JCT  Vol.3 No.5 A , October 2012
Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast
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 mammary 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 conducted 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 mammary 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 application, although NAF and plasma limonene concentrations were not significantly changed after the massage oil application. 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.
Cite this paper: J. A. Miller, P. A. Thompson, I. A. Hakim, A. Maria Lopez, C. A. Thomson, W. Chew, C. Hsu and H. Sherry Chow, "Safety and Feasibility of Topical Application of Limonene as a Massage Oil to the Breast," Journal of Cancer Therapy, Vol. 3 No. 5A, 2012, pp. 749-754. doi: 10.4236/jct.2012.325094.

[1]   C. E. Elson, T. H. Maltzman, J. L. Boston, M. A. Tanner and M. N. Gould, “Anti-Carcinogenic Activity of d-Limonene during the Initiation and Promotion/Progression Stages of DMBA-Induced Rat Mammary Carcinogenesis,” Carcinogenesis, Vol. 9, No. 2, 1988, pp. 331-332. doi:10.1093/carcin/9.2.331

[2]   J. D. Haag, M. J. Lindstrom and M. N. Gould, “Limonene-Induced Regression of Mammary Carcinomas,” Cancer Research, Vol. 52, No. 14, 1992, pp. 4021-4026.

[3]   T. H. Maltzman, L. M. Hurt, C. E. Elson, M. A. Tanner and M. N. Gould, “The Prevention of Nitrosomethylurea-Induced Mammary Tumors by d-Limonene and Orange Oil,” Carcinogenesis, Vol. 10, No. 4, 1989, pp. 781-783. doi:10.1093/carcin/10.4.781

[4]   M. N. Gould, C. J. Moore, R. Zhang, B. Wang, W. S. Kennan and J. D. Haag, “Limonene Chemoprevention of Mammary Carcinoma Induction following Direct in Situ Transfer of V-Ha-Ras,” Cancer Research, Vol. 54, No. 13, 1994, pp. 3540-3543.

[5]   J. A. Elegbede, C. E. Elson, M. A. Tanner, A. Qureshi and M. N. Gould, “Regression of Rat Primary Mammary Tumors following Dietary d-Limonene,” Journal of the National Cancer Institute, Vol. 76, No. 2, 1986, pp. 323-325.

[6]   K. Zhao and J. Singh, “Mechanism(s) of in Vitro Percutaneous Absorption Enhancement of Tamoxifen by Enhancers,” Journal of Pharmaceutical Sciences, Vol. 89, No. 6, 2000, pp. 771-780. doi:10.1002/(SICI)1520-6017(200006)89:6<771::AID-JPS9>3.0.CO;2-Y

[7]   P. A. Cornwell, B. W. Barry, C. P. Stoddart and J. A. Bouwstra, “Wide-Angle X-Ray Diffraction of Human Stratum Corneum: Effects of Hydration and Terpene Enhancer Treatment,” Journal of Pharmacy and Pharmacology, Vol. 46, No. 12, 1994, pp. 938-950. doi:10.1111/j.2042-7158.1994.tb03248.x

[8]   K. Cal, S. Janicki and M. Sznitowska, “In Vitro Studies on Penetration of Terpenes from Matrix-Type Transdermal Systems through Human Skin,” International Journal of Pharmaceutics, Vol. 224, No. 1-2, 2001, pp. 81-88. doi:10.1016/S0378-5173(01)00744-X

[9]   J. R. Trevithick and K. P. Mitton, “Uptake of Vitamin E Succinate by the Skin, Conversion to Free Vitamin E, and Transport to Internal Organs,” Biochemistry & Molecular Biology International, Vol. 47, No. 3, 1999, pp. 509-518.

[10]   J. A. Schroeder, A. A. Masri, M. C. Adriance, J. C. Tessier, K. L. Kotlarczyk, M. C. Thompson and S. J. Gendler, “MUC1 Overexpression Results in Mammary Gland Tumorigenesis and Prolonged Alveolar Differentiation,” Oncogene, Vol. 23, No. 34, 2004, pp. 5739-5747. doi:10.1038/sj.onc.1207713

[11]   S. Wang, Y. Chen, Z. Gao, M. Xiong, Z. Zhong and L. Ye, “Gas Chromatographic-Mass Spectrometric Analysis of d-Limonene in Human Plasma,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 44, No. 5, 2007, pp. 1095-1099. doi:10.1016/j.jpba.2007.04.018

[12]   J. A. Miller, I. A. Hakim, C. Thomson, P. Thompson and H. H. Chow, “Determination of d-Limonene in Adipose Tissue by Gas Chromatography-Mass Spectrometry,” Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, Vol. 870, No. 1, 2008, pp. 68-73. doi:10.1016/j.jchromb.2008.06.002

[13]   M. Matura, A. Goossens, O. Bordalo, B. Garcia-Bravo, K. Magnusson, K. Wrangsjo and A. T. Karlberg, “Patch Testing with Oxidized R-(+)-Limonene and Its Hydroperoxide Fraction,” Contact Dermatitis, Vol. 49, No. 1, 2003, pp. 15-21. doi:10.1111/j.0105-1873.2003.00135.x

[14]   H. Pujol, J. Girault, P. Rouanet, S. Fournier, J. Grenier, J. Simony, J. B. Fourtillan and J. L. Pujol, “Phase I Study of Percutaneous 4-Hydroxy-Tamoxifen with Analyses of 4-Hydroxy-Tamoxifen Concentrations in Breast Cancer and Normal Breast Tissue,” Cancer Chemotherapy and Pharmacology, Vol. 36, No. 6, 1995, pp. 493-498. doi:10.1007/BF00685799

[15]   P. Rouanet, G. Linares-Cruz, F. Dravet, S. Poujol, S. Gourgou, J. Simony-Lafontaine, J. Grenier, A. Kramar, J. Girault, E. Le Nestour, et al., “Neoadjuvant Percutaneous 4-Hydroxytamoxifen Decreases Breast Tumoral Cell Proliferation: A Prospective Controlled Randomized Study Comparing Three Doses Of 4-Hydroxytamoxifen Gel to Oral Tamoxifen,” Journal of Clinical Oncology, Vol. 23, No. 13, 2005, pp. 2980-2987. doi:10.1200/JCO.2005.06.064

[16]   J. A. Miller, I. A. Hakim, W. M. Chew, P. A. Thompson, C. A. Thomson and H. H. Chow, “Adipose Tissue Accumulation of D-Limonene with the Consumption of a Lemonade Preparation Rich in D-Limonene Content.” Nutrition and Cancer, Vol. 6, No. 62, 2010, pp. 783-788. doi:10.1080/01635581003693066

[17]   P. L. Crowell, S. Lin, E. Vedejs and M. N. Gould, “Identification of Metabolites of the Antitumor Agent d-Limonene Capable of Inhibiting Protein Isoprenylation and Cell Growth,” Cancer Chemotherapy and Pharmacology, Vol. 31, No. 3, 1992, pp. 205-212. doi:10.1007/BF00685549

[18]   M. Magnano, S. Silvani, C. Vincenzi, M. Nino and A. Tosti, “Contact allergens and Irritants in Household Washing and Cleaning Products,” Contact Dermatitis, Vol. 61, No. 6, 2009, pp. 337-341. doi:10.1111/j.1600-0536.2009.01647.x

[19]   Association FaEM, “d-Limonene Monograph,” No. 1991, pp. 1-4.

[20]   Geneva WHO, International Programme on Chemical Safety (No. 0918), “International Chemical Safety Card-d-Limonene.” 1993.

[21]   A. S. Malik, O. Boyko, N. Atkar and W. F. Young, “A Comparative Study of MR Imaging Profile of Titanium Pedicle Screws,” Acta Radiologica, Vol. 42, No. 3, 2001, pp. 291-293. doi:10.1080/028418501127346846