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 bio available 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 bio available 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.

Human Breast Tissue Disposition and Bioactivity of Limonene in Women with Early-Stage Breast Cancer

“…Unlike perillyl alcohol, limonene is bioavailable in the systemic circulation in humans after oral administration (16). We, and others, have shown that limonene distributes favorably to adipose and mammary tissues in rodents (17, 18), likely due to its high lipophilicity. In addition, we have recently shown that limonene distributes extensively to adipose tissue in humans (19).…”

Expression of epidermal growth factor, transforming growth factor-β1 and adiponectin in nipple aspirate fluid and plasma of pre and post-menopausal women

“…Details of the trial have been described elsewhere [12]. Participants were excluded if they were pregnant or breastfeeding, had invasive cancers within the past 5 years, participated in another clinical intervention trial within the past 3 months, had uncontrolled metabolic disorders, serious acute or chronic diseases, or were unable to produce NAF.…”

Plasma Metabolomic Profiles of Breast Cancer Patients after Short-term Limonene Intervention

“…The underwhelming results of these trials reduced enthusiasm for limonene development. Unlike perillyl alcohol, limonene distributes favorably to adipose tissue in rodents [18, 19] and humans [20] resulting in tissue levels comparable to the active concentrations in preclinical models. Favorable distribution of limonene to adipose tissue suggests that evaluation of limonene’s potential clinical activity deserves further attention, particularly within the context of cancers arising from organs with high adiposity such as breast.…”