Geospatial Science for the Environmental Epidemiology of Cancer in the Exposome Era.

Geospatial science is the science of location or place that harnesses geospatial tools, such as geographic information systems (GIS), to understand the features of the environment according to their locations. Geospatial science has been transformative for cancer epidemiologic studies through enabling large-scale environmental exposure assessments. As the research paradigm for the exposome, or the totality of environmental exposures across the life course, continues to evolve, geospatial science will serve a critical role in determining optimal practices for how to measure the environment as part of the external exposome. The objectives of this article are to provide a summary of key concepts, present a conceptual framework that illustrates how geospatial science is applied to environmental epidemiology in practice and through the lens of the exposome, and discuss the following opportunities for advancing geospatial science in cancer epidemiologic research: enhancing spatial and temporal resolutions and extents for geospatial data; geospatial methodologies to measure climate change factors; approaches facilitating the use of patient addresses in epidemiologic studies; combining internal exposome data and geospatial exposure models of the external exposome to provide insights into biological pathways for environment-disease relationships; and incorporation of geospatial data into personalized cancer screening policies and clinical decision making.

Long-term exposure to ambient fine particulate matter and risk of liver cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Fine particulate matter (PM2.5) exposure has been associated with liver cancer incidence and mortality in a limited number of studies. We sought to evaluate this relationship for the first time in a U.S. cohort with historical exposure assessment. METHODS: We used spatiotemporal prediction models to estimate annual average historical PM2.5 concentrations (1980-2015) at residential addresses of 499,729 participants in the NIH-AARP Diet and Health Study, a cohort in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, Georgia, and Detroit, Michigan) enrolled in 1995-1996 and followed up through 2017. We used a time-varying Cox model to estimate the association for liver cancer and the predominant histologic type, hepatocellular carcinoma (HCC), per 5 µg/m3 increase in estimated outdoor PM2.5 levels, incorporating a 5-year average, lagged 10 years prior to cancer diagnosis and adjusting for age, sex, race/ethnicity, education level and catchment state. We also evaluated PM2.5 interactions with hypothesized effect modifiers. RESULTS: We observed a non-significantly increased risk of liver cancer associated with estimated PM2.5 exposure (Hazard ratio [HR] = 1.05 [0.96-1.14], N = 1,625); associations were slightly stronger for HCC, (84 % of cases; HR = 1.08 [0.98-1.18]). Participants aged 70 or older at enrollment had an increased risk of liver cancer versus other age groups (HR = 1.50 [1.01-2.23]); p-interaction = 0.01) and risk was elevated among participants who did not exercise (HR = 1.81 [1.22-2.70]; p-interaction = 0.01). We found no evidence of effect modification by sex, smoking status, body mass index, diabetes status, or alcohol consumption (p-interaction > 0.05). CONCLUSIONS: Our findings in this large cohort suggest that residential ambient PM2.5 levels may be associated with liver cancer risk. Further exploration of the variation in associations by age and physical activity are important areas for future research.

Construction of residential histories to estimate long-term environmental exposures in the California Teachers Study cohort.

Environmental epidemiologic studies using geospatial data often estimate exposure at a participant's residence upon enrollment, but mobility during the exposure period can lead to misclassification. We aimed to mitigate this issue by constructing residential histories for participants in the California Teachers Study through follow-up (1995-2018). Address records have been collected from the US Postal Service, LexisNexis, Experian, and California Cancer Registry. We identified records of the same address based on geo-coordinate distance (≤250 m) and street name similarity. We consolidated addresses, prioritizing those confirmed by participants during follow-up questionnaires, and estimating the duration lived at each address using dates associated with records (e.g., date-first-seen). During 23 years of follow-up, about half of participants moved (48%, including 14% out-of-state). We observed greater mobility among younger women, Hispanic/Latino women, and those in metropolitan and lower socioeconomic status areas. The cumulative proportion of in-state movers remaining eligible for analysis was 21%, 32%, and 41% at 5, 10, and 20 years post enrollment, respectively. Using self-reported information collected 10 years after enrollment, we correctly identified 94% of movers and 95% of non-movers as having moved or not moved from their enrollment address. This dataset provides a foundation for estimating long-term environmental exposures in diverse epidemiologic studies in this cohort. IMPACT: Our efforts in constructing residential histories for California Teachers Study participants through follow-up (1995-2018) benefit future environmental epidemiologic studies. Address availability during the exposure period can mitigate misclassification due to residential changes, especially when evaluating long-term exposures and chronic health outcomes. This can reduce differential misclassification among more mobile subgroups, including younger women and those from lower socioeconomic and urban areas. Our approach to consolidating addresses from multiple sources showed high accuracy in comparison to self-reported residential information. The residential dataset produced from this analysis provides a valuable tool for future studies, ultimately enhancing our understanding of environmental health impacts.

Fine particulate matter, noise pollution, and greenspace and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial Cohort.

BACKGROUND: Greenspace is hypothesized as being protective against cancer, whereas noise pollution and fine particulate matter (<2.5 µm in diameter, PM2.5) are both potential risk factors. Findings from recent studies of greenspace and PM2.5 with prostate cancer are not conclusive and the association between noise exposure and cancer has not been evaluated in a U.S. METHODS: We assessed PM2.5, noise, and greenspace exposure using spatiotemporal models and satellite-based estimates at enrollment addresses for N=43,184 male participants of the prospective Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial cohort (enrolled 1994-2001). We used Cox regression models adjusted for age, race and ethnicity, study center, family history of prostate cancer, and Area Deprivation Index to estimate associations between ambient PM2.5 (µg/m3), greenspace (index range from -1 to 1), and noise pollution (loudest 10% of total existing sound, decibels) and incident prostate cancer risk through December 2017. RESULTS: A total of 6,327 cases of prostate cancer were diagnosed among male participants during follow-up. PM2.5 and noise exposures were moderately positively correlated (Spearman's rho=0.46), and PM2.5 and greenspace were not correlated (ρ=0.10); greenspace and noise were inversely correlated (ρ=-0.32). In single-pollutant and multipollutant models mutually adjusted for co-exposures, we found no associations with prostate cancer risk. CONCLUSION: We did not find evidence that PM2.5, greenspace, and noise pollution were associated with prostate cancer risk in this large, geographically spread cohort. IMPACT: This study contributes to a small body of existing literature investigating these biologically plausible associations.

Outdoor air pollution exposure and uterine cancer incidence in the sister study.

BACKGROUND: Outdoor air pollution is a ubiquitous exposure that includes endocrine-disrupting and carcinogenic compounds that may contribute to the risk of hormone-sensitive outcomes such as uterine cancer. However, there is limited evidence about the relationship between outdoor air pollution and uterine cancer incidence. METHODS: We investigated the associations of residential exposure to particulate matter less than 2.5 µm in diameter (PM2.5) and nitrogen dioxide (NO2) with uterine cancer among 33,417 Sister Study participants with an intact uterus at baseline (2003-2009). Annual average air pollutant concentrations were estimated at participants' geocoded primary residential address(es) using validated spatiotemporal models. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between time-varying 12-month PM2.5 (µg/m3) and NO2 (ppb) averages and uterine cancer incidence. RESULTS: Over a median follow-up period of 9.8 years, 319 incident uterine cancer cases were identified. A 5-ppb increase in NO2 was associated with a 23% higher incidence of uterine cancer (HR = 1.23, 95% CI 1.04-1.46), especially among participants living in urban areas (HR = 1.53, 95% CI: 1.13-2.07). However, PM2.5 was not associated with increased uterine cancer incidence. CONCLUSION: In this large U.S. cohort, NO2, a marker of vehicular traffic exposure, was associated with a higher incidence of uterine cancer. These findings expand the scope of health effects associated with air pollution, supporting the need for policy and other interventions designed to reduce air pollutant exposure.

Nitrate exposure from drinking water and dietary sources among Iowa farmers using private wells.

Nitrate levels are increasing in water resources across the United States and nitrate ingestion from drinking water has been associated with adverse health risks in epidemiologic studies at levels below the maximum contaminant level (MCL). In contrast, dietary nitrate ingestion has generally been associated with beneficial health effects. Few studies have characterized the contribution of both drinking water and dietary sources to nitrate exposure. The Agricultural Health Study is a prospective cohort of farmers and their spouses in Iowa and North Carolina. In 2018-2019, we assessed nitrate exposure for 47 farmers who used private wells for their drinking water and lived in 8 eastern Iowa counties where groundwater is vulnerable to nitrate contamination. Drinking water and dietary intakes were estimated using the National Cancer Institute Automated Self-Administered 24-Hour Dietary Assessment tool. We measured nitrate in tap water and estimated dietary nitrate from a database of food concentrations. Urinary nitrate was measured in first morning void samples in 2018-19 and in archived samples from 2010 to 2017 (minimum time between samples: 2 years; median: 7 years). We used linear regression to evaluate urinary nitrate concentrations in relation to total nitrate, and drinking water and dietary intakes separately. Overall, dietary nitrate contributed the most to total intake (median: 97 %; interquartile range [IQR]: 57-99 %). Among 15 participants (32 %) whose drinking water nitrate concentrations were at/above the U.S. Environmental Protection Agency MCL (10 mg/L NO3-N), median intake from water was 44 % (IQR: 26-72 %). Total nitrate intake was the strongest predictor of urinary nitrate concentrations (R2 = 0.53). Drinking water explained a similar proportion of the variation in nitrate excretion (R2 = 0.52) as diet (R2 = 0.47). Our findings demonstrate the importance of both dietary and drinking water intakes as determinants of nitrate excretion.

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.

Sociodemographic inequities in the burden of carcinogenic industrial air emissions in the United States.

BACKGROUND: Industrial facilities are not located uniformly across U.S. communities, but how the burden of exposure to carcinogenic air emissions may vary across population characteristics is unclear. We evaluated differences in carcinogenic industrial pollution among major sociodemographic groups in the U.S. and Puerto Rico. METHODS: We evaluated cross-sectional associations of population characteristics including race and ethnicity, educational attainment, and poverty at the census tract level with point-source industrial emissions of 21 known human carcinogens using regulatory data from the U.S. Environmental Protection Agency. Odds ratios (ORs) and 95% confidence intervals (CIs) comparing the highest emissions (tertile or quintile) to the referent group (zero emissions/non-exposed) for all sociodemographic characteristics were estimated using multinomial, population density-adjusted logistic regression models. RESULTS: In 2018, approximately 7.4 million people lived in Census tracts with nearly 12 million pounds of carcinogenic air releases. The odds of tracts having the greatest burden of benzene, 1,3-butadiene, ethylene oxide, formaldehyde, trichloroethylene, and nickel emissions compared to non-exposed were 10%-20% higher for African Americans, whereas White populations were up to 18% less likely to live in tracts with the highest emissions. Among Hispanics and Latinos, odds were 16%-21% higher for benzene, 1,3-butadiene, and ethylene oxide. Populations experiencing poverty or with less than high school education were associated with up to 51% higher burden, irrespective of race and ethnicity. CONCLUSIONS: Carcinogenic industrial emissions disproportionately impact African Americans, Hispanics and Latinos, and people with limited education or experiencing poverty, thus representing a source of pollution that may contribute to observed cancer disparities.

Exposure to indoor light at night in relation to multiple dimensions of sleep health: findings from the Sister Study.

STUDY OBJECTIVE: To examine the association between light at night (LAN) and multiple sleep health dimensions. METHODS: Among 47 765 Sister Study participants, indoor LAN (TV on in the room, light(s) on in room, light from outside the room, nightlight, no light) and sleep dimensions were self-reported at baseline (2003-2009). We used Poisson regression with robust variance to estimate adjusted prevalence ratios (PR) and 95% confidence intervals (CI) for the cross-sectional associations between LAN and short sleep duration (<7 hours/night), insomnia symptoms (difficulty falling or staying asleep), frequent napping (≥3 naps/week), inconsistent sleep/wake time (differed day-to-day and week-to-week), sleep debt (≥2 hours between longest and shortest duration), recent sleep medication use, and a cumulative poor sleep score (≥3 poor sleep dimensions). Population-attributable risks (PARs) were determined for any light exposure vs. none by race/ethnicity. RESULTS: Compared to sleeping with no light in the bedroom, sleeping with a TV on was associated with a higher prevalence of most dimensions of poor sleep (e.g. short sleep duration: PR = 1.38, 95% CI: 1.32 to 1.45; inconsistent sleep/wake time: PR = 1.55, 95% CI: 1.44 to 1.66; sleep debt: PR = 1.36, 95% CI: 1.29 to 1.44; poor sleep score: PR = 1.58, 95% CI: 1.48-1.68). PARs tended to be higher for non-Hispanic black women compared to non-Hispanic white women. CONCLUSIONS: Sleeping with a TV on was associated with poor sleep health among US women, and non-Hispanic black women may be disproportionately burdened.

Prediagnostic serum concentrations of per- and polyfluoroalkyl substances and risk of papillary thyroid cancer in the Finnish Maternity Cohort.

Human exposure to per- and polyfluoroalkyl substances (PFAS) occurs globally through contaminated food, dust, and drinking water. Studies of PFAS and thyroid cancer have been limited. We conducted a nested case-control study of prediagnostic serum levels of 19 PFAS and papillary thyroid cancer (400 cases, 400 controls) in the Finnish Maternity Cohort (pregnancies 1986-2010; follow-up through 2016), individually matched on sample year and age. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for log2 transformed and categorical exposures, overall and stratified by calendar period, birth cohort, and median age at diagnosis. We adjusted for other PFAS with Spearman correlation rho = 0.3-0.6. Seven PFAS, including perfluoroctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), N-ethyl-perfluorooctane sulfonamidoacetic acid (EtFOSAA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluorohexane sulfonic acid (PFHxS) were detected in >50% of women. These PFAS were not associated with risk of thyroid cancer, except for PFHxS, which was inversely associated (OR log2 = 0.82, 95% CI: 0.70-0.97). We observed suggestive but imprecise increased risks associated with PFOA, PFOS, and EtFOSAA for those diagnosed at ages <40 years, whereas associations were null or inverse among those diagnosed at 40+ years (P-interaction: .02, .08, .13, respectively). There was little evidence of other interactions. These results show no clear association between PFAS and papillary thyroid cancer risk. Future work would benefit from evaluation of these relationships among those with higher exposure levels and during periods of early development when the thyroid gland may be more susceptible to environmental harms.

Outdoor Ultrafine Particulate Matter and Risk of Lung Cancer in Southern California.

Rationale: Particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5) is an established cause of lung cancer, but the association with ultrafine particulate matter (UFP; aerodynamic diameter < 0.1 µm) is unclear. Objectives: To investigate the association between UFP and lung cancer overall and by histologic subtype. Methods: The Los Angeles Ultrafines Study includes 45,012 participants aged ⩾50 years in southern California at enrollment (1995-1996) followed through 2017 for incident lung cancer (n = 1,770). We estimated historical residential ambient UFP number concentrations via land use regression and back extrapolation using PM2.5. In Cox proportional hazards models adjusted for smoking and other confounders, we estimated associations between 10-year lagged UFP (per 10,000 particles/cm3 and quartiles) and lung cancer overall and by major histologic subtype (adenocarcinoma, squamous cell carcinoma, and small cell carcinoma). We also evaluated relationships by smoking status, birth cohort, and historical duration at the residence. Measurements and Main Results: UFP was modestly associated with lung cancer risk overall (hazard ratio [HR], 1.03 [95% confidence interval (CI), 0.99-1.08]). For adenocarcinoma, we observed a positive trend among men; risk was increased in the highest exposure quartile versus the lowest (HR, 1.39 [95% CI, 1.05-1.85]; P for trend = 0.01) and was also increased in continuous models (HR per 10,000 particles/cm3, 1.09 [95% CI, 1.00-1.18]), but no increased risk was apparent among women (P for interaction = 0.03). Adenocarcinoma risk was elevated among men born between 1925 and 1930 (HR, 1.13 [95% CI, 1.02-1.26] per 10,000) but not for other birth cohorts, and was suggestive for men with ⩾10 years of residential duration (HR, 1.11 [95% CI, 0.98-1.26]). We found no consistent associations for women or other histologic subtypes. Conclusions: UFP exposure was modestly associated with lung cancer overall, with stronger associations observed for adenocarcinoma of the lung.

Ambient fine particulate matter and breast cancer incidence in a large prospective US cohort.

BACKGROUND: Fine particulate matter (PM2.5) has been inconsistently associated with breast cancer incidence, however, few studies have considered historic exposure when levels were higher. METHODS: Outdoor residential PM2.5 concentrations were estimated using a nationwide spatiotemporal model for women in the National Institutes of Health-AARP Diet and Health Study, a prospective cohort located in 6 states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and 2 metropolitan areas (Atlanta, GA, and Detroit, MI) and enrolled in 1995-1996 (n = 196 905). Annual average PM2.5 concentrations were estimated for a 5-year historical period 10 years prior to enrollment (1980-1984). We used Cox regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between a 10 µg/m3 increase in PM2.5 and breast cancer incidence overall and by estrogen receptor status and catchment area. RESULTS: With follow-up of participants through 2017, a total of 15 870 breast cancer cases were identified. A 10 ug/m3 increase in PM2.5 was statistically significantly associated with overall breast cancer incidence (HR = 1.08, 95% CI = 1.02 to 1.13). The association was evident for estrogen receptor-positive (HR = 1.10, 95% CI = 1.04 to 1.17) but not estrogen receptor-negative tumors (HR = 0.97, 95% CI = 0.84 to 1.13; Pheterogeneity = .3). Overall breast cancer hazard ratios were more than 1 across the catchment areas, ranging from a hazard ratio of 1.26 (95% CI = 0.96 to 1.64) for North Carolina to a hazard ratio of 1.04 (95% CI = 0.68 to 1.57) for Louisiana (Pheterogeneity = .9). CONCLUSIONS: In this large US cohort with historical air pollutant exposure estimates, PM2.5 was associated with risk of estrogen receptor-positive breast cancer. State-specific estimates were imprecise but suggest that future work should consider region-specific associations and the potential contribution of PM2.5 chemical constituency in modifying the observed association.

Air quality and cancer risk in the All of Us Research Program.

INTRODUCTION: The NIH All of Us Research Program has enrolled over 544,000 participants across the US with unprecedented racial/ethnic diversity, offering opportunities to investigate myriad exposures and diseases. This paper aims to investigate the association between PM2.5 exposure and cancer risks. MATERIALS AND METHODS: This work was performed on data from 409,876 All of Us Research Program participants using the All of Us Researcher Workbench. Cancer case ascertainment was performed using data from electronic health records and the self-reported Personal Medical History questionnaire. PM2.5 exposure was retrieved from NASA's Earth Observing System Data and Information Center and assigned using participants' 3-digit zip code prefixes. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Generalized additive models (GAMs) were used to investigate non-linear relationships. RESULTS: A total of 33,387 participants and 46,176 prevalent cancer cases were ascertained from participant EHR data, while 20,297 cases were ascertained from self-reported survey data from 18,133 participants; 9,502 cancer cases were captured in both the EHR and survey data. Average PM2.5 level from 2007 to 2016 was 8.90 µg/m3 (min 2.56, max 15.05). In analysis of cancer cases from EHR, an increased odds for breast cancer (OR 1.17, 95% CI 1.09-1.25), endometrial cancer (OR 1.33, 95% CI 1.09-1.62) and ovarian cancer (OR 1.20, 95% CI 1.01-1.42) in the 4th quartile of exposure compared to the 1st. In GAM, higher PM2.5 concentration was associated with increased odds for blood cancer, bone cancer, brain cancer, breast cancer, colon and rectum cancer, endocrine system cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. CONCLUSIONS: We found evidence of an association of PM2.5 with breast, ovarian, and endometrial cancers. There is little to no prior evidence in the literature on the impact of PM2.5 on risk of these cancers, warranting further investigation.

Maternal serum concentrations of per- and polyfluoroalkyl substances and childhood acute lymphoblastic leukemia.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widespread and environmentally persistent chemicals with immunotoxic properties. Children are prenatally exposed through maternal transfer of PFAS to cord blood, but no studies have investigated the relationship with childhood leukemia. METHODS: We measured maternal serum levels of 19 PFAS in first-trimester samples collected in 1986-2010 and evaluated associations with acute lymphoblastic leukemia (ALL) in full-term offspring (<15 years) for 400 cases and 400 controls in the Finnish Maternity Cohort, matched on sample year, mother's age, gestational age, birth order, and child's sex. We analyzed continuous and categorical exposures, estimating odds ratios (OR) and 95% confidence intervals (CI) via conditional logistic regression adjusted for maternal smoking and correlated PFAS (ρ ≥ ±0.3). We also stratified by calendar period, mean diagnosis age, and the child's sex. RESULTS: N­methyl­perfluorooctane sulfonamidoacetic acid (MeFOSAA) was associated with ALL in continuous models (per each doubling in levels: ORperlog2=1.22, CI = 1.07-1.39), with a positive exposure-response across categories (OR>90th percentile=2.52, CI = 1.33-4.78; p-trend = 0.01). While we found no relationship with perfluorooctane sulfonic acid (PFOS) overall, an association was observed in samples collected 1986-1995, when levels were highest (median = 17.9 µg/L; ORperlog2=4.01, CI = 1.62-9.93). A positive association with perfluorononanoic acid was suggested among first births (p-interaction = 0.06). The MeFOSAA association was mainly limited to children diagnosed before age 5 (p-interaction = 0.02). We found no consistent patterns of association with other PFAS, nor differences by sex. CONCLUSIONS: These novel data offer evidence of a relationship between some PFAS and risk of the most common childhood cancer worldwide, including associations with the highest levels of PFOS and with a precursor, MeFOSAA.

Associations between per- and polyfluoroalkyl substances, liver function, and daily alcohol consumption in a sample of U.S. adults.

BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and in the serum of the U.S. POPULATION: We sought to evaluate the association of PFAS independently and jointly with alcohol intake on liver function biomarkers in a sample of the U.S. general population. METHODS: Using data from the National Health and Nutrition Examination Survey (2003-2016; N = 11,794), we examined the five most historically prevalent PFAS with >75% detection rates. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between PFAS (quartiles and log-transformed continuous, ng/mL) and high levels (>95th percentile) of liver injury biomarkers using logistic regression models adjusted for key confounders. We evaluated interactions between PFAS and alcohol consumption and sex via stratified analyses and conducted sub-analyses adjusting for daily alcohol intake among those with available drinking history (N = 10,316). RESULT: Serum perfluorooctanoic acid (PFOA) was positively associated with high levels of alanine transferase (ALT) without monotonic trend (ORQ4vsQ1 = 1.45, CI: 0.99-2.12; p-trend = 0.18), and with increased aspartate transaminase when modeled continuously (OR = 1.15, CI: 1.02-1.30; p-trend = 0.03). Perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were both inversely associated with alkaline phosphatase while a trend was evident only for PFHxS (p = 0.02). A non-monotonic inverse association was observed with PFOA (p-trend = 0.10). The highest quartile of PFOS was associated with high total bilirubin (TB; ORQ4vsQ1 = 1.57, CI: 1.01-2.43, p-trend = 0.02). No significant associations were found between any PFAS and γ-glutamyl transpeptidase. We found no associations for perfluorodecanoic acid and perfluorononanoic acid. We observed some suggestive interactions with alcohol intake, particularly among heavy drinkers. CONCLUSION: Consistent with other studies, serum levels of PFOA, PFHxS and PFNA were positively associated with high levels of ALT, and we also observed weak positive associations between some PFAS and TB. Associations observed among heavy drinkers warrant additional evaluation.

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.

State of the science on outdoor air pollution exposure and liver cancer risk.

Background: There is emerging evidence that air pollution exposure increases the risk of developing liver cancer. To date, there have been four epidemiologic studies conducted in the United States, Taiwan, and Europe showing generally consistent positive associations between ambient exposure to air pollutants, including particulate matter <2.5 µm in aerodynamic diameter (PM2.5) and nitrogen dioxide (NO2), and liver cancer risk. There are several research gaps and thus valuable opportunities for future work to continue building on this expanding body of literature. The objectives of this paper are to narratively synthesize existing epidemiologic literature on the association between air pollution exposure and liver cancer incidence and describe future research directions to advance the science of understanding the role of air pollution exposure in liver cancer development. Future research directions: include 1) accounting for potential confounding by established risk factors for the predominant histological subtype, hepatocellular carcinoma (HCC); 2) examination of incident primary liver cancer outcomes with consideration of potential differential associations according to histology; 3) air pollution exposure assessments considering early-life and/or historical exposures, residential histories, residual confounding from other sources of air pollution (e.g., tobacco smoking), and integration of geospatial ambient exposure modeling with novel biomarker technologies; 4) examination of air pollution mixtures experienced in the exposome; 5) consideration of increased opportunities for exposure to outdoor air pollution due to climate change (e.g., wildfires); and 6) consideration of modifying factors for air pollution exposure, such as socioeconomic status, that may contribute to disparities in liver cancer incidence. Conclusions: In light of mounting evidence demonstrating that higher levels of air pollution exposure increase the risk for developing liver cancer, methodological considerations primarily concerning residual confounding and improved exposure assessment are warranted to robustly demonstrate an independent association for air pollution as a hepatocarcinogen.