Exposure to Per- and Polyfluoroalkyl Substances and Breast Cancer Risk: A Systematic Review and Meta-analysis of Epidemiologic Studies.

We synthesized the epidemiologic evidence on the associations between per- and polyfluoroalkyl substances (PFAS) exposure and breast cancer risk. Our systematic review and meta-analysis included 18 and 11 articles, respectively, covering studies up to February 2023. The summary relative risks (RR) estimated by random-effects meta-analyses did not support an association between PFAS and overall breast cancer risk (e.g., a natural log (ln)-unit increase in serum/plasma concentrations [ng/mL] for perfluorooctanoate [PFOA] RR=0.95, 95% confidence interval [CI]:0.77-1.18; perfluorooctane sulfonate [PFOS] RR=0.98, 95%CI: 0.87-1.11). However, when limiting to studies that assessed exposures prior to a breast cancer diagnosis, we observed a positive association with PFOA (a ln-unit increase, RR=1.16, 95%CI: 0.96-1.40). We also observed some possible heterogeneous associations by tumor estrogen and progesterone receptor status among postmenopausal breast cancer cases. No meaningful changes were observed after excluding the studies with high risk-of-bias (Tier 3). Based on the evaluation tool developed by the National Toxicology Program, given the heterogeneity across studies and the variability in timing of exposure measurements, the epidemiologic evidence needed to determine the association between PFAS exposure and breast cancer remains inadequate. Our findings support the need for future studies with improved study designs to determine this association.

Residential proximity to toxic metal-emitting industrial sites and toenail metal concentrations in a United States-wide prospective cohort.

BACKGROUND: Industrial facilities across the United States (US) release millions of pounds of toxic chemicals, including metals. Exposure to toxic metals has been associated with adverse health outcomes, but there is limited evidence on the association between living near metal-releasing facilities and the body burden of emitted compounds. OBJECTIVE: To investigate the association between residential proximity to toxic metal-emitting industrial facilities and toenail metal concentrations and to evaluate whether associations differed by race. METHODS: In a sample of 1556 non-Hispanic Black (32.5%) and non-Hispanic White (67.5%) women from the Sister Study, we used the US Environmental Protection Agency Toxics Release Inventory to identify metal-emitting facilities within 3, 5, and 10 km of participants' baseline residences. We measured toenail concentrations (µg/g) of arsenic, cadmium, cobalt, chromium, and lead. Using multivariable linear regression, we examined associations between residential proximity to and emissions from metal-emitting facilities and toenail metal concentrations, stratifying by race. We explored modification of race-stratified associations by neighborhood deprivation, using the Area Deprivation Index (ADI). RESULTS: Black participants were more likely to reside within 3 km of chromium-releasing facilities and 5 and 10 km of all observed metal-emitting sites. Living near metal-releasing facilities was not associated with higher toenail metal concentrations overall. Among Black women, higher chromium emissions exposure was associated with higher toenail chromium levels (ßTertile3vs.non-exposed = 2.36 µg/g, 95% CI = 0.63, 4.10). An association with lead was observed among Black women residing in the most deprived areas (≥75th ADI percentile: ß = 3.08 µg/g, 95% CI = 1.46, 4.71). No associations were observed for White participants. CONCLUSIONS: Despite low exposure prevalence, our findings suggest that living near chromium- and lead-releasing facilities, especially at shorter distances, may be associated with higher corresponding toenail metal levels among Black women, particularly those residing in the most disadvantaged areas.

Outdoor light at night and risk of endometrial cancer in the NIH-AARP diet and health study.

PURPOSE: Outdoor light at night (LAN) can result in circadian disruption and hormone dysregulation and is a suspected risk factor for some cancers. Our study is the first to evaluate the association between LAN and risk of endometrial cancer, a malignancy with known relationship to circulating estrogen levels. METHODS: We linked enrollment addresses (1996) for 97,677 postmenopausal women in the prospective NIH-AARP cohort to satellite imagery of nighttime radiance to estimate LAN exposure. Multivariable Cox models estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for LAN quintiles and incident endometrial cancer overall (1,669 cases) and endometrioid adenocarcinomas (991 cases) through follow-up (2011). We tested for interaction with established endometrial cancer risk factors. RESULTS: We observed no association for endometrial cancer overall (HRQ1vsQ5 0.92; 95% CI 0.78-1.08; p trend = 0.67) or endometrioid adenocarcinoma (HRQ1vsQ5 1.01; 95% CI 0.82-1.24; p trend = 0.36). Although body mass index and menopause hormone therapy were both associated with risk, there was no evidence of interaction with LAN (p interactions = 0.52 and 0.50, respectively). CONCLUSION: Our study did not find an association between outdoor LAN and endometrial cancer risk, but was limited by the inability to account for individual-level exposure determinants. Future studies should consider approaches to improve characterization of personal exposures to light.

Understanding the role of environmental and socioeconomic factors in the geographic variation of breast cancer risk in the US-wide Sister Study.

OBJECTIVE: To describe the geographic pattern of breast cancer incidence in a nationwide prospective cohort and investigate whether environmental exposures and/or neighborhood socioeconomic status explain observed geographic disparities. METHODS: Using accelerated failure time models with a spatial random effect term, we mapped the health region-level association between residential location and breast cancer incidence for 44,707 participants in the Sister Study after controlling for established individual-level breast cancer risk factors. We performed a variable selection process to select environmental exposures [i.e., ambient nitrogen dioxide (NO2) and fine particulate matter (PM2.5), PM2.5 chemical composition, outdoor light at night (LAN), ambient noise, ultraviolet radiation, and greenspace] and neighborhood-level factors [i.e., population density and area deprivation index (ADI)] that predicted breast cancer incidence and quantified the spatial variation explained by the selected factors. We also considered whether the geographic pattern and predictors were similar when restricting to estrogen receptor-positive (ER+) tumors. RESULTS: We observed a spatial patterning in the incidence of overall breast cancer (Moran's I = 16.7, p < 0.05) and ER+ breast cancer (Moran's I = 13.2, p < 0.05), with a lower risk observed in the South and Southeast and a greater risk in the Northwest and certain areas of the Midwest and Northeast. NO2, LAN, and ADI explained 21.4% of the spatial variation in overall breast cancer incidence whereas NO2, PM2.5 chemical composition, LAN, greenspace, and ADI together explained 63.3% of the spatial variation in ER+ breast cancer incidence. CONCLUSIONS: Our findings provide additional evidence for a role of environmental exposures in breast cancer incidence and suggest that geographic-based risk factors may vary according to breast cancer subtype. Our findings support the need for additional research to quantify the relative contributions of geographic-based risk factors for breast cancer.

Residential proximity to dioxin emissions and risk of breast cancer in the sister study cohort.

Some dioxins are carcinogenic, but few studies have investigated the relationship between ambient polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) and risk of breast cancer. We evaluated associations between proximity-based residential exposure to industrial emissions of PCDD/F and breast cancer risk in a large U.S. cohort. Sister Study participants at enrollment (2003-2009) were followed for incident breast cancer through September 2018. After restricting to participants with ≥10 years of residential history prior to enrollment (n = 35,908), we generated 10-year distance- and toxic equivalency quotient (TEQ)-weighted average emissions indices (AEI [g TEQ/km2]) within 3, 5, or 10 km of participants' residences, overall and by facility type. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between AEI quartiles (vs. zero AEI) and risk of breast cancer [invasive or ductal carcinoma in situ]. There were 2670 incident breast cancer cases over 11 years (median) of follow-up. Breast cancer risk was increased for those in the highest quartile [Q] of AEI exposure within 3 km (HRQ4:1.18, 95% CI: 0.99,1.40, Ptrend = 0.03). The HR was higher for the 10-year AEI at 3 km from municipal solid waste facilities (HR ≥ median.vs.0:1.50, 95% CI: 0.98, 2.29; Ptrend = 0.07). Risk was higher among ever smokers (vs. never smokers) in the top quartile of the 3 km AEI (HRQ4:1.41, 95% CI:1.12,1.77, Ptrend = 0.003; Pinteraction = 0.03) and higher risk for ER negative tumors was suggested (HRQ4:1.47, 95% CI: 0.95, 2.28, Ptrend = 0.07, Pheterogeneity = 0.17). Our findings suggest that residential exposure to PCDD/F emissions may confer an increased risk of breast cancer.

Vitamin D Supplement Use and Risk of Breast Cancer by Race-Ethnicity.

BACKGROUND: Vitamin D has anticarcinogenic properties, but a relationship between vitamin D supplement use and breast cancer is not established. Few studies have accounted for changes in supplement use over time or evaluated racial-ethnic differences. METHODS: The Sister Study is a prospective cohort of 50,884 women with 35-74 years of age who had a sister with breast cancer, but no breast cancer themselves at enrollment (2003-2009). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between vitamin D supplement use and incident breast cancer (3,502 cases; median follow-up 10.5 years). RESULTS: Vitamin D supplement use was common, with 64% reporting ever use (at least once per month) in the year before enrollment. Considering supplement use over time, ever use of vitamin D supplements was not meaningfully associated with breast cancer (HR = 0.96, 95% CI = 0.88, 1.0), relative to never use. However, after adjusting for prior use, recent use of vitamin D supplements ≥1/month was inversely associated with breast cancer (HR = 0.88, 95% CI = 0.78, 1.0), relative to nonrecent use. The inverse association was stronger for ductal carcinoma in situ (HR = 0.67, 95% CI = 0.52, 0.87) than invasive breast cancer (HR = 0.94, 95% CI = 0.72, 1.1, p-for-heterogeneity = 0.02). Supplement use was less common among African American/Black (56%) and non-Black Hispanic/Latina (50%) women than non-Hispanic White women (66%), but there was limited evidence of racial-ethnic differences in HRs (p-for-heterogeneity = 0.16 for ever use, P = 0.55 for recent). CONCLUSIONS: Our findings are consistent with the hypothesis that recent vitamin D use is inversely associated with breast cancer risk.

Use of hair products in relation to ovarian cancer risk.

We evaluated whether hair products, which may contain carcinogens and endocrine disruptors that can be absorbed into the bloodstream, are related to ovarian cancer incidence in a prospective cohort. After excluding women with a history of ovarian cancer or bilateral oophorectomy, 40 559 Sister Study participants ages 35-74 at enrollment (2003-2009) were included. Participants completed questionnaires on hair product use, including hair dyes, straighteners/relaxers and permanents/body waves, in the past 12 months. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between hair products and incident ovarian cancer. We assessed associations stratified by tumor type (serous, non-serous). Over a mean follow-up of 10 years, 241 women were diagnosed with ovarian cancer. Ever use of any of the examined hair products during the past year was not associated with ovarian cancer risk. However, frequent use (>4 times/year) of straighteners/relaxers or pressing products in the past year was associated with an increased risk of ovarian cancer (HR = 2.19, 95% CI: 1.12-4.27). Ever use of permanent hair dye was positively associated with non-serous (HR = 1.94, 95% CI 1.12-3.37), but inversely associated with serous (HR = 0.65, 95% CI: 0.43-0.99) tumors (p-for-heterogeneity = 0.002). Our novel findings suggest that frequent use of hair straighteners/relaxers or pressing products, which are primarily used by African American/Black women, and possibly permanent hair dye, may be associated with the occurrence of ovarian cancers.

Adolescent use of hair dyes, straighteners and perms in relation to breast cancer risk.

Hair products can contain hormonally active and carcinogenic compounds. Adolescence may be a period of enhanced susceptibility of the breast tissue to exposure to chemicals. We therefore evaluated associations between adolescent hair product use and breast cancer risk. Sister Study participants (ages 35-74 years) who had completed enrollment questionnaires (2003-2009) on use of hair dyes, straighteners/relaxers and perms at ages 10 to 13 years (N = 47 522) were included. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for associations between hair products and incident breast cancer (invasive cancer or ductal carcinoma in situ), with consideration of heterogeneity by menopausal status and race/ethnicity. Over an average of 10 years of follow-up, 3380 cases were diagnosed. Frequent use of straighteners and perms was associated with a higher risk of premenopausal (HR = 2.11, 95% CI: 1.26-3.55 and HR = 1.55, 95% CI: 0.96-2.53, respectively) but not postmenopausal breast cancer (HR = 0.99, 95% CI: 0.76-1.30 and HR = 1.09, 95% CI: 0.89-1.35, respectively). Permanent hair dye use during adolescence was uncommon (<3%) and not associated with breast cancer overall (HR = 0.97, 95% CI: 0.78-1.20), though any permanent dye use was associated with a higher risk among black women (HR = 1.77, 95% CI: 1.01-3.11). Although frequency of use of perms (37% non-Hispanic white vs 9% black) and straighteners (3% non-Hispanic white vs 75% black) varied by race/ethnicity, associations with breast cancer did not. Use of hair products, specifically perms and straighteners, during adolescence may be associated with a higher risk of premenopausal breast cancer.

Metals and Breast Cancer Risk: A Prospective Study Using Toenail Biomarkers.

The role of metals in breast cancer is of interest because of their carcinogenic and endocrine-disrupting capabilities. Evidence from epidemiologic studies remains elusive, and prior studies have not investigated metal mixtures. In a case cohort nested within the Sister Study (enrolled in 2003-2009; followed through September 2017), we measured concentrations of 15 metals in toenails collected at enrollment in a race/ethnicity-stratified sample of 1,495 cases and a subcohort of 1,605 women. We estimated hazard ratios and 95% confidence intervals for each metal using Cox regression and robust variance. We used quantile g-computation to estimate the joint association between multiple metals and breast cancer risk. The average duration of follow-up was 7.5 years. There was little evidence supporting an association between individual metals and breast cancer. An exception was molybdenum, which was associated with reduced incidence of overall breast cancer risk (third tertile vs. first tertile: hazard ratio = 0.82, 95% confidence interval: 0.67, 1.00). An inverse association for antimony was observed among non-Hispanic Black women. Predefined groups of metals (all metals, nonessential metals, essential metals, and metalloestrogens) were not strongly associated with breast cancer. This study offers little support for metals, individually or as mixtures, as risk factors for breast cancer. Mechanisms for inverse associations with some metals warrant further study.

Associations of Body Composition and Physical Activity Level With Multiple Measures of Epigenetic Age Acceleration.

Epigenetic clocks use DNA methylation to estimate biological age. Whether body composition and physical activity are associated with these clocks is not well understood. Using blood samples collected at enrollment (2003-2009) from 2,758 women in the US nationwide Sister Study, we calculated 6 epigenetic age acceleration metrics using 4 epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge). Recreational physical activity was self-reported, and adiposity measures were assessed by trained medical examiners (body mass index (BMI), waist-to-hip ratio (WtH), waist circumference). In cross-sectional analyses, all adiposity measures were associated with epigenetic age acceleration. The strongest association was for BMI and PhenoAge, a measure of biological age that correlates with chronic disease (BMI of ≥35.0 vs. 18.5-24.9, ß = 3.15 years, 95% confidence interval (CI): 2.41, 3.90; P for trend < 0.001). In a mutual-adjustment model, both were associated with PhenoAge age acceleration (BMI of ≥35.0 vs. 18.5-24.9, ß = 2.69 years, 95% CI: 1.90, 3.48; P for trend < 0.001; quartile 4 vs.1 WtH, ß = 1.00 years, 95% CI: 0.34, 1.65; P for trend < 0.008). After adjustment, physical activity was associated only with GrimAge (quartile 4 vs. 1, ß = -0.42 years, 95% CI: -0.70, -0.14; P for trend = 0.001). Physical activity attenuated the waist circumference associations with PhenoAge and GrimAge. Excess adiposity was associated with epigenetic age acceleration; physical activity might attenuate associations with waist circumference.

Air pollution and breast cancer risk in the Black Women's Health Study.

BACKGROUND: Air pollution contains numerous carcinogens and endocrine disruptors which may be relevant for breast cancer. Previous research has predominantly been conducted in White women; however, Black women may have higher air pollution exposure due to geographic and residential factors. OBJECTIVE: We evaluated the association between air pollution and breast cancer risk in a large prospective population of Black women. METHODS: We estimated annual average ambient levels of particulate matter <2.5 µm (PM2.5), nitrogen dioxide (NO2) and ozone (O3) at the 1995 residence of 41,317 participants in the Black Women's Health Study who resided in 56 metropolitan areas across the United States. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for an interquartile range (IQR) increase in each pollutant. We evaluated whether the association varied by menopausal status, estrogen receptor (ER) status of the tumor and geographic region of residence. RESULTS: With follow-up through 2015 (mean = 18.3 years), 2146 incident cases of breast cancer were confirmed. Higher exposure to NO2 or O3 was not associated with a higher risk of breast cancer. For PM2.5, although we observed no association overall, there was evidence of modification by geographic region for both ER- (p for heterogeneity = 0.01) and premenopausal breast cancer (p for heterogeneity = 0.01). Among women living in the Midwest, an IQR increase in PM2.5 (2.87 µg/m3), was associated with a higher risk of ER- (HR = 1.53, 95% CI: 1.07-2.19) and premenopausal breast cancer (HR = 1.32, 95% CI: 1.03-1.71). In contrast, among women living in the South, PM2.5 was inversely associated with both ER- (HR = 0.74, 95% CI: 0.56-0.97) and premenopausal breast cancer risk (HR = 0.75, 95% CI: 0.62-0.91). DISCUSSION: Overall, we observed no association between air pollution and increased breast cancer risk among Black women, except perhaps among women living in the Midwestern US.

Outdoor air pollution and terminal duct lobular involution of the normal breast.

BACKGROUND: Exposure to certain outdoor air pollutants may be associated with a higher risk of breast cancer, though potential underlying mechanisms are poorly understood. We examined whether outdoor air pollution was associated with involution of terminal duct lobular units (TDLUs), the histologic site where most cancers arise and an intermediate marker of breast cancer risk. METHODS: Pathologist-enumerated TDLUs were assessed in H&E (hematoxylin and eosin)-stained breast tissue sections from 1904 US women ages 18-75 who donated to the Susan G. Komen Tissue Bank (2009-2012). The 2009 annual fine particulate matter < 2.5 µm in diameter (PM2.5) total mass (µg/m3) at each woman's residential address was estimated from the Environmental Protection Agency's Downscaler Model combining Community Multiscale Air Quality (CMAQ) System modeling with air quality monitoring data. We secondarily considered CMAQ-modeled components of PM2.5 and gaseous pollutants. We used K-means clustering to identify groups of individuals with similar levels of PM2.5 components, selecting groups via cluster stability analysis. Relative rates (RRs) and 95% confidence intervals (95% CIs) for the association between air pollutants and TDLU counts were estimated from a zero-inflated negative binomial regression model adjusted for potential confounders. RESULTS: PM2.5 total mass was associated with higher TDLU counts among all women (interquartile range (IQR) increase, RR = 1.06; 95% CI: 1.01-1.11). This association was evident among both premenopausal and postmenopausal women (premenopausal RR = 1.05, 95% CI: 1.00-1.11; postmenopausal RR = 1.11, 95% CI: 1.00-1.23). We identified 3 groups corresponding to clusters that varied geographically and roughly represented high, medium, and low levels of PM2.5 components relative to population mean levels. Compared to the cluster with low levels, the clusters with both high (RR = 1.74; 95% CI: 1.08-2.80) and medium (RR = 1.82; 95% CI: 1.13-2.93) levels were associated with higher TDLU counts; although not significantly different, the magnitude of the associations was stronger among postmenopausal women. CONCLUSIONS: Higher PM2.5 levels were associated with reduced TDLU involution as measured by TDLU counts. Air pollution exposure may influence the histologic characteristics of normal tissue which could in turn affect breast cancer risk.

Hair dye and chemical straightener use and breast cancer risk in a large US population of black and white women.

Many hair products contain endocrine-disrupting compounds and carcinogens potentially relevant to breast cancer. Products used predominately by black women may contain more hormonally-active compounds. In a national prospective cohort study, we examined the association between hair dye and chemical relaxer/straightener use and breast cancer risk by ethnicity. Sister Study participants (n = 46,709), women ages 35-74, were enrolled between 2003 and 2009, and had a sister with breast cancer but were breast cancer-free themselves. Enrollment questionnaires included past 12-month hair product use. Cox proportional hazards models estimated adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between hair products and breast cancer; effect measure modification by ethnicity was evaluated. During follow-up (mean = 8.3 years), 2,794 breast cancers were identified. Fifty-five percent of participants reported using permanent dye at enrollment. Permanent dye use was associated with 45% higher breast cancer risk in black women (HR = 1.45, 95% CI: 1.10-1.90), and 7% higher risk in white women (HR = 1.07, 95% CI: 0.99-1.16; heterogeneity p = 0.04). Among all participants, personal straightener use was associated with breast cancer risk (HR = 1.18, 95% CI 0.99-1.41); with higher risk associated with increased frequency (p for trend = 0.02). Nonprofessional application of semipermanent dye (HR = 1.28, 95% CI 1.05-1.56) and straighteners (HR = 1.27, 95% CI 0.99-1.62) to others was associated with breast cancer risk. We observed a higher breast cancer risk associated with any straightener use and personal use of permanent dye, especially among black women. These results suggest that chemicals in hair products may play a role in breast carcinogenesis.

Airborne metals exposure and risk of hypertension in the Sister Study.

BACKGROUND: Hypertension-related disease burden is a major challenge globally, with an estimated 1.56 billion adults expected to be affected by hypertension by 2025. Environmental factors, such as metals, could be risk factors for hypertension, but the relationship between airborne metals and hypertension is rarely studied. METHODS: Census-tract airborne metal concentrations (arsenic, cadmium, chromium, cobalt, lead, manganese, mercury, nickel, selenium, and antimony) from the U.S. Environmental Protection Agency 2005 National Air Toxics Assessment database were linked to enrollment residential addresses of 47,595 women in the Sister Study cohort. Hypertension was defined as high systolic (≥140 mm Hg) or diastolic (≥90 mm Hg) blood pressure measured by trained examiners at enrollment or taking anti-hypertensive medications. Multivariable log binomial regression was used to estimate adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between individual metals and hypertension, with and without co-adjustment for other metals. Quantile-based g-computation was used to estimate the joint effect of the overall metal mixture. RESULTS: Comparing the highest to lowest quartiles, risk of hypertension was higher among women with higher residential exposure to arsenic (PR = 1.05, 95%CI = 1.02,1.09), lead (PR = 1.04, 95%CI = 1.01,1.08), chromium (PR = 1.03, 95%CI = 1.00,1.06), cobalt (PR = 1.03, 95%CI = 1.00,1.07), and manganese (PR = 1.03, 95%CI = 1.00,1.06). Selenium was associated with lower risk of hypertension (PR = 0.96, 95%CI = 0.93,0.99). Results were similar with mutual adjustment for all other metals. The associations varied by race/ethnicity, with greater PRs in other races/ethnicities (Hispanic, black, and other participants) compared to non-Hispanic white participants. The joint effect of a quartile increase in exposure to all the metals was 1.02 (95%CI = 0.99,1.04). CONCLUSION: We found that living in areas of higher exposure to arsenic, lead, chromium, cobalt, and manganese was related to higher risk of hypertension, whereas living in areas with higher selenium was inversely related to the risk of hypertension.

Metals and trace elements in relation to body mass index in a prospective study of US women.

BACKGROUND: Epidemiologic studies on the association between metals and body mass index (BMI) have been cross-sectional and have demonstrated inconsistent associations. Our study prospectively examined whether metals measured at baseline were associated with later BMI. We considered metals individually and as joint exposure to pre-defined metal groupings. METHODS: We measured concentrations of 16 metals in toenails collected at baseline (2003-2009) in a subset of 1221 women from the Sister Study. We calculated BMI from height and weight reported on a follow-up questionnaire an average of 5.2 years (range = 3.5-8.3) after baseline. Multivariable linear regression was used to estimate ß coefficients and 95% confidence intervals (CIs) for associations between BMI and individual metals (with estimates given per interquartile range (IQR) increase or in quartiles). Quantile g-computation was used to examine joint associations between groups of metals and BMI. Groups considered were (1) all metals combined, and metals classified as (2) non-essential or (3) essential. RESULTS: In individual metal models we found that, with the exception of cobalt, no single metal was strongly related to BMI. In our mixture analyses, a quartile increase in all non-essential metals was associated with higher BMI (ß = 0.32; 95%CI: 0.00, 0.63 kg/m2), whereas essential metals were suggestively associated with lower BMI (ß = -0.25; 95%CI: 0.58, 0.07 kg/m2). CONCLUSIONS: In this population of women who were, on average, overweight, essential metals were jointly associated with slightly healthier, lower BMI whereas non-essential metals were jointly associated with slightly higher, unhealthier BMI, after controlling for other health indicators and predictors of metals exposures.

Airborne metals and polycyclic aromatic hydrocarbons in relation to mammographic breast density.

BACKGROUND: Breast density is strongly related to breast cancer. Identifying associations between environmental exposures and density may elucidate relationships with breast cancer. Metals and polycyclic aromatic hydrocarbons (PAHs) may influence breast density via oxidative stress or endocrine disruption. METHODS: Study participants (n = 222,581) underwent a screening mammogram in 2011 at a radiology facility in the Breast Cancer Surveillance Consortium. Zip code residential levels of airborne PAHs and metals (arsenic, cadmium, chromium, cobalt, lead, manganese, mercury, nickel, and selenium) were assessed using the 2011 EPA National Air Toxics Assessment. Breast density was measured using the Breast Imaging-Reporting and Data System (BI-RADS) lexicon. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the individual air toxics and dense breasts (BI-RADS 3 or 4). Weighted quantile sum (WQS) regression was used to model the association between the air toxic mixture and density. RESULTS: Higher residential levels of arsenic, cobalt, lead, manganese, nickel, or PAHs were individually associated with breast density. Comparing the highest to the lowest quartile, higher odds of having dense breasts were observed for cobalt (OR = 1.60, 95% CI 1.56-1.64) and lead (OR = 1.56, 95% CI 1.52-1.64). Associations were stronger for premenopausal women. The WQS index was associated with density overall (OR = 1.22, 95% CI 1.20-1.24); the most heavily weighted air toxics were lead and cobalt. CONCLUSIONS: In this first study to evaluate the association between air toxics and breast density, women living in areas with higher concentrations of lead and cobalt were more likely to have dense breasts.

Toenail-Based Metal Concentrations and Young-Onset Breast Cancer.

Several metals have carcinogenic properties, but their associations with breast cancer are not established. We studied cadmium, a metalloestrogen, and 9 other metals-arsenic, cobalt, chromium, copper, mercury, molybdenum, lead, tin, and vanadium--in relation to young-onset breast cancer (diagnosis age <50 years), which tends to be more aggressive than and have a different risk profile from later-onset disease. Recent metal exposure was measured by assessing element concentrations, via inductively coupled plasma mass spectrometry, in toenail clippings of 1,217 disease-discordant sister pairs in the US-based Sister (2003-2009) and Two Sister (2008-2010) studies. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. After correcting for differential calendar time of sample collection, no statistically significant associations were observed between any metals and breast cancer. Vanadium had the largest odds ratio (for fourth vs. first quartile, odds ratio = 1.54, 95% confidence interval: 0.75, 3.16; P for trend = 0.21). The association between cadmium and young-onset breast cancer was near null, with no evidence of a dose-response relationship (for fourth vs. first quartile, odds ratio = 0.95, 95% confidence interval: 0.64, 1.43; P for trend = 0.64). Positive associations between urinary cadmium concentrations and breast cancer have been reported in case-control studies, but we observed no such association between young-onset breast cancer and toenail concentrations of any assessed metals.

Toenail-Based Metal Concentrations and Young-Onset Breast Cancer.

Several metals have carcinogenic properties, but their associations with breast cancer are not established. We studied cadmium, a metalloestrogen, and 9 other metals-arsenic, cobalt, chromium, copper, mercury, molybdenum, lead, tin, and vanadium--in relation to young-onset breast cancer (diagnosis age <50 years), which tends to be more aggressive than and have a different risk profile from later-onset disease. Recent metal exposure was measured by assessing element concentrations, via inductively coupled plasma mass spectrometry, in toenail clippings of 1,217 disease-discordant sister pairs in the US-based Sister (2003-2009) and Two Sister (2008-2010) studies. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. After correcting for differential calendar time of sample collection, no statistically significant associations were observed between any metals and breast cancer. Vanadium had the largest odds ratio (for fourth vs. first quartile, odds ratio = 1.36, 95% confidence interval: 0.84, 2.21; P for trend = 0.17). Cadmium was associated with a small increase in risk, with no evidence of a dose-response relationship (for fourth vs. first quartile, odds ratio = 1.15, 95% confidence interval: 0.82, 1.60; P for trend = 0.67). Positive associations between urinary cadmium concentrations and breast cancer have been reported in case-control studies, but we observed no such association between young-onset breast cancer and toenail concentrations of any assessed metals.

Alcohol and DNA Methylation: An Epigenome-Wide Association Study in Blood and Normal Breast Tissue.

The biological mechanisms driving associations between alcohol consumption and chronic diseases might include epigenetic modification of DNA methylation. We explored the hypothesis that alcohol consumption is associated with methylation in an epigenome-wide association study of blood and normal breast tissue DNA. Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, California) array data on blood DNA methylation was examined in a discovery set of 2,878 non-Hispanic white women from the Sister Study (United States, 2004-2015) who provided detailed questionnaire information on lifetime alcohol use. Robust linear regression modeling was used to identify significant associations (false discovery rate of Q < 0.05) between the number of alcoholic drinks per week and DNA methylation at 5,458 cytosine-phosphate-guanine (CpG) sites. Associations were replicated (P < 0.05) for 677 CpGs in an independent set of 187 blood DNA samples from the Sister Study and for 628 CpGs in an independent set of 171 normal breast DNA samples; 1,207 CpGs were replicated in either blood or normal breast, with 98 CpGs replicated in both tissues. Individual gene effects were notable for phosphoglycerate dehydrogenase (PGHDH), peptidyl-prolyl cis-trans isomerase (PPIF), solute carrier 15 (SLC15), solute carrier family 43 member 1 (SLC43A1), and solute carrier family 7 member 11 (SLC7A11). We also found that high alcohol consumption was associated with significantly lower global methylation as measured by the average of CpGs on the entire array.

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

BACKGROUND: The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS: Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions. RESULTS: All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null. CONCLUSIONS: The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.