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BackgroundPrenatal exposure to drinking water with arsenic concentrations >50 μg/L is associated with adverse birth outcomes, with inconclusive evidence for concentrations ≤50 μg/L. In a collaborative effort by public health experts, hydrologists, and geologists, we used published machine learning model estimates to characterize arsenic concentrations in private wells-federally unregulated for drinking water contaminants-and evaluated associations with birth outcomes throughout the conterminous U.S.MethodsUsing several machine learning models, including boosted regression trees (BRT) and random forest classification (RFC), developed from measured groundwater arsenic concentrations of ∼20,000 private wells, we characterized the probability that arsenic concentrations occurred within specific ranges in groundwater. Probabilistic model estimates and private well usage data were linked by county to all live birth certificates from 2016 (n = 3.6 million). We evaluated associations with gestational age and term birth weight using mixed-effects models, adjusted for potential confounders and incorporated random intercepts for spatial clustering.ResultsWe generally observed inverse associations with term birth weight. For instance, when using BRT estimates, a 10-percentage point increase in the probability that private well arsenic concentrations exceeded 5 μg/L was associated with a -1.83 g (95% CI: -3.30, -0.38) lower term birth weight after adjusting for covariates. Similarly, a 10-percentage point increase in the probability that private well arsenic concentrations exceeded 10 μg/L was associated with a -2.79 g (95% CI: -4.99, -0.58) lower term birth weight. Associations with gestational age were null.ConclusionIn this largest epidemiologic study of arsenic and birth outcomes to date, we did not observe associations of modeled arsenic estimates in private wells with gestational age and found modest inverse associations with term birth weight. Study limitations may have obscured true associations, including measurement error stemming from a lack of individual-level information on primary water sources, water arsenic concentrations, and water consumption patterns.

We conducted a detailed analysis of coronavirus disease in a large population center in southern California, USA (Orange County, population 3.2 million), to determine heterogeneity in risks for infection, test positivity, and death. We used a combination of datasets, including a population-representative seroprevalence survey, to assess the actual burden of disease and testing intensity, test positivity, and mortality. In the first month of the local epidemic (March 2020), case incidence clustered in high-income areas. This pattern quickly shifted, and cases next clustered in much higher rates in the north-central area of the county, which has a lower socioeconomic status. Beginning in April 2020, a concentration of reported cases, test positivity, testing intensity, and seropositivity in a north-central area persisted. At the individual level, several factors (e.g., age, race or ethnicity, and ZIP codes with low educational attainment) strongly affected risk for seropositivity and death.

We conducted a detailed analysis of coronavirus disease in a large population center in southern California, USA (Orange County, population 3.2 million), to determine heterogeneity in risks for infection, test positivity, and death. We used a combination of datasets, including a population-representative seroprevalence survey, to assess the actual burden of disease and testing intensity, test positivity, and mortality. In the first month of the local epidemic (March 2020), case incidence clustered in high-income areas. This pattern quickly shifted, and cases next clustered in much higher rates in the north-central area of the county, which has a lower socioeconomic status. Beginning in April 2020, a concentration of reported cases, test positivity, testing intensity, and seropositivity in a north-central area persisted. At the individual level, several factors (e.g., age, race or ethnicity, and ZIP codes with low educational attainment) strongly affected risk for seropositivity and death.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are ubiquitous in the serum of the general US population. Food, drinking water, consumer products, dust, and air have been assessed as PFAS exposure sources for humans. The effects of various types of carpeting on serum PFAS concentrations have been less studied, despite the known use of PFAS in stain-resistant carpet treatments.ObjectiveThis study aimed to examine the associations between serum PFAS concentrations and type of residential flooring among the general US population aged 12 years and older using the 2005-2006 National Health and Nutrition Examination Survey (NHANES).MethodsWe used multiple linear regressions adjusted for complex survey design and relevant covariates to analyze the relations between serum PFAS concentrations and type of floor covering (smooth surface, low pile carpet, medium to high pile carpet, and combination of carpet and smooth surface), as well as other potential exposure factors. We used multiple imputation to address missing values.ResultsWe found significantly higher serum concentrations of perfluorohexane sulfonic acid (PFHxS) and 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA) in US residents residing in homes with low pile carpeting compared with those residing in homes with smooth surface. We concluded that among US residents aged 12 years and older residing in homes with low pile carpeting in the home in 2005-2006, on average 24% and 19% of the PFHxS and MeFOSAA body burdens, respectively, could be attributed to carpeting. We found associations between other types of floor covering (medium to high pile carpet, combination of carpet and smooth surface) and some PFAS concentrations compared with the smooth surface, but these results were less consistent and generally not statistically significant. Additionally, a group Wald Chi-squared test showed a significant result for PFOS, indicating different contributions of various types of flooring to PFOS serum concentration.SignificanceOur results are representative of the general US population at the time of the survey, and potentially informative regarding ongoing PFAS exposure from a variety of sources including carpeting.

Clinic-based estimates of SARS-CoV-2 may considerably underestimate the total number of infections. Access to testing in the US has been heterogeneous and symptoms vary widely in infected persons. Public health surveillance efforts and metrics are therefore hampered by underreporting. We set out to provide a minimally biased estimate of SARS-CoV-2 seroprevalence among adults for a large and diverse county (Orange County, CA, population 3.2 million). We implemented a surveillance study that minimizes response bias by recruiting adults to answer a survey without knowledge of later being offered SARS-CoV-2 test. Several methodologies were used to retrieve a population-representative sample. Participants (n = 2979) visited one of 11 drive-thru test sites from July 10th to August 16th, 2020 (or received an in-home visit) to provide a finger pin-prick sample. We applied a robust SARS-CoV-2 Antigen Microarray technology, which has superior measurement validity relative to FDA-approved tests. Participants include a broad age, gender, racial/ethnic, and income representation. Adjusted seroprevalence of SARS-CoV-2 infection was 11.5% (95% CI: 10.5-12.4%). Formal bias analyses produced similar results. Prevalence was elevated among Hispanics (vs. other non-Hispanic: prevalence ratio [PR] = 1.47, 95% CI 1.22-1.78) and household income  $100,000: PR = 1.42, 95% CI: 1.14 to 1.79). Results from a diverse population using a highly specific and sensitive microarray indicate a SARS-CoV-2 seroprevalence of ~ 12 percent. This population-based seroprevalence is seven-fold greater than that using official County statistics. In this region, SARS-CoV-2 also disproportionately affects Hispanic and low-income adults.

BackgroundAdvances in untargeted metabolomic technologies have great potential for insight into adverse metabolic effects underlying exposure to environmental chemicals. However, important challenges need to be addressed, including how biological response corresponds to the environmental chemical burden in different target tissues.AimWe performed a pilot study using state-of-the-art ultra-high-resolution mass spectrometry (UHRMS) to characterize the burden of lipophilic persistent organic pollutants (POPs) in metabolic tissues and associated alterations in the plasma metabolome.MethodsWe studied 11 adolescents with severe obesity at the time of bariatric surgery. We measured 18 POPs that can act as endocrine and metabolic disruptors (i.e. 2 dioxins, 11 organochlorine compounds [OCs] and 5 polybrominated diphenyl ethers [PBDEs]) in visceral and subcutaneous abdominal adipose tissue (vAT and sAT), and liver samples using gas chromatography with UHRMS. Biological pathways were evaluated by measuring the plasma metabolome using high-resolution metabolomics. Network and pathway enrichment analysis assessed correlations between the tissue-specific burden of three frequently detected POPs (i.e. p,p'-dichlorodiphenyldichloroethene [DDE], hexachlorobenzene [HCB] and PBDE-47) and plasma metabolic pathways.ResultsConcentrations of 4 OCs and 3 PBDEs were quantifiable in at least one metabolic tissue for > 80% of participants. All POPs had the highest median concentrations in adipose tissue, especially sAT, except for PBDE-154, which had comparable average concentrations across all tissues. Pathway analysis showed high correlations between tissue-specific POPs and metabolic alterations in pathways of amino acid metabolism, lipid and fatty acid metabolism, and carbohydrate metabolism.ConclusionsMost of the measured POPs appear to accumulate preferentially in adipose tissue compared to liver. Findings of plasma metabolic pathways potentially associated with tissue-specific POPs concentrations merit further investigation in larger populations.

BACKGROUND:More than 14,000 women in the United States die of ovarian cancer (OC) every year. Disparities in survival have been observed by race and socioeconomic status (SES), and vary spatially even after adjusting for treatment received. This study aimed to determine the impact of geographic location on receiving treatment adherent to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for OC, independent of other predictors. PATIENTS AND METHODS:Women diagnosed with all stages of epithelial OC (1996-2014) were identified through the California Cancer Registry. Generalized additive models, smoothing for residential location, were used to calculate adjusted odds ratios (ORs) and 95% CIs for receiving nonadherent care throughout California. We assessed the impact of distance traveled for care, distance to closest high-quality hospital, race/ethnicity, and SES on receipt of quality care, adjusting for demographic and cancer characteristics and stratifying by disease stage. RESULTS:Of 29,844 patients with OC, 11,419 (38.3%) received guideline-adherent care. ORs for nonadherent care were lower in northern California and higher in Kern and Los Angeles counties. Magnitudes of associations with location varied by stage (OR range, 0.45-2.19). Living farther from a high-quality hospital increased the odds of receiving nonadherent care (OR, 1.18; 95% CI, 1.07-1.29), but travel >32 km to receive care was associated with decreased odds (OR, 0.76; 95% CI, 0.70-0.84). American Indian/other women were more likely to travel greater distances to receive care. Women in the highest SES quintile, those with Medicare insurance, and women of non-Hispanic black race were less likely to travel far. Patients who were Asian/Pacific Islander lived the closest to a high-quality hospital. CONCLUSIONS:Among California women diagnosed with OC, living closer to a high-quality center was associated with receiving adherent care. Non-Hispanic black women were less likely to receive adherent care, and women with lower SES lived farthest from high-quality hospitals. Geographic location in California is an independent predictor of adherence to NCCN Guidelines for OC.

BackgroundChildren born near New Bedford, Massachusetts, have been prenatally exposed to multiple environmental chemicals, in part due to an older housing stock, maternal diet, and proximity to the New Bedford Harbor (NBH) Superfund site. Chemical exposure measures are not available for all births, limiting epidemiologic investigations and potential interventions.ObjectiveWe linked biomonitoring data from the New Bedford Cohort (NBC) and birth record data to predict prenatal exposures for all contemporaneous area births.MethodsWe used prenatal exposure biomarker data from the NBC, a population-based cohort of 788 mother-infant pairs born during 1993–1998 to mothers living near the NBH, linked to their corresponding Massachusetts birth record data, to build predictive models for cord serum polychlorinated biphenyls (expressed as a sum, [Formula: see text]), [Formula: see text] (DDE), hexachlorobenzene (HCB), cord blood lead (Pb), and maternal hair mercury (Hg). We applied the best fit models (highest pseudo [Formula: see text]), with multivariable smooths of continuous variables, to predict exposure biomarkers for all 10,270 births during 1993–1998 around the NBH. We used 10-fold cross validation to validate the exposure models and the bootstrap method to characterize sampling variability in the exposure predictions.ResultsThe 10-fold cross-validated [Formula: see text] for the [Formula: see text], DDE, HCB, Pb, and Hg exposure models were 0.54, 0.40, 0.34, 0.46, and 0.40, respectively. For each exposure model, multivariable smooths of continuous variables improved the fit compared with linear models. Other variables with significant effects on exposure estimates were paternal education, maternal race/ethnicity, and maternal ancestry. The resulting exposure predictions for all births had variability consistent with the NBC measured exposures.ConclusionsPredictive models using multivariable smoothing explained reasonable amounts of variance in prenatal exposure biomarkers. Our analyses suggest that prenatal chemical exposures can be predicted for all contemporaneous births in the same geographic area by modeling available biomarker data for a subset of that population. https://doi.org/10.1289/EHP4849.

BACKGROUND:Associations between ambient particulate matter

Our aim is to estimate associations between acute increases in particulate matter with diameter of 2.5 µm or less (PM2.5) concentrations and risk of infant bronchiolitis and otitis media among Massachusetts births born 2001 through 2008.Our case-crossover study included 20,017 infant bronchiolitis and 42,336 otitis media clinical encounter visits. PM2.5 was modeled using satellite, remote sensing, meteorological and land use data. We applied conditional logistic regression to estimate odds ratios (ORs) and confidence intervals (CIs) per 10-µg/m3 increase in PM2.5. We assessed effect modification to determine the most susceptible subgroups. Infant bronchiolitis risk was elevated for PM2.5 exposure 1 day (OR = 1.07, 95% CI = 1.03-1.11) and 4 days (OR = 1.04, 95% CI = 0.99-1.08) prior to clinical encounter, but not 7 days. Non-significant associations with otitis media varied depending on lag. Preterm infants were at substantially increased risk of bronchiolitis 1 day prior to clinical encounter (OR = 1.17, 95% CI = 1.08-1.28) and otitis media 4 and 7 days prior to clinical encounter (OR = 1.09, 95% CI = 1.02-1.16 and OR = 1.08, 95% CI = 1.02-1.15, respectively). In conclusion, preterm infants are most susceptible to infant bronchiolitis and otitis media associated with acute PM2.5 exposures.

SummaryPerfluorooctanoic acid (PFOA) is a persistent environmental contaminant that has been detected in >100 public water systems in the United States alone. A variety of epidemiological investigations of PFOA have been published, mostly using measured or modeled serum PFOA concentrations as the exposure metric. Comparison of drinking water PFOA concentrations to those study findings or to typical serum concentrations requires pharmacokinetic modeling. This brief communication describes an online Javascript calculator that easily plots the expected serum PFOA concentration over time and at steady state for adults after starting or stopping consumption of PFOA-contaminated water. Two examples of usage are provided, including increasing serum PFOA after ongoing consumption of contaminated water at the federal limit, and decreasing serum PFOA after carbon filtration began in a contaminated water system. https://doi.org/10.1289/EHP2820.

Chronic particulate matter less than 2.5μm in diameter (PM2.5) exposure can leave infants more susceptible to illness. Our objective is to estimate associations of the chronic PM2.5 exposure with infant bronchiolitis and otitis media (OM) clinical encounters. We obtained all first time bronchiolitis (n=18,029) and OM (n=40,042) clinical encounters among children less than 12 and 36 months of age, respectively, diagnosed from 2001 to 2009 and two controls per case matched on birthdate and gestational age from the Pregnancy to Early Life Longitudinal data linkage system in Massachusetts. We applied conditional logistic regression to estimate odds ratios (OR) and confidence intervals (CI) per 2-μg/m3 increase in lifetime average satellite based PM2.5 exposure. Effect modification was assessed by age, gestational age, frequency of clinical encounter, and income. We examined associations between residential distance to roadways, traffic density, and infant bronchiolitis and OM risk. PM2.5 was not associated with infant bronchiolitis (OR=1.02, 95% CI=1.00, 1.04) and inversely associated with OM (OR=0.97, 95% CI=0.95, 0.99). There was no evidence of effect modification. Compared to infants living near low traffic density, infants residing in high traffic density had elevated risk of bronchiolitis (OR=1.23, 95% CI=1.14, 1.31) but not OM (OR=0.98, 95% CI=0.93, 1.02) clinical encounter. We did not find strong evidence to support an association between early-life long-term PM2.5 exposure and infant bronchiolitis or OM. Bronchiolitis risk was increased among infants living near high traffic density.

Many epidemiology studies have investigated associations of perfluorooctanoate (PFOA) exposures with a variety of adverse health outcomes for participants in the C8 Health Project. The exposure concentrations (i.e., air and groundwater) used in these studies were determined primarily based on participant's residential locations. However, for residential addresses that could not be geocoded to the street level, the exposure concentrations were assigned based on population-weighted ZIP code centroid, which may result in exposure mischaracterization. The aim of this current study is to evaluate the potential impact of mischaracterized exposure concentrations due to geocoding uncertainty on the predicted serum PFOA concentrations and the epidemiological association between PFOA exposure and preeclampsia. For both workplace addresses and incompletely geocoded residential addresses, we used Monte Carlo (MC) simulation to assign alternate geographic locations within the reported ZIP code (instead of population-weighted ZIP code centroids) and the corresponding exposure concentrations. We found that mischaracterization of residential exposure due to population-weighted ZIP code centroid assignment had no significant impact on the serum PFOA concentration predictions and the epidemiological association of PFOA exposure with preeclampsia. In contrast, the uncertainty in workplace exposure moderately impacted the rank exposure among the participants. We observed a 41% increase in the average adjusted odds ratio of preeclampsia occurrence that may be due to differing proportions of cases (64.3%) and controls (54.5%) with workplace address geocodes during pregnancy. This finding suggests that differential exposure mischaracterization can be reduced by obtaining accurate exposure information such as street addresses and tap water consumption, for both workplaces and residences. The analysis we present is one approach for estimating the potential impacts of positional errors in a geocoding-based exposure assessment on exposure estimates and epidemiological study results.

BackgroundPreterm birth (PTB) has been associated with exposure to air pollution, but it is unclear whether effects might vary among air pollution sources and components.ObjectivesWe studied the relationships between PTB and exposure to different components of air pollution, including gases and particulate matter (PM) by size fraction, chemical composition, and sources.MethodsFine and ultrafine PM (respectively, PM2.5 and PM0.1) by source and composition were modeled across California over 2000-2008. Measured PM2.5, nitrogen dioxide, and ozone concentrations were spatially interpolated using empirical Bayesian kriging. Primary traffic emissions at fine scale were modeled using CALINE4 and traffic indices. Data on maternal characteristics, pregnancies, and birth outcomes were obtained from birth certificates. Associations between PTB (n = 442,314) and air pollution exposures defined according to the maternal residence at birth were examined using a nested matched case-control approach. Analyses were adjusted for maternal age, race/ethnicity, education and neighborhood income.ResultsAdjusted odds ratios for PTB in association with interquartile range (IQR) increases in average exposure during pregnancy were 1.133 (95% CI: 1.118, 1.148) for total PM2.5, 1.096 (95% CI: 1.085, 1.108) for ozone, and 1.079 (95% CI: 1.065, 1.093) for nitrogen dioxide. For primary PM, the strongest associations per IQR by source were estimated for onroad gasoline (9-11% increase), followed by onroad diesel (6-8%) and commercial meat cooking (4-7%). For PM2.5 composition, the strongest positive associations per IQR were estimated for nitrate, ammonium, and secondary organic aerosols (11-14%), followed by elemental and organic carbon (2-4%). Associations with local traffic emissions were positive only when analyses were restricted to births with residences geocoded at the tax parcel level.ConclusionsIn our statewide nested case-control study population, exposures to both primary and secondary pollutants were associated with an increase in PTB.CitationLaurent O, Hu J, Li L, Kleeman MJ, Bartell SM, Cockburn M, Escobedo L, Wu J. 2016. A statewide nested case-control study of preterm birth and air pollution by source and composition: California, 2001-2008. Environ Health Perspect 124:1479-1486; http://dx.doi.org/10.1289/ehp.1510133.

BackgroundPerfluorooctanoic acid (PFOA or C8) has hepatotoxic effects in animals. Cross-sectional epidemiologic studies suggest PFOA is associated with liver injury biomarkers.ObjectivesWe estimated associations between modeled historical PFOA exposures and liver injury biomarkers and medically validated liver disease.MethodsParticipants completed surveys during 2008-2011 reporting demographic, medical, and residential history information. Self-reported liver disease, including hepatitis, fatty liver, enlarged liver and cirrhosis, was validated with healthcare providers. Alanine aminotransferase (ALT), γ-glutamyltransferase (GGT) and direct bilirubin, markers of liver toxicity, were obtained from blood samples collected in the C8 Health Project (2005-2006). Historically modeled PFOA exposure, estimated using environmental fate and transport models and participant residential histories, was analyzed in relation to liver biomarkers (n = 30,723, including 1,892 workers) and liver disease (n = 32,254, including 3,713 workers).ResultsModeled cumulative serum PFOA was positively associated with ALT levels (p for trend < 0.0001), indicating possible liver toxicity. An increase from the first to the fifth quintile of cumulative PFOA exposure was associated with a 6% increase in ALT levels (95% CI: 4, 8%) and a 16% increased odds of having above-normal ALT (95% CI: odds ratio: 1.02, 1.33%). There was no indication of association with either elevated direct bilirubin or GGT; however, PFOA was associated with decreased direct bilirubin. We observed no evidence of an effect of cumulative exposure (with or without a 10-year lag) on all liver disease (n = 647 cases), nor on enlarged liver, fatty liver, and cirrhosis only (n = 427 cases).ConclusionResults are consistent with previous cross-sectional studies showing association between PFOA and ALT, a marker of hepatocellular damage. We did not observe evidence that PFOA increases the risk of clinically diagnosed liver disease.CitationDarrow LA, Groth AC, Winquist A, Shin HM, Bartell SM, Steenland K. 2016. Modeled perfluorooctanoic acid (PFOA) exposure and liver function in a Mid-Ohio Valley community. Environ Health Perspect 124:1227-1233; http://dx.doi.org/10.1289/ehp.1510391.

In toxicology studies hormesis refers to a dose-response relationship with a stimulatory response at low doses and an inhibitory response at high doses. In this manuscript, we particularly focus on a J-shaped dose-response relationship for binary cancer responses. We propose and examine two new flexible models for testing the hypothesis of hormesis in a Bayesian framework. The first model is parametric and enhances the flexibility of modeling a hormetic zone by using a non-linear predictor in a multistage model. The second model is non-parametric and allows multiple model specifications, weighting the contribution of each model via Bayesian model averaging (BMA). Simulation studies show that the non-parametric modeling approach with BMA provides robust sensitivity and specificity for detecting hormesis relative to the parametric approach, regardless of the shape of a hormetic zone.

IntroductionIntrauterine growth restriction has been associated with exposure to air pollution, but there is a need to clarify which sources and components are most likely responsible. This study investigated the associations between low birth weight (LBW,

We recently utilized a suite of environmental fate and transport models and an integrated exposure and pharmacokinetic model to estimate individual perfluorooctanoate (PFOA) serum concentrations, and also assessed the association of those concentrations with preeclampsia for participants in the C8 Health Project (a cross-sectional study of over 69,000 people who were environmentally exposed to PFOA near a major U.S. fluoropolymer production facility located in West Virginia). However, the exposure estimates from this integrated model relied on default values for key independent exposure parameters including water ingestion rates, the serum PFOA half-life, and the volume of distribution for PFOA. The aim of the present study is to assess the impact of inter-individual variability and epistemic uncertainty in these parameters on the exposure estimates and subsequently, the epidemiological association between PFOA exposure and preeclampsia. We used Monte Carlo simulation to propagate inter-individual variability/epistemic uncertainty in the exposure assessment and reanalyzed the epidemiological association. Inter-individual variability in these parameters mildly impacted the serum PFOA concentration predictions (the lowest mean rank correlation between the estimated serum concentrations in our study and the original predicted serum concentrations was 0.95) and there was a negligible impact on the epidemiological association with preeclampsia (no change in the mean adjusted odds ratio (AOR) and the contribution of exposure uncertainty to the total uncertainty including sampling variability was 7%). However, when epistemic uncertainty was added along with the inter-individual variability, serum PFOA concentration predictions and their association with preeclampsia were moderately impacted (the mean AOR of preeclampsia occurrence was reduced from 1.12 to 1.09, and the contribution of exposure uncertainty to the total uncertainty was increased up to 33%). In conclusion, our study shows that the change of the rank exposure among the study participants due to variability and epistemic uncertainty in the independent exposure parameters was large enough to cause a 25% bias towards the null. This suggests that the true AOR of the association between PFOA and preeclampsia in this population might be higher than the originally reported AOR and has more uncertainty than indicated by the originally reported confidence interval.

Exposures to particulate matter with diameter of 2.5µm or less (PM2.5) may influence risk of birth defects. We estimated associations between maternal exposure to prenatal traffic-related air pollution and risk of cardiac, orofacial, and neural tube defects among Massachusetts births conceived 2001 through 2008. Our analyses included 2729 cardiac, 255 neural tube, and 729 orofacial defects. We used satellite remote sensing, meteorological and land use data to assess PM2.5 and traffic-related exposures (distance to roads and traffic density) at geocoded birth addresses. We calculated adjusted odds ratios (OR) and confidence intervals (CI) using logistic regression models. Generalized additive models were used to assess spatial patterns of birth defect risk. There were positive but non-significant associations for a 10µg/m(3) increase in PM2.5 and perimembranous ventricular septal defects (OR=1.34, 95% CI: 0.98, 1.83), patent foramen ovale (OR=1.19, 95% CI: 0.92, 1.54) and patent ductus arteriosus (OR=1.20, 95% CI: 0.95, 1.62). There was a non-significant inverse association between PM2.5 and cleft lip with or without palate (OR=0.76, 95% CI: 0.50, 1.10), cleft palate only (OR=0.89, 95% CI: 0.54, 1.46) and neural tube defects (OR=0.77, 95% CI: 0.46, 1.05). Results for traffic related exposure were similar. Only ostium secundum atrial septal defects displayed significant spatial variation after accounting for known risk factors.

BackgroundUncertainty in exposure estimates from models can result in exposure measurement error and can potentially affect the validity of epidemiological studies. We recently used a suite of environmental models and an integrated exposure and pharmacokinetic model to estimate individual perfluorooctanoate (PFOA) serum concentrations and assess the association with preeclampsia from 1990 through 2006 for the C8 Health Project participants.ObjectivesThe aims of the current study are to evaluate impact of uncertainty in estimated PFOA drinking-water concentrations on estimated serum concentrations and their reported epidemiological association with preeclampsia.MethodsFor each individual public water district, we used Monte Carlo simulations to vary the year-by-year PFOA drinking-water concentration by randomly sampling from lognormal distributions for random error in the yearly public water district PFOA concentrations, systematic error specific to each water district, and global systematic error in the release assessment (using the estimated concentrations from the original fate and transport model as medians and a range of 2-, 5-, and 10-fold uncertainty).ResultsUncertainty in PFOA water concentrations could cause major changes in estimated serum PFOA concentrations among participants. However, there is relatively little impact on the resulting epidemiological association in our simulations. The contribution of exposure uncertainty to the total uncertainty (including regression parameter variance) ranged from 5% to 31%, and bias was negligible.ConclusionsWe found that correlated exposure uncertainty can substantially change estimated PFOA serum concentrations, but results in only minor impacts on the epidemiological association between PFOA and preeclampsia.CitationAvanasi R, Shin HM, Vieira VM, Savitz DA, Bartell SM. 2016. Impact of exposure uncertainty on the association between perfluorooctanoate and preeclampsia in the C8 Health Project population. Environ Health Perspect 124:126-132; http://dx.doi.org/10.1289/ehp.1409044.

BackgroundMental health disorders impact approximately one in four US adults. While their causes are likely multifactorial, prior research has linked the risk of certain mental health disorders to prenatal and early childhood environmental exposures, motivating a spatial analysis to determine whether risk varies by birth location.MethodsWe investigated the spatial associations between residence at birth and odds of depression, bipolar disorder, and post-traumatic stress disorder (PTSD) in a retrospective cohort (Cape Cod, Massachusetts, 1969-1983) using generalized additive models to simultaneously smooth location and adjust for confounders. Birth location served as a surrogate for prenatal exposure to the combination of social and environmental factors related to the development of mental illness. We predicted crude and adjusted odds ratios (aOR) for each outcome across the study area. The results were mapped to identify areas of increased risk.ResultsWe observed spatial variation in the crude odds ratios of depression that was still present even after accounting for spatial confounding due to geographic differences in the distribution of known risk factors (aOR range: 0.61-3.07, P = 0.03). Similar geographic patterns were seen for the crude odds of PTSD; however, these patterns were no longer present in the adjusted analysis (aOR range: 0.49-1.36, P = 0.79), with family history of mental illness most notably influencing the geographic patterns. Analyses of the odds of bipolar disorder did not show any meaningful spatial variation (aOR range: 0.58-1.17, P = 0.82).ConclusionSpatial associations exist between residence at birth and odds of PTSD and depression, but much of this variation can be explained by the geographic distributions of available risk factors. However, these risk factors did not account for all the variation observed with depression, suggesting that other social and environmental factors within our study area need further investigation.

BackgroundMethylmercury (MeHg), known for well over a century as a neurotoxin in adults, has more recently been studied for potential detrimental effects during early brain development. While several studies have estimated mercury exposure, they usually rely on either a single biomarker or questionnaire data, each of which has limitations. The goal of this paper was to develop a toxicokinetic model that incorporates both biomarker and questionnaire data to estimate the cumulative exposure to MeHg through seafood consumption using data collected from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study.MethodsWe utilized a previously described discrete-time model that estimates blood MeHg concentration given a piecewise-constant ingestion rate and single-compartment pharmacokinetics. We measured newborn bloodspot Hg concentrations and obtained information pertaining to maternal fish consumption using a questionnaire. Using MeHg concentration estimates from the toxicokinetic model, cumulative MeHg exposure was estimated in children with autism, children with developmental delay, and typically developing children. Median estimated cumulative MeHg was compared among diagnostic groups using the Kruskal-Wallis Test. Multinomial logistic regression models were constructed to assess the association between cumulative MeHg concentration and the risk of autism and developmental delay (vs. typical development).ResultsThe estimated average MeHg concentration of for all fish species consumed by mothers was 42 ppb. Median cumulative MeHg over gestation was similar across diagnostic groups (p-values raged from 0.91 to 0.98). After adjusting for potential confounding, we found no association between cumulative MeHg exposure and the risk of autism (OR = 0.95, 95% CI: 0.95, 1.12) or developmental delay (OR = 1.00, 95% CI: 0.89, 1.13).ConclusionsThe toxicokinetic model described in this paper yielded fish MeHg concentration estimates that are consistent with fish species containing lower levels of MeHg. Overall, cumulative MeHg exposure does not appear to detectably elevate the risk of autism or developmental delay. Based on the regression standard error for the association between ASD and TD, we would have reported statistical significance for an adjusted odds ratio of 1.09 or larger. This method can easily be extended to other epidemiologic studies in which there is a biomarker measurement and questionnaire data regarding exposure.

Estimated historical exposures and serum concentrations of perfluorooctanoic acid (PFOA) have been extensively used in epidemiologic studies that examined associations between PFOA exposures and adverse health outcomes among residents in highly exposed areas in the Mid-Ohio Valley. Using measured serum PFOA levels in 2005-2006, we applied two calibration methods to these retrospective exposure predictions: (1) multiplicative calibration and (2) Bayesian pharmacokinetic calibration with larger adjustments to more recent exposure estimates and smaller adjustments to exposure estimates for years farther in the past. We conducted simulation studies of various hypothetical exposure scenarios and compared hypothetical true historical intake rates with estimates based on mis-specified baseline exposure and pharmacokinetic models to find the method with the least bias. The Bayesian method outperformed the multiplicative method if a change to bottled water consumption was not reported or if the half-life of PFOA was mis-specified. On the other hand, the multiplicative method outperformed the Bayesian method if actual tap water consumption rates were systematically overestimated. If tap water consumption rates gradually decreased over time because of substitution with bottled water or other liquids, neither method clearly outperformed another. Calibration of retrospective exposure estimates using recently collected biomarkers may help reduce uncertainties in environmental epidemiologic studies.

Estimated historical exposures and serum concentrations of perfluorooctanoic acid (PFOA) have been extensively used in epidemiologic studies that examined associations between PFOA exposures and adverse health outcomes among residents in highly exposed areas in the Mid-Ohio Valley. Using measured serum PFOA levels in 2005-2006, we applied two calibration methods to these retrospective exposure predictions: (1) multiplicative calibration and (2) Bayesian pharmacokinetic calibration with larger adjustments to more recent exposure estimates and smaller adjustments to exposure estimates for years farther in the past. We conducted simulation studies of various hypothetical exposure scenarios and compared hypothetical true historical intake rates with estimates based on mis-specified baseline exposure and pharmacokinetic models to find the method with the least bias. The Bayesian method outperformed the multiplicative method if a change to bottled water consumption was not reported or if the half-life of PFOA was mis-specified. On the other hand, the multiplicative method outperformed the Bayesian method if actual tap water consumption rates were systematically overestimated. If tap water consumption rates gradually decreased over time because of substitution with bottled water or other liquids, neither method clearly outperformed another. Calibration of retrospective exposure estimates using recently collected biomarkers may help reduce uncertainties in environmental epidemiologic studies.

Perfluoroalkyl acids (PFAAs) are persistent, synthetic compounds that are used in a number of consumer products. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been associated with cardiovascular risk factors, and changes in gene expression and DNA methylation in animals and cellular systems. However, whether PFAA exposure is associated with LINE-1 DNA methylation, a potential marker of cardiovascular risk, in humans remains unknown. We sought to evaluate the cross-sectional associations between serum PFAAs and LINE-1 DNA methylation in a population highly exposed to PFOA. We measured serum PFAAs twice four to five years apart in 685 adult participants (47% male, mean age±SD=42±11years). We measured percent LINE-1 DNA methylation in peripheral blood leukocytes at the second time point (follow-up), and estimated absolute differences in LINE-1 methylation associated with an interquartile (IQR) shift in mean PFAA serum levels. IQR increases in mean serum PFOA, PFOS, perfluorononanoic acid (PFNA), and perfluorohexane sulfonate (PFHxS) were associated with differences of -0.04 (p=0.16), 0.20 (p=0.001), 0.06 (p=0.19), and 0.02 (p=0.57), respectively, in % LINE-1 methylation at follow-up after adjustment for potential confounders. We observed a monotonic increase in LINE-1 DNA methylation across tertiles of PFOS and PFNA (ptrend=0.02 for both associations), but not across tertiles of PFOA or PFHxS (ptrend=0.71 and 0.44, respectively). In summary, serum PFOS was associated with LINE-1 methylation, while serum PFOA, PFHxS, and PFNA were not. Additional research is needed to more precisely determine whether these compounds are epigenetically active.

Background: Decreased heart rate variability (HRV) has been associated with future cardiac morbidity and mortality and is often used as a marker of altered cardiac autonomic balance in studies of health effects of airborne particulate matter. Fewer studies have evaluated associations between air pollutants and cardiac arrhythmia.Objectives: We examined relationships between cardiac arrhythmias, HRV, and exposures to airborne particulate matter.Methods: We measured HRV and arrhythmia with ambulatory electrocardiograms in a cohort panel study for up to 235 hr per participant among 50 nonsmokers with coronary artery disease who were ≥ 71 years of age and living in four retirement communities in the Los Angeles, California, Air Basin. Exposures included hourly outdoor gases, hourly traffic-related and secondary organic aerosol markers, and daily size-fractionated particle mass. We used repeated measures analyses, adjusting for actigraph-derived physical activity and heart rate, temperature, day of week, season, and community location.Results: Ventricular tachycardia was significantly increased in association with increases in markers of traffic-related particles, secondary organic carbon, and ozone. Few consistent associations were observed for supraventricular tachycardia. Particulates were significantly associated with decreased ambulatory HRV only in the 20 participants using ACE (angiotensin I–converting enzyme) inhibitors.Conclusions: Although these data support the hypothesis that particulate exposures may increase the risk of ventricular tachycardia for elderly people with coronary artery disease, HRV was not associated with exposure in most of our participants. These results are consistent with previous findings in this cohort for systemic inflammation, blood pressure, and ST segment depression.Citation: Bartell SM, Longhurst J, Tjoa T, Sioutas C, Delfino RJ. 2013. Particulate air pollution, ambulatory heart rate variability, and cardiac arrhythmia in retirement community residents with coronary artery disease. Environ Health Perspect 121:1135–1141; http://dx.doi.org/10.1289/ehp.1205914

Perfluorooctanoic acid (PFOA) is a potential cause of adverse pregnancy outcomes, but previous studies have been limited by low exposures and small study size.Using birth certificate information, we examined the relation between estimated PFOA exposure and birth outcomes in an area of West Virginia and Ohio whose drinking water was contaminated by a chemical plant.Births in the study area from 1990 through 2004 were examined to generate case groups of stillbirth (n = 106), pregnancy-induced hypertension (n = 224), preterm birth (n = 3,613), term low birth weight (n = 918), term small-for-gestational-age (SGA) (n = 353), and a continuous measure of birth weight among a sample of term births (n = 4,534). A 10% sample of term births ≥ 2,500 g were selected as a source of controls (n = 3,616). Historical estimates of serum PFOA were derived from a previously developed fate and transport model. In a second study, we examined 4,547 area births linked to a survey with residential history data.In the analysis based only on birth records, we found no consistent evidence of an association between estimated PFOA exposure and stillbirth, pregnancy-induced hypertension, preterm birth, or indices of fetal growth. In the analysis of birth records linked to the survey, PFOA was unrelated to pregnancy-induced hypertension or preterm birth but showed some suggestion of an association with early preterm birth. Measures of growth restriction showed weak and inconsistent associations with PFOA.Based on the analysis using the health survey, these results provide little support for an effect of PFOA exposure on most pregnancy outcomes, except for early preterm birth and possibly fetal growth restriction.

Polychlorinated biphenyls (PCBs) manufactured in Anniston, Alabama, from 1929 to 1971 caused significant environmental contamination. The Anniston population remains one of the most highly exposed in the world.Reports of increased diabetes in PCB-exposed populations led us to examine possible associations in Anniston residents.Volunteers (n = 774) from a cross-sectional study of randomly selected households and adults who completed the Anniston Community Health Survey also underwent measurements of height, weight, fasting glucose, lipid, and PCB congener levels and verification of medications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationships between PCBs and diabetes, adjusting for diabetes risk factors. Participants with prediabetes were excluded from the logistic regression analyses.Participants were 47% African American, 70% female, with a mean age of 54.8 years. The prevalence of diabetes was 27% in the study population, corresponding to an estimated prevalence of 16% for Anniston overall; the PCB body burden of 35 major congeners ranged from 0.11 to 170.42 ppb, wet weight. The adjusted OR comparing the prevalence of diabetes in the fifth versus first quintile of serum PCB was 2.78 (95% CI: 1.00, 7.73), with similar associations estimated for second through fourth quintiles. In participants < 55 years of age, the adjusted OR for diabetes for the highest versus lowest quintile was 4.78 (95% CI: 1.11, 20.6), whereas in those ≥ 55 years of age, we observed no significant associations with PCBs. Elevated diabetes prevalence was observed with a 1 SD increase in log PCB levels in women (OR = 1.52; 95% CI: 1.01, 2.28); a decreased prevalence was observed in men (OR = 0.68; 95% CI: 0.33, 1.41).We observed significant associations between elevated PCB levels and diabetes mostly due to associations in women and in individuals < 55 years of age.

People living or working in eastern Ohio and western West Virginia have been exposed to perfluorooctanoic acid (PFOA) released by DuPont Washington Works facilities.Our objective was to estimate historical PFOA exposures and serum concentrations experienced by 45,276 non-occupationally exposed participants in the C8 Health Project who consented to share their residential histories and a 2005-2006 serum PFOA measurement.We estimated annual PFOA exposure rates for each individual based on predicted calibrated water concentrations and predicted air concentrations using an environmental fate and transport model, individual residential histories, and maps of public water supply networks. We coupled individual exposure estimates with a one-compartment absorption, distribution, metabolism, and excretion (ADME) model to estimate time-dependent serum concentrations.For all participants (n = 45,276), predicted and observed median serum concentrations in 2005-2006 are 14.2 and 24.3 ppb, respectively [Spearman's rank correlation coefficient (r(s)) = 0.67]. For participants who provided daily public well water consumption rate and who had the same residence and workplace in one of six municipal water districts for 5 years before the serum sample (n = 1,074), predicted and observed median serum concentrations in 2005-2006 are 32.2 and 40.0 ppb, respectively (r(s) = 0.82).Serum PFOA concentrations predicted by linked exposure and ADME models correlated well with observed 2005-2006 human serum concentrations for C8 Health Project participants. These individualized retrospective exposure and serum estimates are being used in a variety of epidemiologic studies being conducted in this region.

Widely cited ecological analyses of autism have reported associations with mercury emissions, with precipitation, and race at the level of counties or school districts. However, state educational agencies often suppress any low numerical autism counts before releasing data—a phenomenon known as “administrative censoring.” Previous analyses did not describe appropriate methods for censored data analysis; common substitution or exclusion methods are known to introduce bias and produce artificially narrow confidence intervals. We apply a Bayesian censored random effects Poisson model to reanalyze associations between 2001 Toxic Release Inventory reported mercury emissions and 2000-2001 autism counts in Texas. Relative risk estimates for autism decreased from 4.44 (95% CI: 4.16, 4.74) per thousand lbs. of air mercury emissions using a naive zero-substitution approach to 1.42 (95% CI: 1.09, 1.78) using the Bayesian approach. Inadequate attention to censoring poses a serious threat to the validity of ecological analyses of autism and other health outcomes.

Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid found in > 99% of Americans. Its health effects are unknown. Prior estimates of serum half-life range from 2.3 to 3.8 years.We assessed the impact of years of residence and years since residing in the study area on serum PFOA concentration in a sample of current and former residents who were exposed to PFOA emissions from an industrial facility in six water districts in West Virginia and Ohio.Serum samples and questionnaires, including residential history, were collected in 2005-2006. We modeled log serum PFOA (nanograms per milliliter) for current residents as a function of years of residence in a water district, adjusted for a variety of factors. We modeled the half-life in former residents who lived in two water districts with high exposure levels using a two-segment log-linear spline.We modeled serum PFOA concentration in 17,516 current residents as a function of years of residence (R2 = 0.68). Years of residence was significantly associated with PFOA concentration (1% increase in serum PFOA/year of residence), with significant heterogeneity by water district. Half-life was estimated in two water districts comprising a total of 1,573 individuals. For the participants included in our analyses, we found that years since residing in a water district was significantly associated with serum PFOA, which yielded half-lives of 2.9 and 8.5 years for water districts with higher and lower exposure levels, respectively.Years of residence in an exposed water district is positively associated with observed serum PFOA in 2005-2006. Differences in serum clearance rate between low- and high-exposure water districts suggest a possible concentration-dependent or time-dependent clearance process or inadequate adjustment for background exposures.

The C8 Health Project was established in 2005 to collect data on perfluorooctanoic acid (PFOA, or C8) and human health in Ohio and West Virginia communities contaminated by a fluoropolymer production facility.We assessed PFOA exposure via contaminated drinking water in a subset of C8 Health Project participants who drank water from private wells.Participants provided demographic information and residential, occupational, and medical histories. Laboratory analyses were conducted to determine serum-PFOA concentrations. PFOA data were collected from 2001 through 2005 from 62 private drinking water wells. We examined the relationship between drinking water and PFOA levels in serum using robust regression methods. As a comparison with regression models, we used a first-order, single-compartment pharmacokinetic model to estimate the serum:drinking-water concentration ratio at steady state.The median serum PFOA concentration in 108 study participants who used private wells was 75.7 μg/L, approximately 20 times greater than the levels in the U.S. general population but similar to those of local residents who drank public water. Each 1 μg/L increase in PFOA levels in drinking water was associated with an increase in serum concentrations of 141.5 μg/L (95% confidence interval, 134.9-148.1). The serum:drinking-water concentration ratio for the steady-state pharmacokinetic model was 114.PFOA-contaminated drinking water is a significant contributor to PFOA levels in serum in the study population. Regression methods and pharmacokinetic modeling produced similar estimates of the relationship.

Drinking water in multiple water districts in the Mid-Ohio Valley has been contaminated with perfluorooctanoic acid (PFOA), which was released by a nearby DuPont chemical plant. Two highly contaminated water districts began granular activated carbon filtration in 2007.To determine the rate of decline in serum PFOA, and its corresponding half-life, during the first year after filtration.Up to six blood samples were collected from each of 200 participants from May 2007 until August 2008. The primary source of drinking water varied over time for some participants; our analyses were grouped according to water source at baseline in May-June 2007.For Lubeck Public Service District customers, the average decrease in serum PFOA concentrations between May-June 2007 and May-August 2008 was 32 ng/mL (26%) for those primarily consuming public water at home (n = 130), and 16 ng/mL (28%) for those primarily consuming bottled water at home (n = 17). For Little Hocking Water Association customers, the average decrease in serum PFOA concentrations between November-December 2007 and May-June 2008 was 39 ng/mL (11%) for consumers of public water (n = 39) and 28 ng/mL (20%) for consumers of bottled water (n = 11). The covariate-adjusted average rate of decrease in serum PFOA concentration after water filtration was 26% per year (95% confidence interval, 2528% per year).The observed data are consistent with first-order elimination and a median serum PFOA half-life of 2.3 years. Ongoing follow-up will lead to improved half-life estimation.

Mild cognitive impairment (MCI) often presages development of Alzheimer's disease (AD). We recently completed a cross-sectional study to test the hypothesis that a combination of a brief cognitive screening instrument (Mini-Cog) with a functional scale (Functional Activities Questionnaire; FAQ) would accurately identify individuals with MCI and undiagnosed dementia. The Mini-Cog consists of a clock drawing task and 3-item recall, and takes less than 5 minutes to administer. The FAQ is a 30-item questionnaire completed by an informant. In addition to the Mini-Cog and FAQ, a traditional cognitive test battery was administered, and two neurologists and a neuropsychologist determined a consensus diagnosis of Normal, MCI, or Dementia. A classification tree algorithm was used to pick optimal cutpoints, and, using these cutpoints, the combined Mini-Cog and FAQ (MC-FAQ) predicted the consensus diagnosis with an accuracy of 83% and a weighted kappa of 0.81. When the population was divided into Normal and Abnormal, the sensitivity, specificity and positive predictive value were 89%, 90%, and 95%, respectively. The MC-FAQ discriminates individuals with MCI from cognitively normal individuals and those with dementia, and its ease of administration makes it an attractive screening instrument to aid detection of cognitive impairment in the elderly.

3-Phenoxybenzoic acid (3PBA), a pyrethroid metabolite, was detected in 75% of urine samples analyzed for pesticides in the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002. NHANES also includes 24-hr diet data and information on household pesticide use, activities, occupation, demographics, and other exposure factors.The objective of our study was to explore the relative importance of diet versus nondiet predictors in explaining variability in urinary 3PBA. A secondary objective was to explore whether the NHANES data could be used to identify particular foods driving 3PBA levels.We divided subjects into child (6-10 years of age), teen (11-18 years), and adult (> or = 19 years) age groups and restricted our analyses to subjects in the morning sampling session who fasted for > or = 8 hr beforehand. Regression modeling consisted of several model-building steps and a final Tobit regression on the left-censored log 3PBA measurements. We also conducted bootstrap analyses to evaluate the stability of the regression parameters.Reported household pesticide use was not significantly associated with urinary 3PBA in any age group. Diet was significant for all three groups, and certain foods appeared to contribute more than others. Among adults, tobacco use was positively associated with 3PBA (p = 0.0326), and positive associations were suggested with the number of cytochrome p450-inhibiting medications taken (p = 0.0652) and minutes spent gardening (p = 0.0613) in the past month.Although exploratory, our findings underline the importance of collecting accurate data on household pesticide use and dietary intake when evaluating pyrethroid exposure-biomarker relationships.