Journal of Cancer Therapy, 2012, 3, 749-754
http://dx.doi.org/10.4236/jct.2012.325094 Published Online October 2012 (http://www.SciRP.org/journal/jct)
749
Safety and Feasibility of Topical Application of Limonene
as a Massage Oil to the Breast
Jessica A. Miller1,*, Patricia A. Thompson1, Iman A. Hakim2, Ana Maria Lopez1,
Cynthia A. Thomson2,3, Wade Chew1, Chiu-Hsieh Hsu2, H.-H. Sherry Chow1
1The University of Arizona Cancer Center, Tucson, USA; 2Mel & Enid Zuckerman College of Public Health, The University of Ari-
zona, Tucson, USA; 3Department of Nutritional Sciences, The University of Arizona, Tucson, USA.
Received July 10th, 2012; revised August 12th, 2012; accepted August 23rd, 2012
ABSTRACT
Background: Limonene, a major component in citrus oil, has demonstrated anti-cancer effects in preclinical mammary
cancer models. However, the effective oral dose translates to a human dose that may not be feasible for chronic dosing.
We proposed to evaluate topical application of limonene to the breast as an alternative dosing strategy. Materials and
Methods: We conducted a mouse disposition study to determine whether limonene would be bioavailable in the mam-
mary tissue after topical application. SKH-1 mice received topical or oral administration of limonene in the form of
orange oil every day for 4 weeks. Plasma and mammary pads were collected 4 hrs after the final dosing. We also con-
ducted an exploratory clinical study to evaluate the safety and feasibility of topically applied limonene in the form of
orange oil to the breast. Healthy women were recruited to apply orange oil containing massage oil to their breasts daily
for four weeks. Safety and feasibility were assessed by reported adverse events, clinical labs, and usage compliance. Pre
and post-intervention nipple aspirate fluid (NAF) and plasma were collected for limonene concentration determination.
Results: The mouse disposition study showed that topical and oral orange oil administration resulted in similar mam-
mary tissue disposition of limonene with no clinical signs of toxicity. In the clinical study, the topical application of
limonene containing massage oil to the breast was found to be safe with high levels of usage compliance for daily ap-
plication, although NAF and plasma limonene concentrations were not significantly changed after the massage oil ap-
plication. Conclusions: Our studies showed that limonene is bioavailable in mammary tissue after topical orange oil
application in mice and this novel route of administration to the breast is safe and feasible in healthy women.
Keywords: Limonene; Topical Application; Safety
1. Introduction
Limonene, a monocyclic monoterpene, is a major com-
ponent of the essential oils of citrus fruits. It has been
associated with diverse biological activities, including
antitumor activity, with the most compelling results re-
ported in mammary cancer models. In carcinogen in-
duced rat mammary carcinogenesis models, limonene fed
during the initiation or promotion/progression stage in-
hibits the development of tumors induced by 7,12-di-
methylbenz(a)anthracene (DMBA) or tumors induced by
N-methyl-N-nitrosourea (NMU) [1-3]. Dietary feeding of
limonene also inhibits the development of ras onco-
gene-induced mammary carcinomas in rats [4]. Limo-
nene has also been shown to exert chemotherapeutic ac-
tivity. Oral feeding of limonene results in significant re-
gression of both DMBA- and NMU-induced mammary
carcinoma in a dose dependent manner, without any ob-
servable systemic toxicity [2,5].
A major limitation for further development of limo-
nene for breast cancer prevention or treatment is that the
effective doses determined in animal studies translate to
human equivalent doses not feasible for chronic human
intake. We proposed to evaluate topical application of
limonene to the breast as an alternative dosing strategy
because limonene has long been explored as an enhancer
for dermal absorption of pharmaceutical drugs by inter-
acting with intercellular stratum corneum lipids to in-
crease diffusibility of drugs through the skin [6,7]. In
addition, in vitro studies using isolated human skin have
shown that topically applied limonene can penetrate
through human epidermis and dermis [8]. Here, we re-
port a mouse tissue disposition study and a clinical safety
and tolerability study conducted to evaluate the safety
and feasibility of topical limonene administration to the
breast.
*Corresponding author.

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast
750
2. Methods
2.1. Study Agent
Limonene-containing essential oils are already in use in
aromatherapy massage with no reported clinical toxicity.
We have therefore used a similar preparation for both
animal and human studies to expedite the conduct of cli-
nical research. Organicorange essential oil (NOW Foods,
Bloomingdale, IL, USA) was selected as the source of
limonene. The limonene content in the orange oil was
quantified by gas chromatography-mass spectrometry
(GC-MS) analysis and found to be 93%. Essential oils
are typically diluted with carrier or base oil prior to use
for massage. We selected the fractionated coconut oil
(From Nature with Love, Oxford, CT, USA) as the base
oil because it is a light, non-greasy, non-staining, liquid
oil. There are claims that it helps to carry therapeutical
oils under the skin [9].
2.2. Mouse Disposition Study
Pathogen-free hairless mice (female SKH-1 mice, 4-5
weeks of age, 19.5 - 22.3 g) were purchased from
Charles River Laboratories (Wilmington, MA, USA).
These mice werehoused in temperature and light-con-
trolled rooms and were given water and fed ad libitum.
Mice were divided into seven experimental groups (N =
4 per group); untreated control, topical control receiving
only topical application of base oil, oral control receiving
only oral administration of base oil, topical application of
10% orange oil in base oil, topical application of 20%
orange oil in base oil, oral administration of 10% orange
oil in base oil, and oral administration of 20% orange oil
in base oil. For topical application, 80 μL of the mixed
oil or base oil were applied to the skin directly above the
mammary pads. An Elizabethan collar was placed on the
mice for 20 min after the topical application to prevent
the mice from licking the topically applied oil. For oral
administration, 80 μL of the mixed oil or base oil were
administered via oral gavage. The dose of limonene ad-
ministered was determined to be 6.0 and 12 mg for the
10% and 20% mixed oil, respectively. The administration
was carried out daily for four weeks. At the end of the
four-week administration, mice from each treatment
group were sacrificed 4 hours after the last applica-
tion/dosing. Plasma and left mammary pads were col-
lected for limonene concentration determination. The
fourth right mammary fat pad was collected for whole-
mount histological evaluation [10]. The experimental
protocols for the animal experiments were approved by
the Institutional Animal Care and Use Committee at the
University of Arizona. Studies were performed according
to these ethical guidelines.
2.3. Human Safety and Tolerability Study
We recruited women who were 18 - 65 years of age, had
good performance status, had normal organ and marrow
function, were willing to use adequate contraception,
were willing to avoid citrus products throughout the
study, and had both breasts intact for study participation.
Women were excluded if they were pregnant or breast
feeding, had invasive cancers within the past 5 years,
participated in another clinical intervention trial within
the past 3 months, had uncontrolled severe metabolic
disorders or other serious acute or chronic diseases, were
unable to produce nipple aspirate fluid, had known aller-
gic or sensitive reactions to skin care products, citrus or
coconut oil, or had ongoing skin disorders such as ec-
zema and psoriasis. The study was approved by the Uni-
versity of Arizona Human Subjects Committee and writ-
ten consent was obtained from all participants.
At the initial clinic visit, participants had a blood sam-
ple collected for complete blood count (CBC) with dif-
ferential and a comprehensive blood chemistry panel. A
urine pregnancy test was performed for women who
were not surgically sterile or were less than one year
post-menopausal. A complete medical history was ob-
tained. Height, weight, blood pressure, pulse, and tem-
perature measurements were obtained.
Participants who met all eligible criteria were asked to
refrain from citrus and citrus-containing productsfor a
minimum of four weeks (washout period). Following the
washout period, participants returned to the clinic for
baseline NAF and plasma sample collection. NAF was
collected into small capillary tubes and then immediately
diluted in phosphate buffered saline (1:10). Plasma and
diluted NAF were stored at –80˚C for limonene concen-
tration determination. Following baseline sample collec-
tion, participants underwent their first massage session in
the clinic. The massage oil was prepared fresh by blend-
ing 3 drops of organic orange oil (containing 0.14 g of
limonene) with 1.35 mL base oil to give a final orange
oil concentration of 10%. Participants were instructed to
wear surgical gloves and use their fingertips to massage
the blended massage oil to the breasts in a circular fash-
ion with slight pressure, avoiding areola and nipples, for
5 minutes. Participants were then provided with massage
oil supplies for daily massage application. Participants
were instructed that the massage application could be
performed after showering or bathing and should be at
least 8 hours before next showing/bathing. Participants
were advised to avoid exposing their breasts to direct
sunlight or a tanning bed throughout the intervention
period and were provided with a daily diary to record
adverse events and time of massage application. Follow-
ing the 4-week daily massage intervention, participants

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast 751
returned to the clinic the day after their last massage ap-
plication. Blood and NAF were collected and stored at
–80˚C for limonene concentration determination. Addi-
tional blood samples were collected for post- intervention
CBC and blood chemistry. Massage oil supplies and di-
ary were examined to evaluate compliance. Adverse
events were recorded for two more weeks after the mas-
sage intervention.
2.4. Limonene Concentration Determination
Limonene concentrations in plasma and NAFwere de-
termined using a published assay [11] with minor modi-
fications. Briefly, plasma or NAF samples (50 μL) were
mixed with an equal volume of the internal standard so-
lution (1.2 μg/mL of perillyl aldehyde in 100% acetoni-
trile) andthen extracted with hexane. An aliquot of the
hexane layer was injected into the GC-MSsystem. The
GC-MS system consisted of a GC with a PVT injector
and a DSQ mass spectrometer (Thermo Electron Corpo-
ration, San Jose, CA, USA). Chromatographic separation
of limonene and internal standard was achieved on a high
resolution GC DB-5MS fused silica capillary column
(AgilentTechnologies, Santa Clara, CA, USA). The cali-
bration curve was linear over the concentration range of
5 ng/mL to 2000 ng/mL.
Limonene concentrations in mouse mammary pads
were analyzed according to a method developed in our
laboratory with minor modifications [12]. Mammary
pads were weighed and incubated at 37˚C for 2.5 hours
with 30 µL of 30% potassium hydroxide and 100µL
ethanol to induce saponification. After cooling to room
temperature, 300µL hexane, 50 µL purified H2O, and 10
µL internal standard solution (1.2 µg/mL of perillyl al-
dehyde in methanol) were added. Samples were vortexed
and then centrifuged. An aliquot of the organic layer was
injected into the GC-MS system as described above.
Calibration curves were linear over the range of 6.25 -
2000 ng limonene.
2.5. Statistical Analysis
For the mouse study, plasma or mammary tissue limo-
nene concentrations were compared between oral and
topical administrationat the same dose levelusing the
Wilcoxon rank sum test. Plasma or mammary tissue
limonene concentrations were also compared between
the two dose levels (10% vs. 20% dose groups) for the
same route of administrationusing the Wilcoxon rank
sum test. For the clinical study, NAF or plasma limonene
concentrations between baseline and post-intervention
were compared using the signed rank test. A P-value of <
0.05 was considered statistically significant for all
analyses.
3. Results
3.1. Mouse Disposition Study
Table 1 summarizes mammary tissueand plasmalimo-
nene concentrations from each treatment group. At 4 hrs
after the last dose, mammary tissue limonene concentra-
tions were 47.95 ± 33.96, 44.55 ± 13.21, 46.00 ± 14.37,
115.4 ± 85.43 µM for topical application with 10% or-
ange oil, oral administration with 10% orange oil, topical
application with 20% orange oil, oral administration with
20% orange oil, respectively. All control groups had no
detectable levels of limonene in the mammary tissue
(data not shown). The limonene levels were not different
between topical and oral administration. The limonene
levels were also similar between 10% and 20% dose lev-
els. Limonene levels in the mammary tissue were sig-
nificantly higher than those in matched plasma; on aver-
age 1000-fold higher (Ps < 0.05).
There were no clinical signs of toxicity in any of the
treatment groups. Mammary gland whole-mount prepa-
rations were evaluated for histopathological changes.
As Figure 1 illustrates, no remarkable treatment-related
changes in ductal structure or gland morphology were
observed.
Table 1. Limonene levels in mouse mammary tissue and
plasma after four weeks of daily oral or topical limonene
administration.
Mammary
tissue (M) Plasma (M) Mammary
tisue/Plasma ratio
10% Topical
(N = 4) 47.95 ± 33.96a,b 0.02 ± 0.01 4105 ± 4183
20% Topical
(N = 4) 46.00 ± 14.37b0.02 ± 0.01 3063 ± 2286
10% Oral
(N = 4) 44.55 ± 13.21b0.08 ± 0.11 1434 ± 1195
20% Oral
(N = 4) 115.39 ± 85.43b0.02 ± 0.01 4828 ± 2516
a Mean ± SD; b Significantly higher than plasma (P < 0.05).
Figure 1. Mammary gland whole mounts (a) untreated con-
trol (b) topically applied limonene (c) orally administered
limonene demonstrated that limonene did not adversely
affect normal mammary gland morphology.

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast
752
3.2. Human Safety and Tolerability Study
Forty-four eligible women initiated the massage inter-
vention. Table 2 summarizes participant demographic
data. Four weeks of daily topical application of limonene
containing massage oil was found to be well tolerated.
One woman withdrew from the intervention after a single
massage session due to intolerance to the citrus aroma.
Forty-three completed the study intervention. Table 3
summarizes adverse events (AEs) deemed possibly or
probably related to the study agent. Most AEs were mild
and limited to dermatology-related events at the applica-
tion site. Five women reported mild itching or tingling at
the application site, but continued the study without
dose-reduction. Four women developed a rash in the
sun-exposed area of the application site. The rash was
mild to moderate; all women completed the study with-
out dose reduction. The orange oil preparation used in
these women was analyzed by GC-MS and found to have
increased levels of an oxygenated limonene by-product
(limonene oxide), which has been previously associated
with skin irritation [13]. Subsequent participants were
Table 2. Participants’ demographic data.
Premenopausal Women 16
Postmenopausal Women 28
Age 51.7 ± 9.7a
Body Mass Index (kg/m2) 26.3 ± 4.8a
Race: n (%)
Caucasian 38 (86.3)
Black 2 (4.5)
Native American 2 (4.5)
Unknown 2 (4.5)
a Mean + SD.
Table 3. Summary of possibly or probably related adverse
eventsa.
Adverse Event n (%)
Itching 5 (11.4)
Rash 4 (9.1)
Dry Skin 2 (4.5)
Lightening Skin Color 1 (2.3)
Burning Sensation 1 (2.3)
Acne 1 (2.3)
Headaches 1 (2.3)
aAll events were mild grade except for one rash which was
moderate grade.
supplied with a new batch of orange oil that was tested to
have undetectable levels of limonene oxide and no fur-
ther participants experienced similar rashes. There were
no changes in hematology measurements or blood chem-
istry following 4 weeks of orange oil application (data
not shown). In addition, the intervention was found to
have an average usage compliance of 96.8%, calculated
based on the number of massage oil vials used during the
intervention.
Figure 2 illustrates baseline and post-intervention lev-
els of limonene in matched NAF and plasmasamplesfrom
10 individuals who had sufficient NAF yield. Limonene
levels in NAF were 95.11 ± 50.02 nM at baseline and did
not change significantly after the intervention. Plasma
limonene concentrations were 18.60 ± 24.02 nM at base-
line and were also unchanged after the intervention. In-
terestingly, NAF limonene levels were significantly higher
than the time-matched plasma (P < 0.01).
4. Discussion
The concept of topical application of drugs to the breast
is novel and may provide potential for localized drug
Figure 2. NAF and plasma limonene concentrations at base-
line and after 4 weeks of topical application of limonene
containing massage oil. Limonene levels in NAF were 95.11
± 50.02 nM at baseline and were not significantly different
post-intervention. Plasma limonene concentrations were
18.60 ± 24.02 nM at baseline and were also not significantly
different post-intervention. NAF limonene levels were sig-
nificantly higher than the time-matched plasma (P < 0.01).

Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast 753
delivery with minimal systemic side effects. Studies have
shown that topical application of 4-hydroxyta- moxifen,
the active metabolite of tamoxifen, to the breast resulted
in effective mammary tissue concentration of 4-hydroxy-
tamoxifen with much lower plasma levels [14]. A re-
cent study showed that topical application of 4-hydroxy-
tamoxifen to the breast resulted in reductions in breast
tumor tissue proliferation indexes similar to that seen
with oral administration of tamoxifen [15].
In our study, similar limonene levels were observed in
the mouse mammary pads after oral and topical limonene
administration as orange oil blended with base oil. Two
different limonene dose levels (equivalent to 6 and 12 mg
limonene dose daily) did not result in a dose dependent
increase in the limonene levels in the mammary pads.
Consistent with its high lipophilicity and previous find-
ings in humans [16] and rodents [17], limonene demon-
strated preferential mammary tissue-to-plasma distribu-
tion in mice. Plasma concentrations of limonene were on
average between 0.015 - 0.08 µM, with mammary tissue
levels over 1000-fold higher.
With the demonstration of mammary tissue bioavail-
ability of limonene following topical application in mice,
we conducted a pilot clinical study to determine the
safety and feasibility of topical limonene application in
healthy women. Our pilot study showed that topical ap-
plication of limonene containing massage oil was met
with excellent compliance and good safety profile. Side
effects associated with orange oil application were
mostly mild and limited to dermatological events at the
application site. The rashes developed at the application
site were most likely attributed to an oxidized limonene
by-product and could be avoided by pre-testing the con-
tent of the oxidized limonene by-product in the orange
oil supplies. Additionally, this study demonstrates that
women are willing to apply a topical agent to their breast
daily, providing a potential alternative for women un-
willing or unable to take a daily oral drug.
Interestingly, limonene was detectable at baseline
specimens in most participants despite of a 4-week
washout period. Because limonene is present in many
household cleaning products [18], in the environment
[19], and in foods [20,21], presence of low levels of
limonene in plasma and NAF at baseline was not unex-
pected. However, limonene levels were not changed in
NAF or plasma after four weeks of daily orange oil ap-
plication even though prior in vitro studies have shown
that topically applied limonene can penetrate through
human epidermis and dermis [8]. It is plausible that topi-
cally applied limonene as massage oil has limited ab-
sorption through human breast skin. It is also likely that
dermally absorbed limonene, if any, may concentrate in
the breast adipose tissue with minimal secretion into
NAF or distribution into systemic circulation. Future
clinical studies should consider incorporation of direct
breast tissue sampling such as in women undergoing
breast reduction surgery to assess tissue limonene levels.
In summary, topical administration of limonene to
mice led to high mammary tissue limonene levels with-
out affecting normal mammary gland morphology. A
similar formulation given to women for topical applica-
tion to the breast was met with high compliance and tol-
erability. Future research should assess the efficacy of
topical limonene application in mammary cancer models
and develop topical formulations that may further en-
hance breast tissue drug delivery.
5. Acknowledgements
We would like to thank Donna Vining and Heidi Fritz for
their assistance in the clinical study conduct.
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