Introduction
Phthalates are industrial chemicals that are present in numerous consumer products and solvents, as additives, and plasticizers [
1‐
3], and have known endocrine disrupting properties [
4]. Results from the Third National Health and Nutrition Examination Survey (NHANES III) showed ubiquitous exposure of the US population to a wide variety of phthalates [
5]. 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, although there were age, sex, and racial/ethnic differences that likely reflected variations in exposure patterns [
5] and differences in the metabolism of phthalates [
6]. 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].
Phthalates have been implicated to influence developmental and reproductive processes and exert carcinogenic effects [
1,
8‐
10]. However, epidemiological evidence on the association between phthalate exposure and breast cancer risk remains inconsistent. The first two case-control studies reported significantly elevated risk in relation to exposure to MEP, mono(2ethyl-5-carboxy-pentyl) phthalate (MECPP) [
11] and MEHP [
12], but they were small studies (75 to 233 breast cancers), and measurements were conducted in post-diagnosis samples. Urinary phthalate exposures were unrelated to risk in two larger studies (~ 400–700 breast cancers) [
13,
14]; only one investigated exposures before diagnosis [
14]. These studies differed in study design, sample size, inclusion of in situ and invasive breast cancers [
13,
14], and race/ethnicity composition. Positive associations were reported in studies conducted in Northern Mexico [
11] and Alaska (mostly Eskimos, Indians, and Aleut) [
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]. Breast cancer risk was also associated with di-methyl-phthalate (DMP) exposure in a Danish prospective registry study which quantified phthalate exposure using prescription files [
15].
To further investigate the role of pre-diagnostic urinary phthalates and breast cancer risk, we conducted a nested case-control in the Multiethnic Cohort (MEC) study [
16] that included 274 whites and 758 nonwhites (478 Japanese Americans, 155 Native Hawaiians, 77 Latinos, and 48 African Americans) diagnosed with incident breast cancer, and individually matched control women.
Results
The majority of participants (86%) were from Hawaii, who donated overnight (875 cases, 873 controls) or first morning urines (8 cases, 8 controls), whereas only first morning samples (149 cases, 149 controls) were collected in Los Angeles County (Table
1). Cases compared to control women were more likely to be nulliparous (15.8% vs 10.8%) and had higher BMI at urine collection (27.0 ± 5.6 vs 26.0 ± 5.6 kg/m
2), but were otherwise comparable.
Table 1
Study characteristics of breast cancer cases nested within the Multiethnic Cohort (MEC)
Area |
Hawaii | 883 | 85.6 | 881 | 85.5 |
Los Angeles | 149 | 14.4 | 149 | 14.5 |
Urine typea |
First morning | 157 | 15.2 | 157 | 15.2 |
Overnight | 875 | 84.8 | 873 | 84.8 |
Mean age at urine collection, yrs ± SD | 66.7 ± 7.7 | | 66.8 ±7.7 | |
≤ 64 | 487 | 47.2 | 470 | 45.6 |
65–74 | 376 | 36.4 | 387 | 37.6 |
75+ | 169 | 16.4 | 173 | 16.8 |
Race/ethnicity |
Japanese American | 478 | 46.3 | 478 | 46.4 |
White | 274 | 26.6 | 273 | 26.5 |
African American (AA) | 48 | 4.7 | 49 | 4.8 |
Latino | 77 | 7.5 | 76 | 7.4 |
Native Hawaiian (NH) | 155 | 15.0 | 154 | 15.0 |
Education |
≤ High school | 420 | 40.7 | 424 | 41.2 |
Some college | 216 | 20.9 | 217 | 21.1 |
College graduate | 192 | 18.6 | 202 | 19.6 |
Graduate school | 199 | 19.3 | 180 | 17.5 |
Missing | 5 | 0.5 | 7 | 0.7 |
Age at menarche, yrs |
< 12 | 555 | 53.8 | 570 | 55.3 |
13–14 | 370 | 35.9 | 359 | 34.9 |
> 14 | 100 | 9.7 | 95 | 9.2 |
Missing | 7 | 0.7 | 6 | 0.6 |
Number of children |
Nulliparous | 163 | 15.8 | 111 | 10.8 |
1 child | 98 | 9.5 | 116 | 11.3 |
2–3 children | 523 | 50.7 | 553 | 53.7 |
> 4 children | 245 | 23.7 | 245 | 23.8 |
Missing | 3 | 0.3 | 5 | 0.5 |
Age at first live birth, yrs |
Nulliparous | 163 | 15.8 | 111 | 10.8 |
15–20 | 211 | 20.4 | 208 | 20.2 |
21–30 | 564 | 54.7 | 614 | 59.6 |
> 30 | 82 | 7.9 | 76 | 7.4 |
Missing | 12 | 1.2 | 21 | 2.0 |
Menopausal status |
Premenopause | 213 | 20.6 | 208 | 20.2 |
Natural menopause | 509 | 49.3 | 505 | 49.0 |
Other surgery | 120 | 11.6 | 134 | 13.0 |
Surgical menopause | 160 | 15.5 | 154 | 15.0 |
Other or missing reasons | 30 | 2.9 | 29 | 2.8 |
Use of hormone therapy at urine collection |
Never estrogen (E]) | 400 | 38.8 | 409 | 39.7 |
Past E | 337 | 32.7 | 350 | 34.0 |
Current E alone | 186 | 18.0 | 184 | 17.9 |
Current E + progesterone | 100 | 9.7 | 78 | 7.6 |
Missing | 9 | 0.9 | 9 | 0.9 |
Neighborhood SES at urine collection |
Quintile 1–low | 100 | 9.7 | 123 | 11.9 |
Quintile 2 | 147 | 14.2 | 153 | 14.9 |
Quintile 3 | 154 | 14.9 | 162 | 15.7 |
Quintile 4 | 233 | 22.6 | 220 | 21.4 |
Quintile 5–high | 345 | 33.4 | 316 | 30.7 |
Missing | 53 | 5.1 | 56 | 5.4 |
BMI at urine collection (kg/m2) |
Mean BMI ± SD | 27.1 ± 5.6 | | 26.0 ± 5.6 | |
< 25 | 406 | 39.3 | 529 | 51.4 |
≥ 25- < 30 | 366 | 35.5 | 316 | 30.7 |
≥ 30 | 260 | 25.2 | 185 | 18.0 |
Waist-hip ratio (WHR)d |
Mean ± SD | 0.862 ± 0.076 | | 0.858 ± 0.082 | |
< 0.854 | 384 | 37.2 | 475 | 46.1 |
≥ 0.854 | 457 | 44.3 | 471 | 45.7 |
Missing | 191 | 18.5 | 84 | 8.2 |
Waist (inches)d |
Mean ± SD | 35.51 ± 5.51 | | 34.72 ± 5.47 | |
< 34 | 331 | 32.1 | 425 | 41.3 |
≥ 34 | 513 | 49.7 | 524 | 50.9 |
Missing | 188 | 18.2 | 81 | 7.9 |
Smoking status |
Never | 578 | 56.0 | 618 | 60.0 |
Former | 315 | 30.5 | 300 | 29.1 |
Current | 133 | 12.9 | 104 | 10.1 |
Missing | 6 | 0.6 | 8 | 0.8 |
Mediterranean diet scoree |
Quartile 1–low | 350 | 33.9 | 350 | 34.0 |
Quartile 2 | 207 | 20.1 | 204 | 19.8 |
Quartile 3 | 220 | 21.3 | 204 | 19.8 |
Quartile 4–high | 232 | 22.5 | 252 | 24.5 |
Missing | 23 | 2.2 | 20 | 1.9 |
Stageb |
In situ | 224 | 21.7 | | |
I (1) | 613 | 59.4 | | |
II (2) | 10 | 1.0 | | |
III (3,4,7) | 175 | 17.0 | | |
Missing | 10 | 1.0 | | |
Hormone receptor (HR) statusc |
Estrogen (ER) + or progesterone (PR) | 859 | 83.2 | | |
ER− and PR− | 124 | 12 | | |
Missing | 49 | 4.7 | | |
The individual phthalate metabolites were modestly correlated (rho’s were 0.2 to 0.4;
P < 0.05) whereas the DEHP metabolites were more strongly correlated (rho’s were 0.5 to ~ 0.8). The correlations between phthalic acid and the 10 phthalates ranged from 0.15 to 0.44. (Supplementary Table
2).
The risk of breast cancer in all women combined tended to decrease with increasing exposure to MBzP (
Ptrend = 0.03). In contrast, risk in all women was positively associated with high ratios of MEHP/MEOHP (
Ptrend = 0.04), MEHP/(MEOHP+ MEHHP) (
Ptrend = 0.052), and high MEHP% (
Ptrend = 0.092); the range of ORs associated with exposure in the upper tertile was 1.18 to 1.26 compared to those in the lowest tertile of exposure. These patterns were apparent among white women (Table
2). Although there were no statistically significant racial/ethnic differences in results, some suggestive differences emerged. Among Native Hawaiian women, risks increased in association with eight of the ten individual phthalates, including MiBP (
Ptrend = 0.05), MEHP (
Ptrend = 0.01), MEHHP (
Ptrend = 0.09), MECPP (
Ptrend = 0.06), and phthalic acid (
Ptrend = 0.03); ORs ranged from 1.94 to 2.73 for Native Hawaiians in the upper tertile of phthalate exposures compared to those in the lower tertile. In contrast, the individual metabolites were not associated with risk in African Americans and Latinos combined or in Japanese Americans. Among whites, below unity ORs were found for MBzP (
Ptrend = 0.05) and for all three DEHP secondary metabolites, with strongest inverse trends for MEOHP (
Ptrend = 0.06).
Table 2
Associations of breast cancer risk (invasive and in situ) with phthalate metabolites, ratios of DEHP metabolites, and phthalic acid in all women and by race/ethnicity
MMP |
≤ 2.63 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 2.63–7.40 | 0.82 (0.65–1.04) | 0.71 (0.44–1.13) | 0.86 (0.61–1.23) | 1.16 (0.68–1.99) | 0.54 (0.26–1.10) | |
> 7.40 | 0.89 (0.69–1.15) | 0.89 (0.53–1.49) | 0.84 (0.57–1.24) | 1.22 (0.62–2.37) | 0.74 (0.36–1.50) | |
P trendc | 0.26 | 0.49 | 0.36 | 0.52 | 0.30 | 0.59 |
MEP |
≤ 30.64 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 30.64–84.30 | 1.08 (0.86–1.35) | 0.93 (0.60–1.42) | 1.06 (0.78–1.45) | 1.63 (0.92–2.90) | 0.82 (0.33–2.03) | |
> 84.30 | 1.07 (0.84–1.35) | 1.13 (0.72–1.78) | 0.97 (0.69–1.38) | 1.50 (0.85–2.66) | 0.75 (0.32–1.80) | |
P trendc | 0.56 | 0.67 | 0.95 | 0.12 | 0.52 | 0.63 |
MBP |
≤ 12.92 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 12.92–24.60 | 0.83 (0.66–1.04) | 0.99 (0.62–1.58) | 0.84 (0.61–1.15) | 0.89 (0.51–1.55) | 0.53 (0.24–1.16) | |
> 24.60 | 0.87 (0.69–1.11) | 0.82 (0.52–1.29) | 1.04 (0.73–1.48) | 0.64 (0.34–1.20) | 0.70 (0.35–1.40) | |
P trendc | 0.21 | 0.41 | 0.93 | 0.20 | 0.41 | 0.80 |
MiBP |
≤ 3.12 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 3.12–6.64 | 0.95 (0.75–1.21) | 0.73 (0.44–1.19) | 0.86 (0.60–1.22) | 1.39 (0.77–2.49) | 1.52 (0.68–3.42) | |
> 6.64 | 1.15 (0.89–1.49) | 0.74 (0.45–1.23) | 1.21 (0.82–1.79) | 2.07 (1.02–4.21) | 1.33 (0.64–2.75) | |
P trendc | 0.36 | 0.23 | 0.83 | 0.05 | 0.52 | 0.16 |
MBzP |
≤ 7.66 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 7.66–15.83 | 0.81 (0.65–1.01) | 0.69 (0.45–1.06) | 0.87 (0.63–1.21) | 0.67 (0.37–1.21) | 1.05 (0.56–1.97) | |
> 15.83 | 0.79 (0.63–0.99) | 0.67 (0.43–1.03) | 0.86 (0.61–1.20) | 0.86 (0.47–1.57) | 0.77 (0.41–1.46) | |
P trendc | 0.03 | 0.05 | 0.35 | 0.53 | 0.52 | 0.56 |
MEHP |
≤ 4.72 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 4.72–10.88 | 1.00 (0.79–1.26) | 0.91 (0.57–1.43) | 0.86 (0.61–1.22) | 1.74 (0.94–3.22) | 1.23 (0.61–2.44) | |
> 10.88 | 1.01 (0.77–1.31) | 1.06 (0.46–1.63) | 0.76 (0.52–1.12) | 2.73 (1.25–5.97) | 1.08 (0.52–2.27) | |
P trendc | 0.97 | 0.94 | 0.17 | 0.01 | 0.81 | 0.07 |
MEHHP |
≤ 18.44 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 18.44–39.67 | 0.96 (0.77–1.20) | 0.73 (0.47–1.14) | 0.98 (0.71–1.34) | 1.37 (0.79–2.35) | 1.03 (0.53–2.02) | |
> 39.67 | 0.93 (0.74–1.18) | 0.69 (0.44–1.11) | 0.97 (0.69–1.35) | 1.67 (0.90–3.08) | 0.80 (0.39–1.61) | |
P trendc | 0.56 | 0.11 | 0.83 | 0.09 | 0.56 | 0.23 |
MEOHP |
≤ 11.54 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 11.54–26.28 | 1.03 (0.83–1.28) | 0.66 (0.43–1.02) | 1.21 (0.88–1.67) | 1.21 (0.71–2.05) | 1.09 (0.57–2.12) | |
> 26.28 | 0.90 (0.72–1.13) | 0.66 (0.42–1.05) | 1.03 (0.74–1.44) | 1.27 (0.71–2.24) | 0.65 (0.33–1.29) | |
P trendc | 0.46 | 0.06 | 0.67 | 0.39 | 0.28 | 0.24 |
MECPP |
≤ 23.04 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 23.04–45.35 | 0.94 (0.75–1.18) | 0.81 (0.52–1.26) | 0.91 (0.65–1.26) | 1.22 (0.68–2.19) | 1.10 (0.57–2.14) | |
> 45.35 | 0.99 (0.78–1.25) | 0.77 (0.49–1.22) | 0.98 (0.70–1.38) | 1.94 (1.01–3.70) | 0.80 (0.38–1.66) | |
P trendc | 0.84 | 0.25 | 0.84 | 0.06 | 0.62 | 0.27 |
MCHP |
≤ 0.34 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 0.34–0.57 | 1.11 (0.88–1.39) | 1.10 (0.71–1.70) | 1.19 (0.85–1.67) | 1.28 (0.73–2.25) | 0.72 (0.36–1.44) | |
> 0.57 | 1.16 (0.91–1.47) | 1.25 (0.77–2.03) | 1.08 (0.75–1.54) | 1.78 (0.91–3.47) | 0.86 (0.45–1.64) | |
P trendc | 0.23 | 0.39 | 0.58 | 0.10 | 0.49 | 0.51 |
MEHP%d |
≤ 5.49% | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 5.49–11.08% | 1.27 (1.00–1.61) | 1.46 (0.93–2.30) | 1.09 (0.77–1.56) | 1.63 (0.88–3.03) | 1.22 (0.62–2.38) | |
> 11.08% | 1.23 (0.94–1.62) | 1.81 (1.06–3.08) | 0.97 (0.65–1.46) | 1.46 (0.73–2.92) | 1.03 (0.46–2.28) | |
P trendc | 0.09 | 0.03 | 0.94 | 0.22 | 0.84 | 0.44 |
MEHP/(MEOHP + MEHHP) |
≤ 9.76% | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 9.76–21.36% | 1.32 (1.04–1.68) | 1.57 (1.00–2.44) | 1.18 (0.82–1.71) | 1.46 (0.79–2.70) | 1.21 (0.62–2.38) | |
> 21.36% | 1.26 (0.96–1.66) | 2.10 (1.20–3.65) | 0.98 (0.66–1.47) | 1.14 (0.56–2.34) | 1.38 (0.63–3.03) | |
P trendc | 0.05 | 0.007 | 0.97 | 0.55 | 0.42 | 0.30 |
MEHP/(MECCP + MEHHP) |
≤ 7.87% | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 7.87–16.86% | 1.28 (1.02–1.63) | 1.35 (0.86–2.08) | 1.20 (0.85–1.77) | 1.38 (0.76–2.49) | 1.36 (0.68–2.70) | |
> 16.86% | 1.18 (0.90–1.56) | 1.76 (1.04–2.99) | 1.01 (0.67–1.53) | 1.14 (0.58–2.24) | 0.92 (0.41–2.05) | |
P trendc | 0.13 | 0.04 | 0.82 | 0.56 | 0.93 | 0.64 |
MEHP/MEHHP |
≤ 0.159 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 0.159–0.341 | 1.20 (0.94–1.54) | 1.31 (0.84–2.04) | 1.07 (0.73–1.57) | 1.31 (0.69–2.49) | 1.28 (0.64–2.56) | |
> 0.341 | 1.24 (0.94–1.63) | 1.84 (1.05–3.21) | 1.08 (0.72–1.63) | 0.90 (0.44–1.84) | 1.31 (0.59–2.94) | |
P trendc | 0.11 | 0.04 | 0.70 | 0.92 | 0.45 | 0.60 |
MEHP/MEOHP |
≤ 0.245 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 0.245–0.548 | 1.36 (1.08–1.71) | 1.92 (1.23–2.99) | 1.09 (0.78–1.53) | 1.32 (0.73–2.41) | 1.48 (0.75–2.93) | |
> 0.548 | 1.26 (0.97–1.63) | 2.02 (1.17–3.50) | 0.92 (0.63–1.35) | 1.29 (0.69–2.42) | 1.62 (0.75–3.50) | |
P trendc | 0.04 | 0.004 | 0.79 | 0.38 | 0.20 | 0.14 |
MEHP/MECPP |
≤ 0.137 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 0.137–0.298 | 1.17 (0.93–1.48) | 1.11 (0.72–1.72) | 1.11 (0.78–1.59) | 1.36 (0.75–2.47) | 1.25 (0.63–2.48) | |
> 0.298 | 0.96 (0.73–1.25) | 1.14 (0.69–1.88) | 0.80 (0.53–1.21) | 1.12 (0.57–2.34) | 0.97 (0.43–2.20) | |
P trendc | 0.99 | 0.59 | 0.78 | 0.57 | 0.52 | 0.78 |
Phthalic acid (PA) |
≤ 36.90 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 36.90–79.76 | 1.11 (0.88–1.40) | 0.95 (0.60–1.52) | 1.19 (0.86–1.64) | 1.61 (0.81–3.21) | 0.81 (0.39–1.69) | |
> 79.76 | 1.21 (0.94–1.56) | 0.98 (0.61–1.58) | 1.17 (0.80–1.69) | 2.22 (1.08–4.57) | 1.04 (0.47–2.30) | |
P trendc | 0.14 | 0.94 | 0.32 | 0.03 | 0.92 | 0.39 |
Breast cancer risk in all women combined was not associated with ∑DEHP and ∑HMWP but exposure to ∑LMWP, ∑LMHMPA, and ∑LMHM
molar was positively associated with risk in all women combined, with 18 to 23% higher risk for those in the upper tertile of exposure (Table
3)
. The positive associations were more prominent among Native Hawaiians who displayed statistically significant or suggestive elevated risks with four of the five summation exposures: ∑LMHMPA (
Ptrend = 0.001), ∑LMHM
molar (
Ptrend = 0.03), ∑LMWP (
Ptrend = 0.10), and ∑HMWP (
Ptrend = 0.10). Native Hawaiian women in the upper two tertiles of ∑LMHMPA exposure showed a significant 2.4- to 2.6-fold higher risk than their counterparts in the lowest tertile of exposure.
Table 3
Associations of breast cancer risk with summary phthalate exposures in all women and by race/ethnicity
∑DEHPc |
≤ 63.21 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
63.21–133.05 | 1.03 (0.82–1.27) | 0.83 (0.54–1.29) | 0.99 (0.72–1.36) | 1.29 (0.75–2.22) | 1.38 (0.71–2.69) | |
> 133.05 | 0.93 (0.73–1.17) | 0.74 (0.47–1.18) | 0.97 (0.68–1.36) | 1.49 (0.79–2.79) | 0.76 (0.38–1.52) | |
P trendd | 0.61 | 0.20 | 0.85 | 0.21 | 0.57 | 0.43 |
∑HMWPc |
≤ 78.13 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 78.13–149.24 | 0.95 (0.77–1.18) | 0.73 (0.47–1.14) | 0.95 (0.70–1.30) | 1.18 (0.68–2.04) | 1.29 (0.68–2.43) | |
> 149.24 | 0.99 (0.79–1.25) | 0.75 (0.46–1.20) | 1.03 (0.74–1.44) | 1.76 (0.94–3.29) | 0.78 (0.40–1.50) | |
P trendd | 0.87 | 0.18 | 0.93 | 0.10 | 0.62 | 0.32 |
∑LMWPc |
≤ 64.0 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 64.0–145.29 | 1.15 (0.92–1.44) | 1.05 (0.66–1.67) | 1.13 (0.82–1.55) | 1.38 (0.81–2.38) | 0.88 (0.35–2.23) | |
> 145.29 | 1.18 (0.93–1.50) | 1.10 (0.68–1.78) | 1.24 (0.87–1.77) | 1.64 (0.89–3.04) | 0.66 (0.29–1.53) | |
P trendd | 0.16 | 0.70 | 0.23 | 0.10 | 0.24 | 0.44 |
∑LMHMPAc |
≤ 226.38 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 226.38–442.34 | 1.03 (0.83–1.29) | 0.87 (0.56–1.36) | 0.84 (0.62–1.17) | 2.43 (1.33–4.44) | 1.01 (0.51–1.98) | |
> 442.34 | 1.23 (0.96–1.58) | 1.00 (0.62–1.62) | 1.19 (0.82–1.73) | 2.66 (1.39–5.12) | 0.73 (0.34–1.57) | |
P trendd | 0.15 | 0.96 | 0.65 | 0.001 | 0.47 | 0.05 |
∑LMHMmolarc |
≤ 0.581 | 1.00 | 1.00 | 1.00 | 1.00 | 1.00 | |
> 0.581–1.143 | 1.02 (0.82–1.28) | 1.38 (0.87–2.21) | 0.70 (0.51–0.97) | 1.53 (0.86–2.71) | 1.39 (0.68–2.85) | |
> 1.143 | 1.18 (0.92–1.50) | 1.33 (0.80–2.20) | 1.03 (0.72–1.47) | 1.89 (1.06–3.38) | 0.83 (0.39–1.77) | |
P trendd | 0.23 | 0.25 | 0.78 | 0.03 | 0.64 | 0.18 |
Results did not suggest statistically significant differences in comparisons between HR+ (
n = 694) and HR− (
n = 96) invasive breast cancers in all women combined (Table
4). Risk of HR+ breast was significantly positively associated with ∑LMWP exposure (OR
above vs below median = 1.30, 95% CI 1.05–1.60), but this positive association was also observed for HR− breast cancer (OR
above vs below median = 1.28, 95% CI 0.81–2.00) (
Pheterogeneity = 0.95). In contrast, the risk of HR− breast cancers was increased in association with phthalic acid exposure (OR
above vs below median = 1.59, 95% CI 1.01–2.46) but not HR+ breast cancer (OR
above vs below median = 1.02, 95% CI 0.83–1.26) (
Pheterogeneity = 0.08). Above the median exposure to ∑LMHMPA was also associated with HR− breast cancer (OR
above vs below median = 1.54, 95% CI 0.98–2.41,
P = 0.06); this increased risk was observed in whites, Native Hawaiians, and African Americans and Latinos combined, but it was particularly prominent among Native Hawaiian women (OR
above vs below median = 4.92, 95% CI 1.33–18.2) (Supplementary Table
3).
Table 4
Associations of risk of hormone receptor-positive (HR+) and HR-negative (HR−) invasive breast cancers with summary phthalate exposures in all women combined
∑DEHP |
< 118.53 | 1.00 | 443/508 | 1.00 | 58/508 |
≥ 118.53 | 1.02 (0.82–1.26) | 251/288 | 1.05 (0.67–1.64) | 38/288 |
P value | 0.87 | | 0.83 | |
P hetb | 0.90 | | | |
∑HMWP |
< 106.79 | 1.00 | 369/405 | 1.00 | 45/405 |
≥ 106.79 | 0.93 (0.76–1.15) | 325/391 | 1.15 (0.75–1.78) | 51/391 |
P value | 0.50 | | 0.52 | |
P hetb | 0.39 | | | |
∑LMWP |
< 93.03 | 1.00 | 317/408 | 1.00 | 40/408 |
≥ 93.03 | 1.30 (1.05–1.60) | 377/388 | 1.28 (0.81–2.00) | 56/388 |
P value | 0.015 | | 0.29 | |
P hetb | 0.95 | | | |
∑LMHMPA |
< 310.52 | 1.00 | 332/408 | 1.00 | 38/408 |
≥ 310.52 | 1.17 (0.95–1.44) | 362/388 | 1.54 (0.98–2.41) | 58/388 |
P value | 0.15 | | 0.06 | |
P hetb | 0.28 | | | |
∑LMHMmolar |
< 0.80 | 1.00 | 331/411 | 1.00 | 40/411 |
≥ 0.80 | 1.20 (0.98–1.48) | 363/385 | 1.40 (0.90–2.19) | 56/385 |
P value | 0.08 | | 0.14 | |
P hetb | 0.55 | | | |
Phthalic acid |
< 53.54 | 1.00 | 343/399 | 1.00 | 36/399 |
≥ 53.54 | 1.02 (0.83–1.26) | 351/397 | 1.59 (1.01–2.48) | 60/397 |
P value | 0.84 | | 0.04 | |
P hetb | 0.08 | | | |
Phthalate-breast cancer associations did not differ by years of follow-up after urine collection, or between all (invasive and in situ combined) versus invasive breast cancers only (data not shown). There were also no suggestive differences in breast cancer associations with phthalate exposures by use of hormone therapy or BMI at urine collection (data not shown). However, in the subgroup of women with data on WHR, breast cancer risks increased among those with high (≥ 0.854) WHR in association with exposure to MEHP%, ratio variables of MEHP to secondary metabolites of DEHP, phthalate acid, and ∑LMHMPA (Table
5). The ORs for ∑LMHMPA were elevated among those with high WHR (OR
T3 vs T1 = 2.01, 95% CI 1.22–3.32,
Ptrend = 0.01) but not among those with low (< 0.854) WHR (OR
T3 vs T1 = 0.79, 95% CI 0.47–1.31) (
Pheterogeneity = 0.01).
Table 5
Associations of breast cancer risk and exposures to DEHP metabolites and summary phthalate exposures by waist-hip ratio (WHR)
MEHP%c |
≤ 5.49% | 35 | 147 | 1.00 | 23 | 170 | 1.00 | |
> 5.49–11.08 | 41 | 155 | 1.09 (0.66–1.81) | 47 | 153 | 2.29 (1.32–3.98) | |
> 11.08 | 40 | 173 | 0.94 (0.57–1.57) | 47 | 148 | 2.39 (1.36–4.18) | 0.02 |
P trend | | | 0.86 | | | 0.002 | |
Phthalic acid |
≤ 36.90 | 45 | 143 | 1.00 | 30 | 170 | 1.00 | |
> 36.90–≤ 79.76 | 37 | 161 | 0.74 (0.45–1.20) | 37 | 150 | 1.44 (0.84–2.45) | |
> 79.76 | 34 | 171 | 0.64 (0.38–1.07) | 50 | 151 | 1.98 (1.18–3.33) | 0.002 |
P trend | | 0.08 | | | 0.01 | |
∑DEHP |
≤ 63.21 | 41 | 149 | 1.00 | 39 | 162 | 1.00 | |
63.21–133.05 | 38 | 160 | 0.89 (0.54–1.47) | 39 | 157 | 1.07 (0.65–1.77) | |
> 133.05 | 37 | 166 | 0.90 (0.54–1.50) | 39 | 152 | 1.16 (0.69–1.93) | 0.49 |
P trend | | 0.66 | | | 0.59 | |
∑HMWP |
≤ 78.13 | 38 | 147 | 1.00 | 41 | 165 | 1.00 | |
> 78.13–149.24 | 40 | 159 | 0.99 (0.60–1.64) | 37 | 156 | 0.99 (0.60–1.63) | |
> 149.24 | 38 | 169 | 0.95 (0.57–1.58) | 39 | 150 | 1.13 (0.68–1.88) | 0.68 |
P trend | | 0.85 | | | 0.69 | |
ΣLMWP |
≤ 64.0 | 42 | 154 | 1.00 | 37 | 165 | 1.00 | |
> 64.0–145.29 | 34 | 144 | 0.87 (0.53–1.45) | 39 | 162 | 1.14 (0.69–1.89) | |
> 145.29 | 40 | 177 | 0.86 (0.52–1.43) | 41 | 144 | 1.44 (0.86–2.43) | 0.17 |
P trend | | | | | 0.19 | |
∑LMHMPA |
≤ 226.38 | 39 | 136 | 1.00 | 35 | 175 | 1.00 | |
> 226.38–442.34 | 38 | 157 | 0.86 (0.52–1.43) | 31 | 157 | 1.04 (0.61–1.78) | |
> 442.34 | 39 | 182 | 0.79 (0.47–1.31) | 51 | 139 | 2.01 (1.22–3.32) | 0.01 |
P trend | | | 0.35 | | | 0.01 | |
Discussion
This nested case-control study adds new information on the association of phthalate exposures and breast cancer risk. This is only the second study with data on pre-diagnostic urinary exposures, and the first to examine potential racial/ethnic differences in risk associations in a single study population where similar study methods were used. Although our study still lacked adequate statistical power to detect statistically significant differences in racial/ethnic-specific comparisons, the suggestive risk pattern differences between whites and nonwhites, and between the different groups of nonwhites (Native Hawaiians, African Americans, Latinos, and Japanese Americans), highlight the challenges in studying these ubiquitous chemicals in relation to breast cancer risk. The suggestive differences in associations between HR+ and HR− breast cancer and among those with high WHR warrant confirmation in future studies.
The most consistent findings in all women combined were the inverse associations with MBzP, the increased risks associated with high MEHP%, and high ratios of DEHP metabolites, namely MEHP to MEOHP and MEHHP. The significant inverse association between MBzP exposure and risk is consistent with results observed in Mexico [
11] and among white women in the WHI [
14] and LIBCSP [
13]. While estrogenic effects of BBP, the precursor of MBzP, have been reported in cell culture and other experimental studies [
31‐
33], these estrogenic effects may not be applicable to in vivo environments [
34], and anti-estrogenic effects of BBP have been reported in some studies [
35].
Our findings on the individual DEHP metabolites and ratios of primary to secondary DEHP metabolites suggest potential racial/ethnic differences in exposure and/or metabolism. Exposures to all four DEHP metabolites were inversely associated with risk in whites but were positively associated with risk in Native Hawaiians; the results in whites are supportive of the null/inverse associations reported previously in whites [
13,
14], while the results in Native Hawaiians are broadly consistent with findings among Mexican [
11] and Native Alaska women [
12]. Risk in all women appeared to be higher in association with high MEHP% and high ratios of MEHP/MEOHP and MEHP/MEHHP. As shown in Fig.
1, DEHP and other high molecular weight long-branch phthalates undergo several biotransformations, including further hydroxylation and oxidation before excretion [
36‐
38]. MEHP, the hydrolysis product of DEHP, is not a major metabolite, while the oxidative metabolites (MEHHP, MEOHP, and MECPP) are the major metabolites of DEHP. As MEHP may be more toxic than the oxidative metabolites, higher MEHP% and higher ratios of MEHP to MEHHP or MEHP to MEOHP may implicate greater physiologic effects as compared with individual metabolites; this seemed to be particularly apparent among women with high WHR. While we are not aware of previous investigations of MEHP% and ratios of DEHP metabolites in relation to breast cancer risk, higher MEHP% and higher MEHP ratios may represent more toxicity in terms of male infertility [
29], obesity based on BMI and waist circumferences [
30], inflammation, and oxidative stress represented by gamma glutamyltransferase [
39]. Oxidative stress-stimulated inflammation may be part of the etiologic pathway for DEHP-induced carcinogenesis.
Our finding between HR+ breast cancer and ∑LMWP is supportive of suggestive effects of phthalates on ER+ breast cancer [
32,
40]. In contrast, the risk associations with exposure to phthalic acid, ∑LMHMPA, and ∑LMHM
molar appeared to be stronger for HR− than HR+ breast cancers but this was based on only 96 HR− breast cancers. Although these risk associations were particularly strong among Native Hawaiians, we are cautious in our interpretation because of the very wide confidence intervals (Supplementary Table
3). Further investigations of whether HR− breast cancer may be differentially affected by phthalate exposures are needed, as fewer than 300 HR− breast cancers have been investigated in this (
n = 96) and combined previous studies on urinary phthalates (
n = 58 in WHI [
14] and
n = 109 in LIBCSP [
13]).
Finally, although there was no significant evidence of statistical heterogeneity by race/ethnicity, risk association patterns between phthalate exposures and breast cancer risk were not uniform across the racial/ethnic groups. In particular, risk associations were more prominent among Native Hawaiians; in that group, risk was positively associated with eight of the ten individual phthalate metabolites, phthalic acids, and total phthalates (∑LMHMPA, ∑LMHM
molar) while the associations were less consistent in the other racial/ethnic groups. We are not aware of previous studies on exposures of phthalates among Native Hawaiians and Japanese Americans in the USA, but the divergent risk patterns may be due to differences in their use of phthalate containing products as suggested by racial/ethnic differences in profiles of individual urinary phthalates (Supplementary Table
1). Variations in genetic susceptibility to metabolize phthalates and other factors affecting metabolism may be also important and warrant investigation.
Strengths of this study include being the first prospective study to investigate urinary phthalate metabolites among five racial/ethnic groups in the same study, and providing the first of such data in Native Hawaiians and Japanese Americans, and carefully considering potential confounders (Supplementary Table
4). We used a highly sensitive assay and carefully examined risk associations with both individual metabolites and all metabolites combined as they may represent different sources and routes of exposure. However, there are several limitations. We relied on a single urine sample measurement; the within-person variability is modest for phthalate metabolites in this study as in other studies [
41] and may have reduced the statistical power of our study. Sample sizes of African Americans and Latinas were also modest, which precluded examining their risk patterns separately. In addition, information on pre-diagnostic WHR was available on only a subset of breast cancer cases. Due to the number of tests performed, some of the findings are likely due to chance. All the samples from Los Angeles County were first morning samples, whereas almost all urine specimens from Hawaii were overnight specimens. While misclassification of exposure is unavoidable, we believe that non-differential misclassification of exposure would tend to attenuate the overall results and underestimate the true association.
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