Department of Preventive Medicine, University of Southern California Keck School of Medicine, 1441 Eastlake Avenue, Rm 4443, Los Angeles, CA, 90089, USA.
University of Hawaii Cancer Center, Honolulu, HI, USA.
Breast Cancer Res. 2021 Apr 6;23(1):44. doi: 10.1186/s13058-021-01419-6.
The 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.
We 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 (∑LMHM) and adjusted for creatinine and potential confounders.
Among 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) (P = 0.05). Risk among Native Hawaiian women increased with exposures to eight of ten individual phthalates and total phthalates (∑LMHMPA OR = 2.66, 95% CI 1.39-5.12, P = 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 (OR = 1.59, 95% CI 1.01-2.48).
Further 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.
基于观察性研究的乳腺癌风险与邻苯二甲酸酯（内分泌干扰化学物质）的流行病学证据并不一致。在之前唯一一项基于诊断前尿液邻苯二甲酸酯和乳腺癌风险的研究中，结果在大多数白人女性中呈阴性。
我们在多民族队列（MEC）研究中进行了一项嵌套病例对照研究，以检查诊断前尿液邻苯二甲酸酯与乳腺癌之间的关联，该研究首次提供了来自美国五个主要种族/族裔群体的数据。我们使用灵敏的液相色谱-质谱联用测定法测量了 1032 名乳腺癌患者（48 名非裔美国人、77 名拉丁裔人、155 名夏威夷原住民、478 名日裔美国人、274 名白种人）和 1030 名匹配对照者的 10 种邻苯二甲酸酯代谢物和邻苯二甲酸。使用条件逻辑回归来检查个体代谢物和二-2-乙基己基邻苯二甲酸（DEHP）中主要（MEHP，单-2-乙基己基邻苯二甲酸）与次要（MEHHP，单（2-乙基-5-羟基己基）；MEOHP，单（2-乙基-5-氧代己基））代谢物的比例与乳腺癌风险之间的相关性，DEHP 是一种广泛使用的增塑剂。此外，我们还研究了与高分子量（∑HMWP）和低分子量（∑LMWP）邻苯二甲酸以及包括高分子量和低分子量邻苯二甲酸与邻苯二甲酸（∑LMHMPA）或摩尔比无邻苯二甲酸（∑LMHM）的总邻苯二甲酸与肌酐和潜在混杂因素调整后的风险关联。
在所有女性中，与 tertile 1 相比，DEHP 中主要到次要代谢物（MEHP/（MEHHP + MEOHP））处于 tertile 2 和 tertile 3 的女性乳腺癌风险更高；相应的比值比分别为 1.32（95%CI 1.04-1.68）和 1.26（95%CI 0.96-1.66）（P=0.05）。夏威夷原住民女性的风险随着对十种个体邻苯二甲酸酯和总邻苯二甲酸（∑LMHMPA）的暴露而增加（OR=2.66，95%CI 1.39-5.12，P=0.001）。根据激素受体（HR）状态进行分析，∑LMWP 中位数以上的暴露与 HR 阳性乳腺癌的风险增加相关（OR=1.30，95%CI 1.05-1.60），而邻苯二甲酸中位数以上的暴露与 HR 阴性乳腺癌的风险增加相关（OR=1.59，95%CI 1.01-2.48）。
需要进一步研究提示与 DEHP 中主要到次要代谢物的比值升高以及种族/族裔和 HR 状态的风险模式差异相关的升高乳腺癌风险的关联。
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