may lead to metaplasia after 3 months.
Although we obtained important and useful findings, further investigation is required to identify the causes of nonallergic disease and
examine different RAFS dosages. It is not possible to perform human
studies because of ethical and practical concerns. Therefore, the rat
will continue to be a useful model for investigating the effects on

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e207

7.

8.

9.
10.

11.
12.

Figure 6. This diagram shows the analysis of 97 room air freshener spray
(RAFS) samples.

nasal mucosa. However, additional studies, especially on long-term

treatment with different RAFSs, should be conducted. These results
are novel and the frequent use of these chemicals may have a significant effect on human health.

13.

14.

15.

ACKNOWLEDGMENTS
The authors thank Assistant Professor Yilmaz Palanci of the Department of Public Health, Dicle University School of Medicine, for
his valuable statistical assistance; Mehmet Zulkuf Akdag from the
Department of Biophysics for her valuable support; Nesrin Genisel
from the Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Dicle University; and DUBAP for their editing system.

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