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.

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.

Prediagnostic serum polychlorinated biphenyl concentrations and primary liver cancer: A case-control study nested within two prospective cohorts.

BACKGROUND: Polychlorinated biphenyls (PCBs) were used in electrical equipment and a range of construction materials. Although banned in the United States and most of Europe in the 1970s, they are highly persistent in the environment and bioaccumulate. Whether PCBs are associated with liver cancer risk at general population levels is unknown. METHODS: This study consisted of 136 incident liver cancer cases and 408 matched controls from the Kaiser Permanente Northern California Multiphasic Health Checkup (MHC) cohort and 84 cases and 252 matched controls from the Norwegian Janus cohort. Sera collected in the 1960s-1980s were measured for 37 PCB congeners and markers of hepatitis B (HBV) and C (HCV) infection. Odds ratios (OR) and 95% confidence intervals (CI) for tertiles of each lipid-adjusted PCB were estimated from conditional logistic regression. We also examined the molar sum of congeners in groups: total PCBs; low, medium, and high chlorination; and Wolff functional groups. RESULTS: Concentrations of individual congeners from the 1960s/1970s sera ranged from 1.3-123.0 and 1.4-116.0 ng/g lipid among MHC cases and controls, respectively, and from 1.9-258.0 and 1.9-271.0 ng/g lipid among Janus cases and controls, respectively. Among MHC participants with sera from the 1960s, collected an average of 27 years before diagnosis among cases, the top tertile of PCBs 151, 170, 172, 177, 178, 180, and 195 was significantly associated with elevated odds of liver cancer (OR range = 2.01-2.38); most of these congeners demonstrated exposure-response trends. For example, ORtertile 3vs1 = 2.38 (95% CI: 1.22-4.64, p-trend = 0.01) for PCB 180. As a group, Wolff group 1b congeners, which are biologically persistent and weak phenobarbital inducers, were associated with increased odds. In MHC participants, ever vs. never HBV or HCV infection modified the PCB-liver cancer associations. There was little evidence of an association between PCBs and odds of liver cancer among the Janus cohort. DISCUSSION: We observed associations between a number of PCB congeners and increased odds of liver cancer among MHC, but not Janus, participants with sera from the 1960s/1970s.

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.

Metallic Air Pollutants and Breast Cancer Risk in a Nationwide Cohort Study.

BACKGROUND: Toxic metals show evidence of carcinogenic and estrogenic properties. However, little is known about the relationship between airborne metals and breast cancer. We evaluated the risk of breast cancer in relation to exposure to toxic metallic substances in air, individually and combined, in a US-wide cohort. METHODS: Sister Study participants (n = 50,884), breast cancer-free women who had a sister with breast cancer were recruited, from 2003 to 2009. The 2005 Environmental Protection Agency National Air Toxic Assessment's census-tract estimates of metal concentrations in air (antimony, arsenic, cadmium, chromium, cobalt, lead, manganese, mercury, nickel, and selenium) were matched to participants' enrollment residence. We used Cox regression to estimate the association between quintiles of individual metals and breast cancer incidence and weighted quantile sum regression to model the association between the metal mixture and breast cancer. RESULTS: A total of 2,587 breast cancer cases were diagnosed during follow-up (mean = 7.4 years). In individual chemical analyses comparing the highest to lowest quintiles, postmenopausal breast cancer risk was elevated for mercury (hazard ratio [HR] = 1.3, 95% confidence interval [CI], 1.1, 1.5), cadmium (HR = 1.1, 95% CI, 0.96, 1.3), and lead (HR = 1.1, 95% CI, 0.98, 1.3). The weighted quantile sum index was associated with postmenopausal breast cancer (odds ratio [OR] = 1.1, 95% CI, 1.0, 1.1). Consistent with the individual chemical analysis, the most highly weighted chemicals for predicting postmenopausal breast cancer risk were lead, cadmium, and mercury. Results were attenuated for overall breast cancer. CONCLUSIONS: Higher levels of some airborne metals, specifically mercury, cadmium, and lead, were associated with a higher risk of postmenopausal breast cancer.

Childhood and teenage physical activity and breast cancer risk.

PURPOSE: Adult physical activity is associated with reduced breast cancer risk, but few studies have evaluated activity before adulthood. Early life may be an important period because of rapid breast development and hormonal changes. This study contributes new information by examining childhood (ages 5-12) and teenage (ages 13-19) activity separately and overall. METHODS: The Sister Study is a cohort of 50,884 women aged 35-74. Women reported age 5-19 sports/exercise activities and age 10 and 16 unstructured activities. Both hours and MET-hours of activity were considered in association with breast cancer overall, by ER status, and by menopausal status. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models. RESULTS: 2416 cases were diagnosed during follow-up (mean = 6.4 years). Participation in 7+ hours (vs <1 h) per week of sports/exercise during ages 5-19 was associated with reduced breast cancer risk (HR = 0.75; 95% CI 0.57-0.99). 7+ hours (vs <1 h) per week of unstructured physical activity at age 16, but not age 10, was inversely associated with breast cancer (HR = 0.81; 95% CI 0.70-0.95). Associations were more pronounced for ER+ tumors, especially for activity during the childhood (ages 5-12) period. Due to low correlation between childhood/teenage and adulthood activity in this study (r = 0.1), it is unlikely that recent activity explains our results. CONCLUSIONS: Findings from this large cohort indicate higher levels of physical activity during ages 5-19 are inversely associated with breast cancer risk, supporting early life as a window of susceptibility for breast cancer development.

Childhood and Adolescent Pesticide Exposure and Breast Cancer Risk.

BACKGROUND: To date, epidemiologic studies have not strongly supported an association between pesticide exposure and breast cancer. However, few previous studies had the ability to assess specific time periods of exposure. Studies that relied on adult serum levels of metabolites of organochlorine pesticides may not accurately reflect exposure during developmental periods. Furthermore, exposure assessment often occurred after diagnosis and key tumor characteristics, such as hormone receptor status, have rarely been available to evaluate tumor subtype-specific associations. We examined the association between pesticide exposure during childhood and adolescence and breast cancer risk in the prospective Sister Study cohort (N = 50,884 women) to assess this relation by tumor subtype. METHODS: During an average 5-year follow-up, 2,134 incident invasive and in situ breast cancer diagnoses were identified. Residential and farm exposure to pesticides were self-reported at study enrollment during standardized interviews. Multivariable hazard ratios and 95% confidence intervals for breast cancer risk were calculated with Cox proportional hazards regression. RESULTS: HRs were near null for the association between childhood/adolescent pesticide exposure and breast cancer risk overall or among ER+/PR+ invasive tumors. However, among women who were ages 0-18 before the ban of dichlordiphenyltrichloroethane in the US, exposure to fogger trucks or planes was associated with a hazard ratio = 1.3 for premenopausal breast cancer (95% confidence interval: 0.92, 1.7). CONCLUSION: These findings do not support an overall association between childhood and adolescent pesticide exposure and breast cancer risk. However, modest increases in breast cancer risk were associated with acute events in a subgroup of young women.

Toenail and serum levels as biomarkers of iron status in pre- and postmenopausal women: correlations and stability over eight-year follow-up.

Iron status is often assessed in epidemiologic studies, and toenails offer a convenient alternative to serum because of ease of collection, transport, and storage, and the potential to reflect a longer exposure window. Very few studies have examined the correlation between serum and toenail levels for trace metals. Our aim was to compare iron measures using serum and toenails on both a cross-sectional and longitudinal basis. Using a subset of the US-wide prospective Sister Study cohort, we compared toenail iron measures to serum concentrations for iron, ferritin and percent transferrin saturation. Among 146 women who donated both blood and toenails at baseline, a subsample (59%, n = 86) provided specimens about 8 years later. Cross-sectional analyses included nonparametric Spearman's rank correlations between toenail and serum biomarker levels. We assessed within-woman maintenance of rank across time for the toenail and serum measures and fit mixed effects models to measure change across time in relation to change in menopause status. Spearman correlations at baseline (follow-up) were 0.08 (0.09) for serum iron, 0.08 (0.07) for transferrin saturation, and - 0.09 (- 0.17) for ferritin. The within-woman Spearman correlation for toenail iron between the two time points was higher (0.47, 95% CI 0.30, 0.64) than for serum iron (0.30, 95% CI 0.09, 0.51) and transferrin saturation (0.34, 95% CI 0.15, 0.54), but lower than that for ferritin (0.58, 95% CI 0.43, 0.73). Serum ferritin increased over time while nail iron decreased over time for women who experienced menopause during the 8-years interval. Based on cross-sectional and repeated assessments, our evidence does not support an association between serum biomarkers and toenail iron levels. Toenail iron concentrations did appear to be moderately stable over time but cannot be taken as a proxy for serum iron biomarkers and they may reflect physiologically distinct fates for iron.

Outdoor air pollution and histologic composition of normal breast tissue.

BACKGROUND: Biologic pathways underlying the association between outdoor air pollution and breast cancer risk are poorly understood. Breast tissue composition may reflect cumulative exposure to breast cancer risk factors and has been associated with breast cancer risk among patients with benign breast disease. Herein, we evaluated whether fine particulate matter (PM2.5) was associated with the histologic composition of normal breast tissue. METHODS: Machine-learning algorithms were applied to digitized hematoxylin and eosin-stained biopsies of normal breast tissue to quantify the epithelium, stroma, adipose and total tissue area from 3,977 individuals aged 18-75 years from a primarily Midwestern United States population who donated breast tissue samples to the Susan G. Komen Tissue Bank (2009-2019). Annual levels of PM2.5 were assigned to each woman's residential address based on year of tissue donation. We applied predictive k-means to assign participants to clusters with similar PM2.5 chemical composition and used linear regression to examine the cross-sectional associations between a 5-µg/m3 increase in PM2.5 and square root-transformed proportions of epithelium, stroma, adipose, and epithelium-to-stroma proportion [ESP], overall and by PM2.5 cluster. RESULTS: Higher residential PM2.5 was associated with lower proportion of breast stromal tissue [ß = -0.93, 95% confidence interval: (-1.52, -0.33)], but was not related to the proportion of epithelium [ß = -0.11 (-0.34, 0.11)]. Although PM2.5 was not associated with ESP overall [ß = 0.24 (-0.16, 0.64)], the association significantly differed by PM2.5 chemical composition (p-interaction = 0.04), with a positive association evident only among an urban, Midwestern cluster with higher concentrations of nitrate (NO3-) and ammonium (NH4+) [ß = 0.49 (0.03, 0.95)]. CONCLUSIONS: Our findings are consistent with a possible role of PM2.5 in breast cancer etiology and suggest that changes in breast tissue composition may be a potential pathway by which outdoor air pollution impacts breast cancer risk. This study further underscores the importance of considering heterogeneity in PM2.5 composition and its impact on breast carcinogenesis.

The importance of addressing early life environmental exposures in cancer epidemiology.

Purpose of Review: Environmental exposures during early stages of life may be particularly relevant for cancer etiology because of the rapid hormonal and tissue changes that occur during puberty and, in women, through first birth. We review evidence from the past five years on environmental exposures during childhood/adolescence through first birth and the risk of breast and other cancers during adulthood. Recent Findings: The studies of breast cancer (n=14) reported associations for childhood/adolescent environmental tobacco smoke (ETS), smoking initiation, pesticides, hair dye use, and living on a road with high traffic. Smoking before first childbirth was also associated with increased breast cancer risk. We identified 12 studies on other cancers, with only 1-2 studies per cancer type, with most focused on ETS or active smoking. Summary: Despite studies suggesting an important role of exposure to environmental factors during early life and cancer risk in adulthood, few studies have been conducted. Future studies could utilize stored biologic samples from relevant periods or complete residential histories for geographically-based exposures.

Fossil-fuel and combustion-related air pollution and hypertension in the Sister Study.

Hypertension is a leading risk factor for disease burden, with more than 200 million disability-adjusted life-years attributed to high blood pressure in 2015. While outdoor air pollution is associated with cardiovascular disease, the joint effect of exposure to air pollution from combustion products on hypertension has rarely been studied. We conducted a cross-sectional analysis to explore the association between combustion-related air pollution and hypertension. Census-tract levels of ambient concentrations of nine fossil-fuel and combustion-related air toxics (biphenyl, naphthalene, polycyclic organic matter, diesel emissions, 1,3-butadiene, acetaldehyde, benzene, acrolein, and formaldehyde) from the 2005 National Air Toxics Assessment database and NO2 from 2005 monitoring data were linked to baseline residential addresses of 47,467 women in the Sister Study cohort. Hypertension at enrollment (2003-2009) was defined as high systolic (≥140 mm Hg) or diastolic (≥90 mm Hg) blood pressure or taking antihypertensive medication. We used log-binomial regression and quantile-based g-computation to estimate the individual and joint effects of fossil-fuel and combustion-related air pollution on hypertension. Comparing the highest to lowest quartiles, diesel emissions (prevalence ratio (PR) = 1.05, 95% confidence interval (CI) = 1.01,1.08), 1,3-butadiene (PR = 1.04, 95%CI = 1.00,1.07), acetaldehyde (PR = 1.08, 95%CI = 1.04,1.12), benzene (PR = 1.05, 95%CI = 1.02,1.08), formaldehyde (PR = 1.08, 95%CI = 1.04,1.11), and NO2 (PR = 1.08, 95%CI = 1.05,1.12) were individually associated with higher prevalence of hypertension. The PR for the joint effect of increasing all ambient air toxics and NO2 by one quartile was 1.02 (95%CI = 1.01,1.04). Associations varied by race/ethnicity, with stronger associations observed among women reporting races/ethnicities (Hispanic/Latina, non-Hispanic Black and other) other than non-Hispanic White. In conclusion, we found that air pollution from fossil fuel and combustion may be a risk factor for hypertension.

Air Pollution and Breast Cancer: An Examination of Modification By Underlying Familial Breast Cancer Risk.

BACKGROUND: An increased familial risk of breast cancer may be due to both shared genetics and environment. Women with a breast cancer family history may have a higher prevalence of breast cancer-related gene variants and thus increased susceptibility to environmental exposures. We evaluated whether air pollutant and breast cancer associations varied by familial risk. METHODS: Sister Study participants living in the contiguous United States at enrollment (2003-2009; N = 48,453), all of whom had at least one first-degree relative with breast cancer, were followed for breast cancer. Annual NO2 and PM2.5 concentrations were estimated at the enrollment addresses. We predicted 1-year familial breast cancer risk using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Using Cox regression, we estimated HRs and 95% confidence intervals (CI) for associations between each pollutant dichotomized at the median and breast cancer with interaction terms to examine modification by BOADICEA score. RESULTS: NO2 was associated with a higher breast cancer risk among those with BOADICEA score >90th percentile (HR, 1.28; 95% CI, 1.05-1.56) but not among those with BOADICEA score ≤90th percentile (HR, 0.98; 95% CI, 0.90-1.06; P interaction = 0.01). In contrast to NO2, associations between PM2.5 and breast cancer did not vary between individuals with BOADICEA score >90th percentile and ≤90th percentile (P interaction = 0.26). CONCLUSIONS: Our results provide additional evidence that air pollution may be implicated in breast cancer, particularly among women with a higher familial risk. IMPACT: Women at higher underlying breast cancer risk may benefit more from interventions to reduce exposure to NO2.

Associations between airborne crude oil chemicals and symptom-based asthma.

RATIONALE: The 2010 Deepwater Horizon (DWH) oil spill response and cleanup (OSRC) workers were exposed to airborne total hydrocarbons (THC), benzene, toluene, ethylbenzene, o-, m-, and p-xylenes and n-hexane (BTEX-H) from crude oil and PM2.5 from burning/flaring oil and natural gas. Little is known about asthma risk among oil spill cleanup workers. OBJECTIVES: We assessed the relationship between asthma and several oil spill-related exposures including job classes, THC, individual BTEX-H chemicals, the BTEX-H mixture, and PM2.5 using data from the Gulf Long-Term Follow-up (GuLF) Study, a prospective cohort of 24,937 cleanup workers and 7,671 nonworkers following the DWH disaster. METHODS: Our analysis largely focused on the 19,018 workers without asthma before the spill who had complete exposure, outcome, and covariate information. We defined incident asthma 1-3 years following exposure using both self-reported wheeze and self-reported physician diagnosis of asthma. THC and BTEX-H were assigned to participants based on measurement data and work histories, while PM2.5 used modeled estimates. We used modified Poisson regression to estimate risk ratios (RR) and 95% confidence intervals (CIs) for associations between spill-related exposures and asthma and a quantile-based g-computation approach to explore the joint effect of the BTEX-H mixture on asthma risk. RESULTS: OSRC workers had greater asthma risk than nonworkers (RR: 1.60, 95% CI: 1.38, 1.85). Higher estimated THC exposure levels were associated with increased risk in an exposure-dependent manner (linear trend test p < 0.0001). Asthma risk also increased with increasing exposure to individual BTEX-H chemicals and the chemical mixture: A simultaneous quartile increase in the BTEX-H mixture was associated with an increased asthma risk of 1.45 (95% CI: 1.35,1.55). With fewer cases, associations were less apparent for physician-diagnosed asthma alone. CONCLUSIONS: THC and BTEX-H were associated with increased asthma risk defined using wheeze symptoms as well as a physician diagnosis.

Urinary polycyclic aromatic hydrocarbon metabolites and mortality in the United States: A prospective analysis.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous organic compounds associated with chronic disease in epidemiologic studies, though the contribution of PAH exposure on fatal outcomes in the U.S. is largely unknown. OBJECTIVES: We investigated urinary hydroxylated PAH metabolites (OH-PAHs) with all-cause and cause-specific mortality in a representative sample of the U.S. population. METHODS: Study participants were ≥20 years old from the National Health and Nutrition Examination Survey 2001-2014. Concentrations (nmol/L) of eight OH-PAHs from four parent PAHs (naphthalene, fluorene, phenanthrene, pyrene) were measured in spot urine samples at examination. We identified all-cause, cancer-specific, and cardiovascular-specific deaths through 2015 using the National Death Index. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ΣOH-PAHs and mortality endpoints. We assessed potential heterogeneity by age, gender, smoking status, poverty, and race/ethnicity. Additionally, we examined the overall mixture effect using quantile g-computation. RESULTS: In 9,739 eligible participants, there were 934 all-cause deaths, 159 cancer-specific deaths, and 108 cardiovascular-specific deaths (median 6.75 years follow-up). A log10 increase in ΣOH-PAHs was associated with higher all-cause mortality (HRadj = 1.39 [95%CI: 1.21, 1.61]), and possibly cancer-specific mortality (HRadj = 1.15 [95%CI: 0.79, 1.69]), and cardiovascular-specific mortality (HRadj = 1.49 [95%CI: 0.94, 2.33]). We observed substantial effect modification by age, smoking status, gender, and race/ethnicity across mortality endpoints. Risk of cardiovascular mortality was higher for non-Hispanic blacks and those in poverty, indicating potential disparities. Quantile g-computation joint associations for a simultaneous quartile increase in OH-PAHs were HRadj = 1.15 [95%CI: 1.02, 1.31], HRadj = 1.41 [95%CI: 1.05, 1.90], and HRadj = 0.98 [95%CI: 0.66, 1.47] for all-cause, cancer-specific, and cardiovascular-specific mortalities, respectively. DISCUSSION: Our results support a role for total PAH exposure in all-cause and cause-specific mortality in the U.S. population.

Mixtures modeling identifies chemical inducers versus repressors of toxicity associated with wildfire smoke.

Exposure to wildfire smoke continues to be a growing threat to public health, yet the chemical components in wildfire smoke that primarily drive toxicity and associated disease are largely unknown. This study utilized a suite of computational approaches to identify groups of chemicals induced by variable biomass burn conditions that were associated with biological responses in the mouse lung, including pulmonary immune response and injury markers. Smoke condensate samples were collected and characterized, resulting in chemical distribution information for 86 constituents across ten different exposures. Mixtures-relevant statistical methods included (i) a chemical clustering and data-reduction method, weighted chemical co-expression network analysis (WCCNA), (ii) a quantile g-computation approach to address the joint effect of multiple chemicals in different groupings, and (iii) a correlation analysis to compare mixtures modeling results against individual chemical relationships. Seven chemical groups were identified using WCCNA based on co-occurrence showing both positive and negative relationships with biological responses. A group containing methoxyphenols (e.g., coniferyl aldehyde, eugenol, guaiacol, and vanillin) displayed highly significant, negative relationships with several biological responses, including cytokines and lung injury markers. This group was further shown through quantile g-computation methods to associate with reduced biological responses. Specifically, mixtures modeling based on all chemicals excluding those in the methoxyphenol group demonstrated more significant, positive relationships with several biological responses; whereas mixtures modeling based on just those in the methoxyphenol group demonstrated significant negative relationships with several biological responses, suggesting potential protective effects. Mixtures-based analyses also identified other groups consisting of inorganic elements and ionic constituents showing positive relationships with several biological responses, including markers of inflammation. Many of the effects identified through mixtures modeling in this analysis were not captured through individual chemical analyses. Together, this study demonstrates the utility of mixtures-based approaches to identify potential drivers and inhibitors of toxicity relevant to wildfire exposures.

Outdoor air pollution and anti-Müllerian hormone concentrations in the Sister Study.

BACKGROUND: Anti-Müllerian hormone (AMH) concentrations are a marker of ovarian reserve and are indicative of a woman's reproductive lifespan. Exposure to tobacco smoke has been associated with lower AMH concentrations; however, less is known about the association between ambient air pollution and ovarian reserve. METHODS: For 883 premenopausal Sister Study participants recruited between 2003 and 2009 in the United States, adult residential annual average concentrations of PM2.5, PM10, and NO2 were estimated using validated universal kriging models incorporating land-use regression. We estimated the distance in meters to the nearest major road for both adult enrollment and childhood residences. Serum AMH was measured using an ultrasensitive ELISA assay. Samples with AMH concentrations below the detection limit were analyzed using a picoAMH ELISA assay. Multivariable-adjusted linear regression was used to estimate the percent change in AMH in relation to ambient residential air pollution, categorized in quartiles and per interquartile range increase, and distance to a major roadway. RESULTS: Overall, we observed little to no evidence of associations between AMH and air pollution concentrations or proximity to roadways. Women in the highest quartile of NO2 exposure, a traffic-related pollutant, had higher estimated AMH concentrations (Q4 vs. Q1, 42.9%; 95% CI = -3.4, 111.4) compared with the lowest quartile. However, lower mean AMH concentrations were observed for women living closer to a major roadway (<50 m to nearest roadway vs. ≥200 m = -32.9%; 95% CI = -56.1, 2.6). CONCLUSIONS: We saw little consistent evidence to support an association between outdoor air pollution and diminished ovarian reserve in US women ages 35-54.

Physical Activity and Breast Cancer: Focusing on High-Risk Subgroups and Putting Recommendations in Context.

While it is well-established that physical activity is associated with a decreased risk of breast cancer, most studies have been conducted in populations at an average underlying breast cancer risk. In this issue of Cancer Research, Kehm and colleagues present compelling evidence that adulthood physical activity is beneficial across the risk spectrum, including among women with BRCA1 and BRCA2 mutations. These findings are significant because women who are at a higher baseline risk are not engaging in sufficient physical activity to meet current guidelines but may be more motivated to do so knowing that they, like women in the general population, may benefit.See related article by Kehm et al., p. 116.