Cosmic Ionizing Radiation: A DNA Damaging Agent That May Underly Excess Cancer in Flight Crews.

In the United States, the Federal Aviation Administration has officially classified flight crews (FC) consisting of commercial pilots, cabin crew, or flight attendants as "radiation workers" since 1994 due to the potential for cosmic ionizing radiation (CIR) exposure at cruising altitudes originating from solar activity and galactic sources. Several epidemiological studies have documented elevated incidence and mortality for several cancers in FC, but it has not yet been possible to establish whether this is attributable to CIR. CIR and its constituents are known to cause a myriad of DNA lesions, which can lead to carcinogenesis unless DNA repair mechanisms remove them. But critical knowledge gaps exist with regard to the dosimetry of CIR, the role of other genotoxic exposures among FC, and whether possible biological mechanisms underlying higher cancer rates observed in FC exist. This review summarizes our understanding of the role of DNA damage and repair responses relevant to exposure to CIR in FC. We aimed to stimulate new research directions and provide information that will be useful for guiding regulatory, public health, and medical decision-making to protect and mitigate the risks for those who travel by air.

Impact of simulated flight conditions on supraventricular and ventricular ectopy.

Though billions of passengers and crew travel by air each year and are exposed to altitude equivalents of 7000-8000 feet, the health impact of cabin oxygenation levels has not been well studied. The hypoxic environment may produce ectopic heartbeats that may increase the risk of acute in-flight cardiac events. We enrolled forty older and at-risk participants under a block-randomized crossover design in a hypobaric chamber study to examine associations between flight oxygenation and both ventricular (VE) and supraventricular ectopy (SVE). We monitored participant VE and SVE every 5 min under both flight and control conditions to investigate the presence and rate of VE and SVE. While the presence of VE did not differ according to condition, the presence of SVE was higher during flight conditions (e.g. OR ratio = 1.77, 95% CI: 1.21, 2.59 for SVE couplets). Rates of VE and SVE were higher during flight conditions (e.g. RR ratio = 1.25, 95% CI: 1.03, 1.52 for VE couplets, RR ratio = 1.76, 95% CI: 1.39, 2.22 for SVE couplets). The observed higher presence and rate of ectopy tended to increase with duration of the flight condition. Further study of susceptible passengers and crew may elucidate the specific associations between intermittent or sustained ectopic heartbeats and hypoxic pathways.

Cancer risks from cosmic radiation exposure in flight: A review.

Aircrew (consisting of flight attendants, pilots, or flight engineers/navigators) are exposed to cosmic ionizing radiation (CIR) at flight altitude, which originates from solar activity and galactic sources. These exposures accumulate over time and are considerably higher for aircrew compared to the general population, and even higher compared to U.S. radiation workers. Many epidemiological studies on aircrew have observed higher rates of specific cancers compared to the general population. Despite high levels of CIR exposure and elevated rates of cancer in aircrew, a causal link between CIR and cancer has yet to be established. Many challenges still exist in effectively studying this relationship, not the least of which is evaluating CIR exposure separately from the constellation of factors that occur as part of the flight environment. This review concentrates on cancer incidence and mortality observed among aircrew in epidemiologic studies in relation to CIR exposure and limitation trends observed across the literature. The aim of this review is to provide an updated comprehensive summary of the literature that will support future research by identifying epidemiological challenges and highlighting existing increased cancer concerns in an occupation where CIR exposure is anticipated to increase in the future.

Changes in Heart Rate and Rhythm During a Crossover Study of Simulated Commercial Flight in Older and Vulnerable Participants.

Objectives: Elderly passengers and those with preexisting disease are flying with increasing frequency and in-flight cardiac emergencies are a more frequent occurrence. We conducted a study of the physiological effects of simulated cabin altitudes and resulting lower oxygen levels among such passengers. Methods: We monitored 41 participants in a hypobaric chamber for 2 days, one at an equivalent of 7,000 feet altitude (regulations limit pressurization to 8,000 feet) for a 4-5 h simulated flight and the other at ground level using generalized least squares models to account for repeated measures. We evaluated associations between simulated flight, heart rate (HR) and measures of heart rate variability(HRV) (root mean square of successive R-R interval differences [RMSSD], standard deviation of normal-to-normal intervals [SDNN], high-frequency power [HF], and low-frequency power [LF]). Results: Heart rate was 3.9% (95% CI: 2.1, 5.8) higher on simulated flight days compared with non-flight days. The RMSSD was 10.6% (95% CI: -21.3, 0.05) lower during simulated flight days, indicative of reduced HRV. The remaining HRV measures were also lower on simulated flight days, though associations were less precise. Conclusion: We report that typical simulated flight conditions elicit changes in cardiac autonomic control, suggesting sympathetic arousal or reductions in parasympathetic drive. Our findings, if confirmed, may suggest the need for guidelines to protect vulnerable passengers including prescreens, symptom evaluation after air travel, the use of oxygen concentrators, and education about healthy behaviors in flight.

The Impact of Workplace Harassment on Health in a Working Cohort.

Background: Workplace abuse, including sexual harassment, is frequently experienced worldwide and is related to adverse mental health outcomes, and injuries. Flight attendants are an understudied occupational group and are susceptible to harassment due to working in a feminized, client-facing occupation with few protections or sanctioned responses against aggressive behaviors. Objective: We investigated the relationship between workplace abuse and health in a cohort of cabin crew. We also aimed to characterize perpetrator profiles. Methods: We conducted our study among 4,459U.S. and Canada-based participants from the Harvard Flight Attendant Health Study using multivariate logistic regression. Our exposures of interest were episodes of workplace abuse in the past year. We evaluated several mental and physical health outcomes, including depression, fatigue, musculoskeletal injuries, and general workplace injuries. Results: We report that exposures to verbal abuse, sexual harassment, and sexual assault are common among cabin crew, with 63, 26, and 2% of respondents, respectively, reporting harassment in the past year alone. Workplace abuse was associated with depression, sleep disturbances, and musculoskeletal injuries among male and female crew, with a trend toward increasing odds ratios (ORs) given a higher frequency of events. For example, sexual harassment was related to an increased odds for depression (OR = 1.91, 95% confidence interval [CI]: 1.51-2.30), which increased in a dose response-like manner among women reporting harassment once (OR = 1.44, 95% CI: 0.93-1.95), 2-3 times (OR = 1.83, 95% CI: 1.29-2.38), and 4 or more times (OR = 4.12, 95% CI: 3.18-5.06). We found that passengers were the primary perpetrators of abuse. Conclusions: Our study is the first to comprehensively characterize workplace abuse and harassment and its relation to health in a largely female customer-facing workforce. The strong associations with health outcomes observed in our study highlights the question of how workplace policies can be altered to mitigate prevalent abuses. Clinicians could also consider how jobs with high emotional labor demands may predispose people to adverse health outcomes, educate patients regarding their psychological/physical responses and coping strategies, and be aware of signs of distress in patients working in such occupations in order to direct them to the appropriate treatments and therapies.

Legacy health effects among never smokers exposed to occupational secondhand smoke.

OBJECTIVES: Secondhand tobacco smoke (SHTS) is a tremendous public health hazard, leading to morbidity and premature mortality worldwide, with racial and ethnic minorities and those of lower socioeconomic status disproportionately affected. Flight attendants were historically exposed to high levels of SHTS in the aircraft cabin. The health effects of active smoking are known to persist for up to a lifetime, but the legacy effects of SHTS exposure have not been well characterized. DESIGN: We aimed to evaluate the legacy health effects of occupational SHTS exposure among never smoking workers using the resources of the Harvard Flight Attendant Health Study, a large study of cabin crew health. We evaluated associations between SHTS exposure and a range of diagnoses using multivariate logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), employing a case-control sampling method and applying the bootstrap method to increase accuracy and precision of results. RESULTS: We found no evidence of positive associations between SHTS and any cancer, but observed associations between SHTS and cardiac outcomes, including myocardial infarction (OR = 140, 95% CI: 1·04, 3·27) and peripheral artery disease (OR = 1·27, 95% CI: 1·00, 1·97). We also found associations between SHTS exposure and repeated pneumonia (OR = 1·06, 95% CI: 1·02, 1·10). CONCLUSIONS: Our study reports associations between legacy SHTS exposure going back decades and severe cardiac and respiratory health outcomes. Given the high prevalence of ongoing and historical SHTS exposure, our findings, if confirmed, have important implications for smoking cessation efforts, health education, and clinical guidelines.

Cancer prevalence among flight attendants compared to the general population.

BACKGROUND: Flight attendants are an understudied occupational group, despite undergoing a wide range of adverse job-related exposures, including to known carcinogens. In our study, we aimed to characterize the prevalence of cancer diagnoses among U.S. cabin crew relative to the general population. METHODS: In 2014-2015, we surveyed participants of the Harvard Flight Attendant Health Study. We compared the prevalence of their self-reported cancer diagnoses to a contemporaneous cohort in the National Health and Nutrition Examination Survey (NHANES 2013-2014) using age-weighted standardized prevalence ratios (SPRs). We also analyzed associations between job tenure and the prevalence of selected cancers, using logistic regression and adjusting for potential confounders. RESULTS: Compared to NHANES participants with a similar socioeconomic status (n = 2729), flight attendants (n = 5366) had a higher prevalence of every cancer we examined, especially breast cancer, melanoma, and non-melanoma skin cancer among females. SPR for these conditions were 1.51 (95% CI: 1.02, 2.24), 2.27 (95% CI: 1.27, 4.06), and 4.09 (95% CI: 2.70, 6.20), respectively. Job tenure was positively related to non-melanoma skin cancer among females, with borderline associations for melanoma and non-melanoma skin cancers among males. Consistent with previous studies, we observed associations between job tenure and breast cancer among women who had three or more children. CONCLUSIONS: We observed higher rates of specific cancers in flight attendants compared the general population, some of which were related to job tenure. Our results should be interpreted in light of self-reported health information and a cross-sectional study design. Future longitudinal studies should evaluate associations between specific exposures and cancers among cabin crew.

Estimating the health consequences of flight attendant work: comparing flight attendant health to the general population in a cross-sectional study.

BACKGROUND: Flight attendants are an understudied occupational group, despite undergoing a wide and unique range of adverse job-related exposures. In our study, we aimed to characterize the health profile of cabin crew relative to the U.S. general population. METHODS: In 2014-2015, we surveyed participants of the Harvard Flight Attendant Health Study. We compared the prevalence of their health conditions to a contemporaneous cohort in the National Health and Nutrition Examination Survey (NHANES 2013-2014) using age-weighted standardized prevalence ratios (SPRs). We also analyzed associations between job tenure and selected health outcomes, using logistic regression and adjusting for potential confounders. RESULTS: Compared to the NHANES population (n = 2729), flight attendants (n = 5366) had a higher prevalence of female reproductive cancers (SPR = 1.66, 95% CI: 1.18-2.33), cancers at all sites (SPR = 2.15, 95% CI: 1.73-2.67 among females), as well as sleep disorders, fatigue, and depression, with SPRs ranging between 1.98 and 5.57 depending on gender and the specific condition examined. In contrast, we observed a decreased prevalence of cardiac and respiratory outcomes among flight crew relative to NHANES. Health conditions that increased with longer job tenure were sleep disorders, anxiety/depression, alcohol abuse, any cancer, peripheral artery disease, sinusitis, foot surgery, infertility, and several perinatal outcomes. CONCLUSIONS: We observed higher rates of specific adverse health outcomes in U.S. flight attendants compared to the general population, as well as associations between longer tenure and health conditions, which should be interpreted in light of recall bias and a cross-sectional design. Future longitudinal studies should evaluate specific exposure-disease associations among flight crew.

Symptoms related to new flight attendant uniforms.

BACKGROUND: Flight attendants at Alaska Airlines reported health symptoms after the introduction of new uniforms in 2011. The airline replaced the uniforms in 2014 without acknowledging harm. To understand possible uniform-related health effects, we analyzed self-reported health symptoms in crew who participated in the Harvard Flight Attendant Health Study between 2007 and 2015, the period before, during, and after the introduction of new uniforms. METHODS: We calculated a standardized prevalence of respiratory, dermatological and allergic symptoms at baseline, as well as during and after uniform changes in 684 flight attendants with a varying number of surveys completed across each time point. We used Generalized Estimating Equations (GEE) to model the association between symptoms at baseline versus the exposure period after adjusting for age, gender and smoking status and weighting respondents for the likelihood of attrition over the course of the study period. RESULTS: We found the following symptom prevalence (per 100) increased after the introduction of new uniforms: multiple chemical sensitivity (10 vs 5), itchy/irritated skin (25 vs 13), rash/hives (23 vs 13), itchy eyes (24 vs 14), blurred vision (14 vs 6), sinus congestion (28 vs 24), ear pain (15 vs 12), sore throat (9 vs 5), cough (17 vs 7), hoarseness/loss of voice (12 vs 3), and shortness of breath (8 vs 3). The odds of several symptoms significantly increased compared to baseline after adjusting for potential confounders. CONCLUSION: This study found a relationship between health complaints and the introduction of new uniforms in this longitudinal occupational cohort.

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study.

Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4× 10-9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.

Polycyclic aromatic hydrocarbons and postmenopausal breast cancer: An evaluation of effect measure modification by body mass index and weight change.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) have been linked to breast cancer in many, but not all, previous studies. PAHs are lipophilic and stored in fat tissue, which we hypothesized may result in constant low-dose exposure to these carcinogens. No previous studies have evaluated whether obesity modifies associations between multiple measures of PAHs and breast cancer incidence. METHODS: This population-based study included 1,006 postmenopausal women with first primary in situ or invasive breast cancer and 990 age-frequency matched controls. To evaluate effect modification by obesity (adult body mass index (BMI, kg/m2) and weight change) on multiple PAH measures (the biomarker PAH-DNA adducts, and long-term sources active cigarette smoking, living with a smoking spouse, grilled/smoked meat intake, residential synthetic log burning, and vehicular traffic), interaction contrast ratios (ICRs) for the additive scale, and ratio of odds ratios (RORs) with log-likelihood ratio tests (LRT) for the multiplicative scale, were determined using unconditional logistic regression. RESULTS: BMI modified the PAH-DNA adduct and postmenopausal breast cancer association on the additive (ICR: 0.49; 95% CI: 0.01, 0.96) and multiplicative (ROR: 1.56; 95% CI: 0.91, 2.68) scales. The odds ratio for detectable vs. non-detectable adducts was increased among women with BMI ≥25 (OR=1.34; 95% CI: 0.94, 1.92), but not in those with BMI <25 (OR=0.86; 95% CI: 0.57, 1.28) (LRT p=0.1). For most other PAH measures, the pattern of modification by BMI/weight gain was similar, but estimates were imprecise. CONCLUSIONS: The association between PAH-DNA adducts and breast cancer incidence may be elevated among overweight/obese women.

Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence.

Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes. Residential histories of 1,508 cases and 1,556 controls were assessed in the Long Island Breast Cancer Study Project between 1996 and 1997 and used to reconstruct residential traffic exposures to benzo[a]pyrene, as a proxy for traffic-related PAHs. Likelihood ratio tests from adjusted unconditional logistic regression models were used to assess multiplicative interactions. A gene-traffic interaction was evident (p = 0.04) for ERCC2 (Lys751); when comparing the upper and lower tertiles of 1995 traffic exposure estimates, the odds ratio (95% confidence interval) was 2.09 (1.13, 3.90) among women with homozygous variant alleles. Corresponding odds ratios for 1960-1990 traffic were also elevated nearly 2-3-fold for XRCC1(Arg194Trp), XRCC1(Arg399Gln) and OGG1(Ser326Cys), but formal multiplicative interaction was not evident. When DNA repair variants for ERCC2, XRCC1 and OGG1 were combined, among women with 4-6 variants, the odds ratios were 2.32 (1.22, 4.49) for 1995 traffic and 2.96 (1.06, 8.21) for 1960-1990 traffic. Our study is first to report positive associations between traffic-related PAH exposure and breast cancer incidence among women with select biologically plausible DNA repair genotypes.

Exposure to multiple sources of polycyclic aromatic hydrocarbons and breast cancer incidence.

BACKGROUND: Despite studies having consistently linked exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to breast cancer, it is unclear whether single sources or specific groups of PAH sources should be targeted for breast cancer risk reduction. OBJECTIVES: This study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures. METHODS: In a population-based case-control study conducted on Long Island, New York (N=1508 breast cancer cases/1556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake. RESULTS: Most women were exposed to PAHs from multiple sources, and the most common included active/passive smoking and grilled/smoked food intake. In multiple-PAH source models, breast cancer incidence was associated with residential ETS from a spouse (OR=1.20, 95%CrI=1.03, 1.40) and synthetic firelog burning (OR=1.29, 95%CrI=1.06, 1.57); these estimates are similar, but slightly attenuated, to those from single-source models. Additionally when we considered PAH exposure groups, the most pronounced significant associations included total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR=1.45, 95%CrI=1.02, 2.04). CONCLUSIONS: Groups of PAH sources, particularly indoor sources, were associated with a 30-50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor.

Vehicular Traffic-Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP).

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure. OBJECTIVES: Our study aim was to evaluate the association between residential exposure to vehicular traffic and breast cancer incidence. METHODS: Residential histories of 1,508 participants with breast cancer (case participants) and 1,556 particpants with no breast cancer (control participants) were assessed in a population-based investigation conducted in 1996-1997. Traffic exposure estimates of benzo[a]pyrene (B[a]P), as a proxy for traffic-related PAHs, for the years 1960-1995 were reconstructed using a model previously shown to generate estimates consistent with measured soil PAHs, PAH-DNA adducts, and CO readings. Associations between vehicular traffic exposure estimates and breast cancer incidence were evaluated using unconditional logistic regression. RESULTS: The odds ratio (95% CI) was modestly elevated by 1.44 (0.78, 2.68) for the association between breast cancer and long-term 1960-1990 vehicular traffic estimates in the top 5%, compared with below the median. The association with recent 1995 traffic exposure was elevated by 1.14 (0.80, 1.64) for the top 5%, compared with below the median, which was stronger among women with low fruit/vegetable intake [1.46 (0.89, 2.40)], but not among those with high fruit/vegetable intake [0.92 (0.53, 1.60)]. Among the subset of women with information regarding traffic exposure and tumor hormone receptor subtype, the traffic-breast cancer association was higher for those with estrogen/progesterone-negative tumors [1.67 (0.91, 3.05) relative to control participants], but lower among all other tumor subtypes [0.80 (0.50, 1.27) compared with control participants]. CONCLUSIONS: In our population-based study, we observed positive associations between vehicular traffic-related B[a]P exposure and breast cancer incidence among women with comparatively high long-term traffic B[a]P exposures, although effect estimates were imprecise. CITATION: Mordukhovich I, Beyea J, Herring AH, Hatch M, Stellman SD, Teitelbaum SL, Richardson DB, Millikan RC, Engel LS, Shantakumar S, Steck SE, Neugut AI, Rossner P Jr., Santella RM, Gammon MD. 2016. Vehicular traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence: the Long Island Breast Cancer Study Project (LIBCSP). Environ Health Perspect 124:30-38; http://dx.doi.org/10.1289/ehp.1307736.

Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer.

BACKGROUND: Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer. METHODS: In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1055 cases/1101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.26, 95%CI=1.06-4.79), HIN1 (OR=2.14, 95%CI=1.34-3.42) and RARß (OR=1.80, 95%CI=1.16-2.78) and decreased ORs for BRCA1 (OR=0.44, 95%CI=0.30-0.66). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST1 methylation (OR=2.79, 95%CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 (OR=0.59, 95%CI=0.41-0.86). DISCUSSION: PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the associations between PAHs and breast cancer incidence.

Association Between Particulate Air Pollution and QT Interval Duration in an Elderly Cohort.

BACKGROUND: Short-term fine particulate matter (PM2.5) exposure has been linked with increased QT interval duration, a marker of ventricular repolarization and a risk factor for cardiac arrhythmia and sudden death, in several studies. Only one previous study evaluated whether long-term PM exposure is related to the QT interval. We aim to evaluate whether subchronic and long-term exposure to PM2.5 at home is linked with QT duration in an elderly cohort. METHODS: We measured heart-rate corrected QT interval duration among 404 participants from the Greater Boston area between 2003 and 2011. We modeled residential PM2.5 exposures using a hybrid satellite- and land use-based model. We evaluated associations between moving averages of short-term (1-2 days), subchronic (3-28 days), and long-term (1 year) pollutant exposures and corrected QT duration using linear mixed models. We also evaluated effect modification by oxidative stress genetic score using separated regression models and interaction terms. RESULTS: We observed positive associations between subchronic and long-term PM2.5 exposure and corrected QT duration, with the strongest results for longer-term exposures. For example, a one standard deviation increase in 1-year PM2.5 was associated with a 6.3 ms increase in corrected QT (95% confidence interval: 1.8, 11). We observed somewhat greater effects among subjects with higher (8.5 ms) rather than lower (3.1 ms) oxidative stress allelic profiles (P interaction = 0.25). CONCLUSIONS: PM2.5 was associated with increased corrected QT duration in an elderly cohort. While most previous studies focused on short-term air pollution exposures, our results suggest that longer-term exposures are associated with cardiac repolarization.

Exposure to sub-chronic and long-term particulate air pollution and heart rate variability in an elderly cohort: the Normative Aging Study.

BACKGROUND: Short-term particulate air pollution exposure is associated with reduced heart rate variability (HRV), a risk factor for cardiovascular morbidity and mortality, in many studies. Associations with sub-chronic or long-term exposures, however, have been sparsely investigated. We evaluated the effect of fine particulate matter (PM2.5) and black carbon (BC) exposures on HRV in an elderly cohort: the Normative Aging Study. METHODS: We measured power in high frequency (HF) and low frequency (LF), standard deviation of normal-to-normal intervals (SDNN), and the LF:HF ratio among participants from the Greater Boston area. Residential BC exposures for 540 men (1161 study visits, 2000-2011) were estimated using a spatio-temporal land use regression model, and residential PM2.5 exposures for 475 men (992 visits, 2003-2011) were modeled using a hybrid satellite based and land-use model. We evaluated associations between moving averages of sub-chronic (3-84 day) and long-term (1 year) pollutant exposure estimates and HRV parameters using linear mixed models. RESULTS: One-standard deviation increases in sub-chronic, but not long-term, BC were associated with reduced HF, LF, and SDNN and an increased LF:HF ratio (e.g., 28 day BC: -2.3% HF [95% CI:-4.6, -0.02]). Sub-chronic and long-term PM2.5 showed evidence of relations to an increased LF and LF:HF ratio (e.g., 1 year PM: 21.0% LF:HF [8.6, 34.8]), but not to HF or SDNN, though the effect estimates were very imprecise and mostly spanned the null. CONCLUSIONS: We observed some evidence of a relation between longer-term BC and PM2.5 exposures and changes in HRV in an elderly cohort. While previous studies focused on short-term air pollution exposures, our results suggest that longer-term exposures may influence cardiac autonomic function.

The effect of oxidative stress polymorphisms on the association between long-term black carbon exposure and lung function among elderly men.

BACKGROUND: Black carbon (BC) is a pro-oxidant, traffic-related pollutant linked with lung function decline. We evaluated the influence of genetic variation in the oxidative stress pathway on the association between long-term BC exposure and lung function decline. METHODS: Lung function parameters (FVC and FEV1) were measured during one or more study visits between 1995 and 2011 (n=651 participants) among an elderly cohort: the Normative Aging Study. Residential BC exposure levels were estimated using a spatiotemporal land use regression model. We evaluated whether oxidative stress variants, combined into a genetic score, modify the association between 1-year and 5-year moving averages of BC exposure and lung function levels and rates of decline, using linear mixed models. RESULTS: We report stronger associations between long-term BC exposure and increased rate of lung function decline, but not baseline lung function level, among participants with higher oxidative stress allelic risk profiles compared with participants with lower risk profiles. Associations were strongest when evaluating 5-year moving averages of BC exposure. A 0.5 µg/m(3) increase in 5-year BC exposure was associated with a 0.1% yearly increase in FVC (95% CI -0.5 to 0.7) among participants with low genetic risk scores and a 1.3% yearly decrease (95% CI -1.8 to -0.8) among those with high scores (p-interaction=0.0003). DISCUSSION: Our results suggest that elderly men with high oxidative stress genetic scores may be more susceptible to the effects of BC on lung function decline. The results, if confirmed, should inform air-quality recommendations in light of a potentially susceptible subgroup.

Indoor air pollution exposure from use of indoor stoves and fireplaces in association with breast cancer: a case-control study.

BACKGROUND: Previous studies suggest that polycyclic aromatic hydrocarbons (PAHs) may adversely affect breast cancer risk. Indoor air pollution from use of indoor stoves and/or fireplaces is an important source of ambient PAH exposure. However, the association between indoor stove/fireplace use and breast cancer risk is unknown. We hypothesized that indoor stove/fireplace use in a Long Island, New York study population would be positively associated with breast cancer and differ by material burned, and the duration and timing of exposure. We also hypothesized that the association would vary by breast cancer subtype defined by p53 mutation status, and interact with glutathione S-transferases GSTM1, T1, A1 and P1 polymorphisms. METHODS: Population-based, case-control resources (1,508 cases/1,556 controls) were used to conduct unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Breast cancer risk was increased among women reporting ever burning synthetic logs (which may also contain wood) in their homes (OR = 1.42, 95% CI 1.11, 1.84), but not for ever burning wood alone (OR = 0.93, 95% CI 0.77, 1.12). For synthetic log use, longer duration >7 years, older age at exposure (>20 years; OR = 1.65, 95% CI 1.02, 2.67) and 2 or more variants in GSTM1, T1, A1 or P1 (OR = 1.71, 95% CI 1.09, 2.69) were associated with increased risk. CONCLUSIONS: Burning wood or synthetic logs are both indoor PAH exposure sources; however, positive associations were only observed for burning synthetic logs, which was stronger for longer exposures, adult exposures, and those with multiple GST variant genotypes. Therefore, our results should be interpreted with care and require replication.

Imputation method for lifetime exposure assessment in air pollution epidemiologic studies.

BACKGROUND: Environmental epidemiology, when focused on the life course of exposure to a specific pollutant, requires historical exposure estimates that are difficult to obtain for the full time period due to gaps in the historical record, especially in earlier years. We show that these gaps can be filled by applying multiple imputation methods to a formal risk equation that incorporates lifetime exposure. We also address challenges that arise, including choice of imputation method, potential bias in regression coefficients, and uncertainty in age-at-exposure sensitivities. METHODS: During time periods when parameters needed in the risk equation are missing for an individual, the parameters are filled by an imputation model using group level information or interpolation. A random component is added to match the variance found in the estimates for study subjects not needing imputation. The process is repeated to obtain multiple data sets, whose regressions against health data can be combined statistically to develop confidence limits using Rubin's rules to account for the uncertainty introduced by the imputations. To test for possible recall bias between cases and controls, which can occur when historical residence location is obtained by interview, and which can lead to misclassification of imputed exposure by disease status, we introduce an "incompleteness index," equal to the percentage of dose imputed (PDI) for a subject. "Effective doses" can be computed using different functional dependencies of relative risk on age of exposure, allowing intercomparison of different risk models. To illustrate our approach, we quantify lifetime exposure (dose) from traffic air pollution in an established case-control study on Long Island, New York, where considerable in-migration occurred over a period of many decades. RESULTS: The major result is the described approach to imputation. The illustrative example revealed potential recall bias, suggesting that regressions against health data should be done as a function of PDI to check for consistency of results. The 1% of study subjects who lived for long durations near heavily trafficked intersections, had very high cumulative exposures. Thus, imputation methods must be designed to reproduce non-standard distributions. CONCLUSIONS: Our approach meets a number of methodological challenges to extending historical exposure reconstruction over a lifetime and shows promise for environmental epidemiology. Application to assessment of breast cancer risks will be reported in a subsequent manuscript.