Abstract
BackgroundThe epidemiologic evidence from observational studies on breast cancer risk and phthalates, endocrine disrupting chemicals, has been inconsistent. In the only previous study based on pre-diagnostic urinary phthalates and risk of breast cancer, results were null in mostly white women.MethodsWe examined the association between pre-diagnostic urinary phthalates and breast cancer in a nested case-control study within the Multiethnic Cohort (MEC) study, presenting the first data from five major racial/ethnic groups in the USA. We measured 10 phthalate metabolites and phthalic acid, using a sensitive liquid chromatography mass spectrometry assay on 1032 women with breast cancer (48 African Americans, 77 Latinos, 155 Native Hawaiians, 478 Japanese Americans, and 274 Whites) and 1030 matched controls. Conditional logistic regression was used to examine risk with individual metabolites and ratios of primary (MEHP, mono-2-ethylhexyl-phthalate) to secondary (MEHHP, mono(2-ethyl-5-hydroxyhexyl); MEOHP, mono(2-ethyl-5-oxohexy)) metabolites of di-2-ethylhexyl phthalate (DEHP), a widely used plasticizer. In addition, we investigated risk associations with high (∑HMWP) and low molecular weight (∑LMWP) phthalates, as well as total phthalates which included high and low molecular weight phthalates with phthalic acid (∑LMHMPA) or without phthalic acid in molar ratios (∑LMHMmolar) and adjusted for creatinine and potential confounders.ResultsAmong all women, breast cancer risk was higher for those in tertile 2 and tertile 3 of primary to secondary metabolites of DEHP (MEHP/(MEHHP + MEOHP)) in comparison to those in tertile 1; the respective odds ratios were 1.32 (95% CI 1.04–1.68) and 1.26 (95% CI 0.96–1.66) (Ptrend = 0.05). Risk among Native Hawaiian women increased with exposures to eight of ten individual phthalates and total phthalates (∑LMHMPA ORT3 vs T1 = 2.66, 95% CI 1.39–5.12, Ptrend = 0.001). In analysis by hormone receptor (HR) status, exposure above the median of ∑LMWP was associated with an increased risk of HR-positive breast cancer (OR = 1.30, 95% CI 1.05–1.60) while above the median exposure to phthalic acid was associated with an increased risk of HR-negative breast cancer (ORabove vs below median = 1.59, 95% CI 1.01–2.48).ConclusionsFurther investigations of suggestive associations of elevated breast cancer risk with higher ratios of primary to secondary metabolites of DEHP, and differences in risk patterns by race/ethnicity and HR status are warranted.
Highlights
Phthalates are industrial chemicals that are present in numerous consumer products and solvents, as additives, and plasticizers [1,2,3], and have known endocrine disrupting properties [4]
Phthalates are typically metabolized by phase I hydrolysis to their respective monoesters, followed by phase II conjugation, which depending on the specific phthalates can be further metabolized via oxidation to secondary metabolites [7]
Positive associations were reported in studies conducted in Northern Mexico [11] and Alaska [12] whereas null results were found in studies of mainly whites from the Women’s Health Initiative (WHI) [14] and the Long Island Breast Cancer Study Project (LIBCSP) [13]
Summary
Phthalates are industrial chemicals that are present in numerous consumer products and solvents, as additives, and plasticizers [1,2,3], and have known endocrine disrupting properties [4]. Mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MBP), and mono-benzyl phthalate (MBzP), metabolites of phthalates, frequently found in personal care products, were detectable in over 97% of urine samples while mono-2-ethylhexyl-phthalate (MEHP), a metabolite of di-2-ethylhexyl phthalate (DEHP), found commonly in plasticizers, food packaging, and household products, was detectable in over 75% of the samples. These high exposures were observed across all ages, in whites and nonwhites, there were age, sex, and racial/ethnic differences that likely reflected variations in exposure patterns [5] and differences in the metabolism of phthalates [6]. In the only previous study based on pre-diagnostic urinary phthalates and risk of breast cancer, results were null in mostly white women
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