Table 4.

Epidemiologic studies of measurement of phthalates and bisphenols in a patient BC.

Study Population	Objective	Results/Conclusion	Ref.
Phthalates
Women with BC (233) residing in northern Mexico. 221 healthy women.	Phthalates were determined in urine samples by isotope dilution/high performance liquid chromatography coupled to tandem mass spectrometry.	Concentrations of mono-ethyl phthalate (MEP) were higher in cases (169.58 µg/g creatinine) than in controls (106.78 µg/g creatinine) Controls showed significantly higher concentrations of mono-n-butyl phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(3-carboxypropyl) phthalate (MCPP) than did the cases. The authors show for the first time that exposure to diethyl phthalate (DEP), the parent compound of MEP, may be associated with an increased risk of BC, whereas exposure to the parent phthalates of MBzP and MCPP (BBP and dioctyl phthalate, DOP, respectively) might be negatively associated with the incidence of this disease.	[20]
Association of phthalate exposures and breast cancer risk in a Danish nationwide cohort (1,122,042 women), using redeemed prescriptions for phthalate-containing drug products to measure exposure.	Drugs containing phthalates that were marketed in Denmark were registered in an internal Danish Medicines Agency database. The authors enrolled a Danish nationwide cohort of 1.12 million women at risk for a first cancer diagnosis on 1 January 2005. The authors calculated the annual cumulative phthalate exposure content of each filled prescription by multiplying the mass of phthalate per capsule by the fill amount. They calculated the cumulative milligrams of cellulose acetate (CAP) phthalate or polyvinyl acetate phthalate contained in all prescriptions filled by a patient during each year of follow-up. Finally, they made a multivariable Cox regression to estimate the associations between phthalate exposure and the incidence of invasive breast carcinoma according to the ER status of tumors.	High-level dibutyl phthalate (DBP) exposure (>10,000 cumulative mg) was associated with an approximately two-fold increase in the incidence rate of ER+ breast cancer. Cumulative exposures to DBP, cellulose acetate phthalate (CAP), and hydroxypropyl methylcellulose phthalate (HPMCP) were categorized as no exposure, 1 to 249 mg, 250 to 999 mg, 1000 to 9999 mg, and 10,000 mg or more. Cumulative exposure to DEP was categorized as unexposed, 1 to 9 mg, 10 to 99 mg, and 100 mg or more. Polyvinyl acetate phthalate (PVAP) exposure was rare and therefore modeled as a dichotomous variable (unexposed to any exposure [range, 1.3 to 682 cumulative grams]).	[21]
Case-control study within the Women’s Health Initiative (WHI) prospective cohort (419 invasive cases and 838 controls)	Quantification of 13 phthalate metabolites and creatinine in two or three urine samples per participant over one to three years	The urinary concentration of phthalates did not result in an increased risk of developing invasive BC in postmenopausal women. However, not entirely consistent, but the authors observed some positive effects between phthalate biomarker concentrations and BC diagnosed within three years. In addition, the majority of the positive association was significant for ER+/PR+ disease. It is worth noting that the positive effects estimated were closer to null and not statistically significant when analyses were extended to include case subjects diagnosed within five years or among the full study population. The above suggests that urine phthalate biomarker concentrations predict short-term, but not long-term BC risk. The authors grouped phthalate biomarkers by their parent phthalates by dividing the concentrations of each metabolite of a single parent by its molecular weight and then summing the concentrations across metabolites were corrected for creatinine concentration. The authors did not report a range of concentrations of phthalates, they reported the odds ratios established for each phthalate.	[22]
Case-control study of Alaskan native women 170 women (75 cases, 95 controls)	To measure the association between exposure to environmental chemicals and breast cancer. Seven to ten phthalate metabolites were measured in urine samples.	The authors found a potential association for DEHP exposure, which results in high levels of monoethylhexyl phthalate (MEHP) metabolites and the progression of breast cancer. The concentrations of phthalate metabolites were creatinine corrected (3.5 µg/g creatinine in controls and 5.3 µg/g creatinine in cases). Although urinary concentrations for most of the 7 phthalates metabolites were higher among cases than controls, these differences were not statistically significant. 40 of the 62 women who had invasive tumors had BC with an ER+/PR+ phenotype; the rest of them were negative for hormone markers. Urine concentrations were higher in 3 of 7 phthalate metabolites among women with ER-/PR-tumors. The differences were not statistically significant	[23]
Women resident of northern Mexico with histologically confirmed BC (233 individuals) and healthy controls (221 individuals)	To evaluate if phthalate exposure interacts with a flavonoid diet to promote the risk of BC. Urinary metabolites concentrations of nine phthalates were made and corrected to creatinine concentration.	A higher intake of anthocyanidins and flavan-3-ols (from vegetables), synergistically increased the a negative association between monobenzyl phthalate (MBzP), a metabolite of BBP, and the risk of BC. The consumption of some flavonoids may interact with exposure to phthalates with the risk of BC. Concentrations of urine metabolites of phthalates were found in a range of (5–139 μg/g creatinine).	[24]
U.S women with BC (cases = 43, controls = 1964 individuals)	Examination the relationship between the exposure to different endocrine disruptor compounds such as polychlorinated biphenyls (PCBs), BPA or phthalates; and risk of BC in U.S. women. The authors measured the urinary levels (ng/g) of BPA and ten metabolites of phthalates. Urinary levels were corrected to the creatinine concentration.	There were no significant associations between phthalates or BPA and BC.	[25]
Meta-analysis Search in the literature with different databases were performed in PubMed, Embase, and Cochrane library (2288 articles were included)	Assessment of the association between urinary phthalate metabolites and risk of BC and uterine leiomyoma.	DEHP metabolites were associated with an increased risk of BC as well as uterine leiomyoma. Important considerations for the authors: The ranges of cut-off levels of urinary phthalate metabolites were not consistent among the studies, which affect the general conclusions. Most of the studies reviewed analyzed the exposure of phthalates at a specific point in the disease, but it was impossible to calculate exactly the cumulative exposure dose, which might lead to limited conclusions. It is necessary to extend the study to different geographic regions or ethnic populations	[26]
Bisphenols
Polish women with or without BC in post-menopause. (1962) BC cases (1338 postmenopausal) and 2241 controls (1529 postmenopausal)	To evaluate the association between urinary unconjugated BPA and a metabolite of BPA, the BPA-glucuronide (BPA-G) and risk of BC in postmenopausal women from Poland. Urinary levels of BPA-G were calculated and creatinine-adjusted (ng-BPa-G/mg creatinine). The range of BPA concentrations for BC cases was around 2.29–4.78 ng/mg; and in controls was 2.76 ng/mg	There was no association between BPA-G and women with BC in the postmenopausal stage.	[27]
711 women with BC and 598 women without BC belonged to Nassau and Suffolk Counties on Long Island, NY	To evaluate the association of seven urinary phenol biomarkers and BC incidence with subsequent mortality. The authors also examined the effect measure modification by body mass index (BMI). The measurements were made in urine samples and corrected for concentrations of creatinine	The concentrations of BPA found in the control group were around 1.2 μg/g creatinine and 1.3 in women with BC. There was no association between BPA levels and BC incidence. Mortality associations were more pronounced among women with high body mass index. BC incidences were strongly related to urinary concentrations of parabens	[28]
Korean women with or without BC (N = 167)	Potential associations between BPA exposure and risk of BC in Korean women among patients with BC and controls (N = 167). The levels of BPA were monitored in serum samples (μg/L)	There were no significant differences in the serum levels of BPA (conjugated + free form) between the cases and controls. The range of conjugated BPA levels was 0–13.87 μg/L, and the levels of free BPA were 0.012–0.04 μg/L.	[29]