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Background: Pesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides. Objectives: We conducted an EWAS of DNA methylation in relation to several pesticide active ingredients. Methods: The Agricultural Lung Health Study is a case–control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina’s EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009–2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users. Results: Using family-wise error rate (p

Background: Type 2 diabetes is a leading contributor to the global burden of morbidity and mortality. Ozone (O3) exposure has previously been linked to diabetes. Objective: We studied the impact of O3 exposure on incident diabetes risk in elderly Mexican Americans and investigated whether outdoor physical activity modifies the association. Methods: We selected 1,090 Mexican American participants from the Sacramento Area Latino Study on Aging conducted from 1998 to 2007. Ambient O3 exposure levels were modeled with a land-use regression built with saturation monitoring data collected at 49 sites across the Sacramento metropolitan area. Using Cox proportional hazard models, we estimated the risk of developing incident diabetes based on average O3 exposure modeled for 5-y prior to incident diabetes diagnosis or last follow-up. Further, we estimated outdoor leisure-time physical activity at baseline and investigated whether higher vs. lower levels modified the association between O3 exposure and diabetes. Results: In total, 186 incident diabetes cases were identified during 10-y follow-up. Higher levels of physical activity were negatively associated with incident diabetes [hazard ratio (HR)=0.64 (95% CI: 0.43, 0.95)]. The estimated HRs for incident diabetes was 1.13 (95% CI: 1.00, 1.28) per 10-ppb increment of 5-y average O3 exposure; also, this association was stronger among those physically active outdoors [HR=1.52 (95% CI: 1.21, 1.90)], and close to null for those reporting lower levels of outdoor activity [HR=1.04 (95% CI: 0.90, 1.20), pinteraction=0.01]. Conclusions: Our findings suggest that ambient O3 exposure contributes to the development of type 2 diabetes, particularly among those with higher levels of leisure-time outdoor physical activity. Policies and strategies are needed to reduce O3 exposure to guarantee that the health benefits of physical activity are not diminished by higher levels of O3 pollution in susceptible populations such as older Hispanics. https://doi.org/10.1289/EHP8620

Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States.We evaluated the association between time-varying, 10-y average fine particulate matter (Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-basedWe report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y averageIn this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to

Introduction: Ambient air pollution is a known risk factor for adverse birth outcomes, but the role of ultrafine particles (UFPs) is not well understood. Aircraft-origin UFPs adversely affect air quality over large residential areas downwind of airports, but their reproductive health burden remains uninvestigated. Objectives: This analysis evaluated whether UFPs from jet aircraft emissions are associated with increased rates of preterm birth (PTB) among pregnant mothers living downwind of Los Angeles International Airport (LAX). Methods: This population-based study used birth records, provided by the California Department of Public Health, to ascertain birth outcomes and a novel, validated geospatial UFP dispersion model approach to estimate in utero exposures. All mothers who gave birth from 2008 to 2016 while living within 15km of LAX were included in this analysis (N=174,186; including 15,134 PTBs). Results: In utero exposure to aircraft-origin UFPs was positively associated with PTB. The odds ratio (OR) per interquartile range (IQR) increase [9,200 particles per cubic centimeter (cc)] relative UFP exposure was 1.04 [95% confidence interval (CI): 1.02, 1.06]. When comparing the fourth quartile of UFP exposure to the first quartile, the OR for PTB was 1.14 (95% CI: 1.08, 1.20), adjusting for maternal demographic characteristics, exposure to traffic-related air pollution, and airport-related noise. Conclusion: Our results suggest that emissions from aircraft play an etiologic role in PTBs, independent of noise and traffic-related air pollution exposures. These findings are of public health concern because UFP exposures downwind of airfields are common and may affect large, densely populated residential areas. https://doi.org/10.1289/EHP5732

Background: Nitric oxide synthase (NOS) genes are candidates for Parkinson’s disease (PD) because NOS enzymes produce nitric oxide (NO), a pro-oxidant that can damage neurons. Widely used organophosphate (OP) pesticides can induce oxidative stress and are reported to increase PD risk. Additionally, two single nucleotide polymorphisms (SNPs) from the PON1 (paraoxonase 1) gene influence the ability to metabolize OPs. Objective: Here, we investigated contributions of NOS genes and OP pesticides to PD risk, controlling for PON1 status. Methods: In 357 incident PD cases and 495 population controls, we investigated eight NOS SNPs and interactions with both household and ambient agricultural OP exposures assessed with geographic information system (GIS). Results: In comparing PD in homozygous variant carriers of NOS2A rs1060826 versus homozygous wild-type or heterozygotes, we estimate an adjusted odds ratio (OR) of 1.51 (95% CI: 0.95, 2.41). When considering interactions between NOS1 rs2682826 and OP exposure from household use, the OR for frequent OP use alone was 1.30 (95% CI: 0.72, 2.34) and for the CT+TT genotype alone was 0.89 (95% CI: 0.58, 1.39), and for frequent OP use combined with the CT+TT genotype the OR was 2.84 (95% CI: 1.49, 5.40) (interaction p-value 0.04). Similar results were seen for ambient OP exposure. Interactions between OP exposure and three other NOS1 SNPs and a genetic risk score combining all NOS1 SNPs reached statistical significance. Conclusions: We found that OP pesticides were more strongly associated with PD among participants with variant genotypes in NOS1, consistent with the importance of oxidative stress-inducing mechanisms. Our data provide evidence for NOS1 modifying PD risk in OP exposed populations. Citation: Paul KC, Sinsheimer JS, Rhodes SL, Cockburn M, Bronstein J, Ritz B. 2016. Organophosphate pesticide exposures, nitric oxide synthase gene variants, and gene–pesticide interactions in a case–control study of Parkinson’s disease, California (USA). Environ Health Perspect 124:570–577; http://dx.doi.org/10.1289/ehp.1408976

Background: Perfluoroalkyl substances (PFASs) are persistent pollutants found to be endocrine disruptive and neurotoxic in animals. Positive correlations between PFASs and neurobehavioral problems in children were reported in cross-sectional data, but findings from prospective studies are limited. Objectives: We investigated whether prenatal exposure to PFASs is associated with attention deficit/hyperactivity disorder (ADHD) or childhood autism in children. Methods: Among 83,389 mother–child pairs enrolled in the Danish National Birth Cohort during 1996–2002, we identified 890 ADHD cases and 301 childhood autism cases from the Danish National Hospital Registry and the Danish Psychiatric Central Registry. From this cohort, we randomly selected 220 cases each of ADHD and autism, and we also randomly selected 550 controls frequency matched by child’s sex. Sixteen PFASs were measured in maternal plasma collected in early or mid-pregnancy. We calculated risk ratios (RRs) using generalized linear models, taking into account sampling weights. Results: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples; four other PFASs were quantified in ≥ 90% of the samples. We did not find consistent evidence of associations between mother’s PFAS plasma levels and ADHD [per natural log nanograms per milliliter increase: PFOS RR = 0.87 (95% CI: 0.74, 1.02); PFOA RR = 0.98 (95% CI: 0.82, 1.16)] or autism [per natural log nanograms per milliliter increase: PFOS RR = 0.92 (95% CI: 0.69, 1.22); PFOA RR = 0.98 (95% CI: 0.73, 1.31)]. We found positive as well as negative associations between higher PFAS quartiles and ADHD in models that simultaneously adjusted for all PFASs, but these estimates were imprecise. Conclusions: In this study we found no consistent evidence to suggest that prenatal PFAS exposure increases the risk of ADHD or childhood autism in children. Citation: Liew Z, Ritz B, von Ehrenstein OS, Bech BH, Nohr EA, Fei CY, Bossi R, Henriksen TB, Bonefeld-Jørgensen EC, Olsen J. 2015. Attention deficit/hyperactivity disorder and childhood autism in association with prenatal exposure to perfluoroalkyl substances: a nested case–control study in the Danish National Birth Cohort. Environ Health Perspect 123:367–373; http://dx.doi.org/10.1289/ehp.1408412

All EHP content is accessible to individuals with disabilities. A fully accessible (Section 508–compliant) HTML version of this article is available at http://dx.doi.org/10.1289/ehp.1306761. Research | Children’s Health Childhood Cancer and Traffic-Related Air Pollution Exposure in Pregnancy and Early Life Julia E. Heck, 1 Jun Wu, 2 Christina Lombardi, 1 Jiaheng Qiu, 3 Travis J. Meyers, 1 Michelle Wilhelm, 1 Myles Cockburn, 4 and Beate Ritz 1 1 Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, California, USA; 2 Program in Public Health and Department of Epidemiology, University of California, Irvine, Irvine, California, USA; 3 Department of Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, California, USA; 4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA B ackground : The literature on traffic-related air pollution and childhood cancers is inconclusive, and little is known on rarer cancer types. O bjectives : We sought to examine associations between childhood cancers and traffic-related p ­ ollution exposure. M ethods : The present study included children < 6 years of age identified in the California Cancer Registry (born 1998–2007) who could be linked to a California birth certificate (n = 3,590). Controls were selected at random from California birthrolls (n = 80,224). CAlifornia LINE Source Dispersion Modeling, version 4 (CALINE4) was used to generate estimates of local traffic exposures for each trimester of pregnancy and in the first year of life at the address indicated on the birth certificate. We checked our findings by additionally examining associations with particulate matter (≤ 2.5 μm in aerodynamic diameter; PM 2.5 ) pollution measured by community-based air pollution monitors, and with a simple measure of traffic density. R esults : With unconditional logistic regression, a per interquartile range increase in exposure to traffic-related pollution during the first trimester (0.0538 ppm carbon monoxide, estimated using CALINE4) was associated with acute lymphoblastic leukemia [ALL; first trimester odds ratio (OR) = 1.05; 95% CI: 1.01, 1.10]; germ cell tumors (OR = 1.16; 95% CI: 1.04, 1.29), particularly teratomas (OR = 1.26; 95% CI: 1.12, 1.41); and retinoblastoma (OR = 1.11; 95% CI: 1.01, 1.21), particularly bilateral retinoblastoma (OR = 1.16; 95% CI: 1.02, 1.33). Retinoblastoma was also associated with average PM 2.5 concentrations during pregnancy, and ALL and teratomas were asso- ciated with traffic density near the child’s residence at birth. C onclusions : We estimated weak associations between early exposure to traffic pollution and several childhood cancers. Because this is the first study to report on traffic pollution in relation to retinoblastoma or germ cell tumors, and both cancers are rare, these findings require replication in other studies. C itation : Heck JE, Wu J, Lombardi C, Qiu J, Meyers TJ, Wilhelm M, Cockburn M, Ritz B. 2013. Childhood cancer and traffic-related air pollution exposure in pregnancy and early life. Environ Health Perspect 121:1385–1391; http://dx.doi.org/10.1289/ehp.1306761 Introduction Motor vehicle emissions are a major source of ambient air pollution in the United States and elsewhere. In a recent meeting, the International Agency for Research on Cancer (IARC) classified diesel exhaust as carcinogenic and gasoline exhaust as possibly carcinogenic to humans (Benbrahim-Tallaa et al. 2012). Traffic exhaust contains carbon monoxide, nitrogen oxides, and toxic air con- taminants such as benzene, formaldehyde, 1,3‑butadiene, and nitroarenes. Particulate components of traffic exhaust include met- als, elemental carbon, organic carbon, and sulphate. A number of these components have been classified as established or sus- pected carcinogens in occupational settings (IARC 2012). The literature on traffic-related air pol- lution and childhood cancers has been equivocal, likely for several reasons, includ- ing variation in exposure assessment methods and time periods of exposure. In addition, because of small numbers of cases, disparate cancer types were grouped as a single out- come. Many studies have used simple proxy measures of exposure such as rates of neigh- borhood car ownership, gas station density, or residential proximity to roads, gas stations, or car repair shops (Abdul Rahman et al. 2008; Alexander et al. 1996; Brosselin et al. 2009; Harrison et al. 1999; Nordlinder and Jarvholm 1997; Reynolds et al. 2002; Steffen et al. 2004; Weng et al. 2009). Other stud- ies have classified exposure based on traffic density (Harrison et al. 1999; Langholz et al. 2002; Pearson et al. 2000; Reynolds et al. 2001, 2002, 2004; Savitz and Feingold 1989; Visser et al. 2004; Von Behren et al. 2008). Only a few studies have classified exposure based on measurements of air pollutants from air monitors (Amigou et al. 2011; Weng et al. 2008) or sophisticated air pollution modeling strategies that consider more factors that influ- ence exhaust levels such as chemical reactions of pollutants, background pollution levels, land use, or weather (Crosignani et al. 2004; Feychting et al. 1998; Raaschou-Nielsen Environmental Health Perspectives • volume 121 | number 11-12 | November-December 2013 et al. 2001; Vinceti et al. 2012). In a previ- ous study that compared different ways of measuring traffic-related air pollution expo- sures in relation to birth outcomes, Wu et al. (2011) showed that traffic density yields lower effect estimates than those generated in more ­complex models. The literature is also limited in scope because most studies have reported only on leukemias, central nervous system (CNS) tumors, or all childhood cancer types com- bined, and few have had sufficient sample sizes to stratify by cancer subtypes or estimate associations with rarer tumors. Further, most studies assessed exposure using the child’s address at the time of diagnosis, study entry, or death, and are therefore best interpreted as estimating associations with traffic exposure during childhood. Because the pathogenesis of at least some childhood cancers is likely to begin in utero, these studies may not capture an important exposure period for early child- hood cancers (Greaves and Wiemels 2003; Lafiura et al. 2007). We a priori hypothesized that because of the fetus’s greater vulnerability to environ- mental toxins, exposures during the preg- nancy period would be most relevant for childhood cancer risk (Selevan et al. 2000). To our knowledge, six studies have examined associations between childhood cancers and exposures during pregnancy. Two reported that living near gas stations or auto repair garages was associated with acute lympho- blastic leukemia (ALL) and acute myeloid leukemia (AML) (Brosselin et al. 2009) or with all leukemias combined (Steffen et al. 2004). Of studies that evaluated traffic den- sity near the child’s residence, two reported Address correspondence to J. Heck, Department of Epidemiology, Box 951772, 650 Charles E. Young Dr., Los Angeles, CA 90095-1772 USA. Telephone: (310) 825-8579. E-mail: jeheck@ucla.edu We thank A. Park for his assistance with the ­manuscript. This study was supported by grants from the National Institute of Environmental Health Sciences (R21ES018960, R21ES019986, P30ES007048) and the National Cancer Institute (R25CA087949). The authors declare they have no actual or potential competing financial interests. Received: 5 March 2013; Accepted: 9 September 2013; Advance Publication: 10 September 2013; Final Publication: 1 December 2013.

© 2016, Public Health Services, US Dept of Health and Human Services. All rights reserved. Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.

Background: Numerous studies have linked criteria air pollutants with adverse birth outcomes, but there is less information on the importance of specific emission sources, such as traffic, and air toxics. Objectives: We used three exposure data sources to examine odds of term low birth weight (LBW) in Los Angeles, California, women when exposed to high levels of traffic-related air pollutants during pregnancy. Methods: We identified term births during 1 June 2004 to 30 March 2006 to women residing within 5 miles of a South Coast Air Quality Management District (SCAQMD) Multiple Air Toxics Exposure Study (MATES III) monitoring station. Pregnancy period average exposures were estimated for air toxics, including polycyclic aromatic hydrocarbons (PAHs), source-specific particulate matter < 2.5 μm in aerodynamic diameter (PM2.5) based on a chemical mass balance model, criteria air pollutants from government monitoring data, and land use regression (LUR) model estimates of nitric oxide (NO), nitrogen dioxide (NO2) and nitrogen oxides (NOx). Associations between these metrics and odds of term LBW (< 2,500 g) were examined using logistic regression. Results: Odds of term LBW increased approximately 5% per interquartile range increase in entire pregnancy exposures to several correlated traffic pollutants: LUR measures of NO, NO2, and NOx, elemental carbon, and PM2.5 from diesel and gasoline combustion and paved road dust (geological PM2.5). Conclusions: These analyses provide additional evidence of the potential impact of traffic-related air pollution on fetal growth. Particles from traffic sources should be a focus of future studies.

Epidemiologic studies since the early 1990s have suggested that exposure to various classes of pesticides increases the risk of developing Parkinson’s disease (PD). Animal studies have backed up that link, revealing how pesticides may target the dopaminergic system, which is damaged in PD. New data from the Parkinson’s Environment and Genes Study show that residents of California’s Central Valley who over many years drank well water that was probably highly contaminated with certain pesticides were more likely to have PD or PD symptoms than residents who didn’t drink contaminated well water [EHP 117:1912–1918; Gatto et al.]. Private wells are at risk of pesticide contamination because pesticides can drift several hundred meters from application sites and travel through the soil. Moreover, many of the private wells studied were less than 15–20 yd deep, lessening the likelihood that pesticides will have degraded by the time they reach the water supply. Unlike municipal water supplies, private well water is not required to be monitored for contamination. The researchers analyzed long-term data on pesticide application rates near the homes of the study participants, who included 368 people clinically confirmed to have possible or probable PD and 341 controls. The authors had access to 26 years’ worth of data collected under California’s mandated pesticide use reports program on the commercial application of pesticides, including where the pesticides were applied, on what date, and in what quantities. They studied 26 pesticides that were potential groundwater contaminants or that had been previously linked to PD. The researchers combined those data with land-use maps, which the California Department of Water Resources updates every 7–10 years, to pinpoint more precisely where pesticides had been applied. Using geographic information system software, they were able to merge historical data on home addresses, land use, and pesticide applications. The result was a prediction of amounts of pesticides applied per acre per year within 500 m of the study participants’ homes. People with PD were more likely to get their water from private wells and to have drunk well water longer than controls. Whereas people with exposure to ambient pesticides—essentially, proximity to sites where pesticides were applied—were 15–57% more likely to be classified as having PD than people without ambient exposure, those with combined ambient exposure and exposure via well water potentially contaminated with methomyl, chlorpyrifos, or propargite were 67%, 87%, or 92% more likely to be cases. The odds of PD also increased as the number of different pesticides that potentially contaminated a subject’s drinking water increased. Unlike previous research on the link between PD and pesticide exposures, this study used a semiquantitative approach to estimating pesticide exposure and did not rely on study subjects’ recall. Also, all PD cases were clinically confirmed by a movement disorder specialist. The results therefore considerably strengthen the evidence that exposure to pesticides in well water may contribute to PD.

Background Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson’s disease (PD) risk. Materials Methods: In 324 incident PD patients and 334 population controls from our rural California case–control study, we genotyped rs2652510, rs2550956 (for the DAT 5′ clades), and the 3′ variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele–pesticide interactions. Results PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08–2.57] and 3′ VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96–3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88–10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70–12.1). We obtained similar results for occupational pesticide measures. Discussion Using two independent pesticide measures, we a) replicated previously reported gene–environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure. Conclusion Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.

Background Despite extensive evidence that air pollution affects childhood asthma, state-level and national-level tracking of asthma outcomes in relation to air pollution is limited. Objectives Our goals were to evaluate the feasibility of linking the 2001 California Health Interview Survey (CHIS), air monitoring, and traffic data; estimate associations between traffic density (TD) or outdoor air pollutant concentrations and childhood asthma morbidity; and evaluate the usefulness of such databases, linkages, and analyses to Environmental Public Health Tracking (EPHT). Methods We estimated TD within 500 feet of residential cross-streets of respondents and annual average pollutant concentrations based on monitoring station measurements. We used logistic regression to examine associations with reported asthma symptoms and emergency department (ED) visits/hospitalizations. Results Assignment of TD and air pollution exposures for cross-streets was successful for 82% of children with asthma in Los Angeles and San Diego, California, Counties. Children with asthma living in high ozone areas and areas with high concentrations of particulate matter < 10 μm in aerodynamic diameter experienced symptoms more frequently, and those living close to heavy traffic reported more ED visits/hospitalizations. The advantages of the CHIS for asthma EPHT include a large and representative sample, biennial data collection, and ascertainment of important socio-demographic and residential address information. Disadvantages are its cross-sectional design, reliance on parental reports of diagnoses and symptoms, and lack of information on some potential confounders. Conclusions Despite limitations, the CHIS provides a useful framework for examining air pollution and childhood asthma morbidity in support of EPHT, especially because later surveys address some noted gaps. We plan to employ CHIS 2003 and 2005 data and novel exposure assessment methods to re-examine the questions raised here.

International audience; BACKGROUND: There is a growing body of epidemiologic literature reporting associations between atmospheric pollutants and reproductive outcomes, particularly birth weight and gestational duration. OBJECTIVES: The objectives of our international workshop were to discuss the current evidence, to identify the strengths and weaknesses of published epidemiologic studies, and to suggest future directions for research. DISCUSSION: Participants identified promising exposure assessment tools, including exposure models with fine spatial and temporal resolution that take into account time-activity patterns. More knowledge on factors correlated with exposure to air pollution, such as other environmental pollutants with similar temporal variations, and assessment of nutritional factors possibly influencing birth outcomes would help evaluate importance of residual confounding. Participants proposed a list of points to report in future publications on this topic to facilitate research syntheses. Nested case-control studies analyzed using two-phase statistical techniques and development of cohorts with extensive information on pregnancy behaviors and biological samples are promising study designs. Issues related to the identification of critical exposure windows and potential biological mechanisms through which air pollutants may lead to intrauterine growth restriction and premature birth were reviewed. CONCLUSIONS: To make progress, this research field needs input from toxicology, exposure assessment, and clinical research, especially to aid in the identification and exposure assessment of feto-toxic agents in ambient air, in the development of early markers of adverse reproductive outcomes, and of relevant biological pathways. In particular, additional research using animal models would help better delineate the biological mechanisms underpinning the associations reported in human studies.

Objectives We evaluated the association between drinking-water disinfection by-products and preterm births using improved exposure assessment and more appropriate analysis methods than used in prior studies. Methods During 1999–2001, vital record data were obtained for a large, racially diverse population residing in 27 Massachusetts communities that received drinking water from a single public utility. This water system was monitored weekly for total trihalomethanes (TTHM), and it maintained geographically stable total TTHM levels system-wide during the study period. We employed proportional hazards regression to examine the effects of trimester-specific and shorter-term peak exposures to TTHM in drinking water late in pregnancy on preterm births in 37,498 singletons. Results For all women, our data suggested no more than a small increase, if any, in risk for delivering a preterm baby when exposed to ≥ 60 μg/L TTHM during the 4 weeks before birth [hazard ratio (HR) = 1.13; 95% confidence interval (CI), 0.95–1.35]. However, women who depended on a governmental source of payment for prenatal care were at increased risk when exposed at such levels late in gestation (HR = 1.39; 95% CI, 1.06–1.81). In contrast, exposure to high levels of TTHM during the second trimester and high exposure throughout pregnancy resulted in a 15–18% reduction in risk for preterm delivery in our population. Conclusions This finding confirms previous reports of a negative association during the second trimester. Our data also suggested a possible positive association with shorter-term third-trimester TTHM exposure in mothers of lower socioeconomic status.

Background Very little is currently known about air pollutants’ adverse effects on neurodegenerative diseases even though recent studies have linked particulate exposures to brain pathologies associated with Parkinson’s and Alzheimer’s disease. Objective In the present study, we investigated long-term exposure to traffic-related air pollution and Parkinson’s disease. Methods In a case–control study of 1,696 Parkinson’s disease (PD) patients identified from Danish hospital registries and diagnosed 1996–2009 and 1,800 population controls matched by sex and year of birth, we assessed long-term traffic-related air pollutant exposures (represented by nitrogen dioxide; NO2) from a dispersion model, using residential addresses from 1971 to the date of diagnosis or first cardinal symptom for cases and the corresponding index date for their matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with logistic regression, adjusting for matching factors and potential confounders. Results We found ambient air pollution from traffic sources to be associated with risk of PD, with a 9% higher risk (95% CI: 3, 16.0%) per interquartile range increase (2.97 μg/m3) in modeled NO2. For participants living for ≥ 20 years in the capital city, ORs were larger (OR = 1.21; 95% CI: 1.11, 1.31) than in provincial towns (OR = 1.10; 95% CI: 0.97, 1.26), whereas there was no association among rural residents. Conclusions Our findings raise concerns about potential effects of air pollution from traffic and other sources on the risk of PD, particularly in populations with high or increasing exposures. Citation Ritz B, Lee PC, Hansen J, Funch Lassen C, Ketzel M, Sørensen M, Raaschou-Nielsen O. 2016. Traffic-related air pollution and Parkinson’s disease in Denmark: a case–control study. Environ Health Perspect 124:351–356; http://dx.doi.org/10.1289/ehp.1409313

We extended our previous analyses of term low birth weight (LBW) and preterm birth to 1994-2000, a period of declining air pollution levels in the South Coast Air Basin. We speculated that the effects we observed previously for carbon monoxide, particulate matter10 microm in aerodynamic diameter (PM10), and traffic density were attributable to toxins sorbed to primary exhaust particles. Focusing on CO, PM10, and particulate matter2.5 microm in aerodynamic diameter (PM2.5), we examined whether varying residential distances from monitoring stations affected risk estimates, because effect attenuation may result from local pollutant heterogeneity inadequately captured by ambient stations. We geocoded home locations, calculated the distance to the nearest air monitors, estimated exposure levels by pregnancy period, and performed logistic regression analyses for subjects living within 1-4 mi of a station. For women residing within a 1-mi distance, we observed a 27% increase in risk for high (or = 75th percentile) first-trimester CO exposures and preterm birth and a 36% increase for high third-trimester pregnancy CO exposures and term LBW. For particles, we observed similar size effects during early and late pregnancy for both term LBW and preterm birth. In contrast, smaller or no effects were observed beyond a 1-mi distance of a residence from a station. Associations between CO and PM10 averaged over the whole pregnancy and term LBW were generally smaller than effects for early and late pregnancy. These new results for 1994-2000 generally confirm our previous observations for the period 1989-1993, again linking CO and particle exposures to term LBW and preterm birth. In addition, they confirm our suspicions about having to address local heterogeneity for these pollutants in Los Angeles.

We used California's Pesticide Use Report (PUR) and land-use survey data to conduct a simulation study evaluating the potential consequences of misclassifying residential exposure from proximity to agricultural pesticide application in health effect studies. We developed a geographic model linking the PUR with crop location data from land-use surveys to assess the impact of exposure misclassification from simpler exposure models based solely on PUR or land-use data. We simulated the random selection of population controls recruited into a hypothetical case-control study within an agricultural region. Using residential parcel data, we derived annual exposure prevalences, sensitivity, and specificity for five pesticides and relied on the PUR plus land-use model as the "gold standard." Based on these estimates, we calculated the attenuation of prespecified true odds ratios (ORs), assuming nondifferential exposure misclassification. True ORs were severely attenuated a) when residential exposure status was based on a larger geographic area yielding higher sensitivity but low specificity for exposure, in contrast to relying on a smaller area and increasing specificity; b) for less frequently applied pesticides; and c) with increasing mobility of residents among the study population. Considerable effect estimate attenuation also occurred when we used residential distance to crops as a proxy for pesticide exposure. Finally, exposure classifications based on annual instead of seasonal summaries of PUR resulted in highly attenuated ORs, especially during seasons when applications of specific pesticides were unlikely to occur. These results underscore the importance of increasing the spatiotemporal resolution of pesticide exposure models to minimize misclassification.

We reported previously that increases in ambient air pollution in the Los Angeles basin increased the risk of low weight and premature birth. However, ambient concentrations measured at monitoring stations may not take into account differential exposure to pollutants found in elevated concentrations near heavy-traffic roadways. Therefore, we used an epidemiologic case-control study design to examine whether residential proximity to heavy-traffic roadways influenced the occurrence of low birth weight (LBW) and/or preterm birth in Los Angeles County between 1994 and 1996. We mapped subject home locations at birth and estimated exposure to traffic-related air pollution using a distance-weighted traffic density (DWTD) measure. This measure takes into account residential proximity to and level of traffic on roadways surrounding homes. We calculated odds ratios (ORs) and risk ratios (RRs) for being LBW and/or preterm per quintile of DWTD. The clearest exposure-response pattern was observed for preterm birth, with an RR of 1.08 [95% confidence interval (CI), 1.01-1.15] for infants in the highest DWTD quintile. Although higher risks were observed for LBW infants, exposure-response relations were less consistent. Examining the influence of season, we found elevated risks primarily for women whose third trimester fell during fall/winter months (OR(term LBW) = 1.39; 95% CI, 1.16-1.67; OR(preterm and LBW) = 1.24; 95% CI = 1.03-1.48; RR(all preterm) = 1.15; 95% CI, 1.05-1.26), and exposure-response relations were stronger for all outcomes. This result is consistent with elevated pollution in proximity to sources during more stagnant air conditions present in winter months. Our previous research and these latest results suggest exposure to traffic-related pollutants may be important.

Evidence that indoor dampness and mold growth are associated with respiratory health has been accumulating, but few studies have been able to examine health risks in relation to measured levels of indoor mold exposure. In particular, little is known about the contribution of indoor molds to the development of allergic sensitization. As a part of an ongoing study examining the effects of ambient air pollutants on respiratory health and atopic diseases in German school children, we examined the relation between viable mold levels indoors and allergic sensitization in 272 children. We examined whether allergic sensitization in children is associated with higher fungal spore count in settled house dust sampled from living room floors. Adjusting for age, sex, parental education, region of residency, and parental history of atopy, we found that mold spore counts for Cladosporium and Aspergillus were associated with an increased risk of allergic sensitization. Sensitized children exposed to high levels of mold spores (> 90th percentile) were more likely to suffer from symptoms of rhinoconjunctivitis. We conclude that elevated indoor concentrations of molds in wintertime might play a role in increasing the risk of developing atopic symptoms and allergic sensitization not only to molds but also to other common, inhaled allergens. These effects were strongest in the group of children who had lived in the same home since birth.

Background: Little is known about the influence of environmental factors on the etiology of childhood brain tumors. Objectives: We examined risks for brain tumors in children after prenatal and infant exposure to monitored ambient air toxics. Methods: We ascertained all cases of medulloblastoma, central nervous system primitive neuroectodermal tumor (PNET), and astrocytoma before 6 years of age diagnosed in 1990–2007 from the California Cancer Registry and selected controls randomly from birth rolls matched by birth year. Exposures to air toxics during pregnancy/infancy for 43 PNET, 34 medulloblastoma, and 106 astrocytoma cases and 30,569 controls living within 5 mi of a monitor were determined. With factor analysis we assessed the correlational structures of 26 probable carcinogenic toxics, and estimated odds ratios by brain tumor type in logistic regression models. Results: PNETs (≤ 38 cases) were positively associated with interquartile range (IQR) increases in prenatal exposure to acetaldehyde [odds ratio (OR) = 2.30; 95% CI: 1.44, 3.67], 1,3-butadiene (OR = 2.23; 95% CI: 1.28, 3.88), benzene, and toluene; and with IQR increases in exposure during the first year of life to ortho-dichlorobenzene (OR = 3.27; 95% CI: 1.17, 9.14), 1,3-butadiene (OR = 3.15; 95% CI: 1.57, 6.32), and benzene. All exposures except ortho-dichlorobenzene loaded on the same factor. Medulloblastoma (≤ 30 cases) was associated with prenatal exposure to polycyclic aromatic hydrocarbons (PAHs combined: OR = 1.44; 95% CI: 1.15, 1.80). Exposures to lead and some PAHs during the first year of life were positively associated with astrocytoma, but the confidence intervals included the null value (e.g., for lead, OR = 1.40; 95% CI: 0.97, 2.03). Conclusions: Our data suggest that in utero and infancy exposures to air toxics generated by industrial and road traffic sources may increase the risk of PNET and medulloblastoma, with limited support for increased risks for astrocytoma in children up to age 6. Citation: von Ehrenstein OS, Heck JE, Park AS, Cockburn M, Escobedo L, Ritz B. 2016. In Utero and early-life exposure to ambient air toxics and childhood brain tumors: a population-based case–control study in California, USA. Environ Health Perspect 124:1093–1099; http://dx.doi.org/10.1289/ehp.1408582

This cross-sectional epidemiological study collected health data for 2,470 school children between 5 and 14 years of age (89% of eligible children) who had lived most of their lives in either one of two counties strongly impacted by industrial pollution (Bitterfeld and Hettstedt) or in a neighboring county without any sources of industrial pollution (Zerbst). The objective of the study was to examine whether regional differences--with respect to the occurrence of childhood respiratory diseases and symptoms or allergies--exist and, if such differences are found, whether they persist when we adjust for the effects of known risk factors such as medical and sociodemographic factors or factors related to the indoor environment. Controlling for medical, sociodemographic, and indoor factors, according to parental reports, children residing in Hettstedt have about a 50% increased lifetime prevalence for physician-diagnosed allergies, eczema, and bronchitis compared to children from Zerbst and about twice the number of respiratory symptoms such as wheeze, shortness of breath, and cough without cold. Sensitization to common aeroallergens according to skin prick tests [odds ratio (OR) = 1.38; 95% confidence interval (CI), 1.02-1.86] and specific IgE levels (OR = 1.75; CI, 1.31-2.33) was more common for children from Hettstedt than children from the nonpolluted county. Bitterfeld children, on the other hand, more often received a diagnosis of asthma and eczema than children residing in Zerbst and also showed slightly increased sensitization rates. In conclusion, industrial pollution related to mining and smelting operations in the county of Hettstedt were associated with a higher lifetime prevalence of respiratory disorders and an increased rate of allergic sensitization in children between the ages of 5 and 14 years. Further studies are needed to determine what role the high dust content of heavy metals plays in Hettstedt.

We evaluated the effect of carbon monoxide (CO) exposures during the last trimester of pregnancy on the frequency of low birth weight among neonates born 1989-1993 to women living in the Los Angeles, California, area. Using birth certificate data for that period, we assembled a retrospective cohort of infants whose mothers resided within 2 miles of 1 of 18 CO monitoring stations. Based on the gestational age and birth date of each child, we estimated last-trimester exposure by averaging the corresponding 3 months of daily CO concentrations registered at the monitoring station closest to the mother's residence (determined from the birth certificate). Where data were available (at 6 stations), we also averaged measurements taken daily for nitrogen dioxide and ozone and those taken at 6-day intervals for particulate matter [less than/equal to]10 microm (PM10) to approximate last-trimester exposures to other pollutants. Overall, the study cohort consisted of 125,573 singleton children, excluding infants born before 37 or after 44 weeks of gestation, those weighing below 1,000 or above 5,500 g at birth, those for whom fewer than 10 days of CO measurements were available during the last trimester, and those whose mothers suffered from hypertension, diabetes, or uterine bleeding during pregnancy. Within the cohort, 2,813 (2.2%) were low in birth weight (between 1,000 and 2,499 g). Exposure to higher levels of ambient CO (>5.5 ppm 3-month average) during the last trimester was associated with a significantly increased risk for low birth weight [odds ratio (OR) = 1.22; 95% confidence interval (CI), 1.03-1.44] after adjustment for potential confounders, including commuting habits in the monitoring area, sex of the child, level of prenatal care, and age, ethnicity, and education of the mother.

Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967

Background Preeclampsia is a major complication of pregnancy that can lead to substantial maternal and perinatal morbidity, mortality, and preterm birth. Increasing evidence suggests that air pollution adversely affects pregnancy outcomes. Yet few studies have examined how local traffic-generated emissions affect preeclampsia in addition to preterm birth. Objectives We examined effects of residential exposure to local traffic-generated air pollution on preeclampsia and preterm delivery (PTD). Methods We identified 81,186 singleton birth records from four hospitals (1997–2006) in Los Angeles and Orange Counties, California (USA). We used a line-source dispersion model (CALINE4) to estimate individual exposure to local traffic-generated nitrogen oxides (NOx) and particulate matter < 2.5 μm in aerodynamic diameter (PM2.5) across the entire pregnancy. We used logistic regression to estimate effects of air pollution exposures on preeclampsia, PTD (gestational age < 37 weeks), moderate PTD (MPTD; gestational age < 35 weeks), and very PTD (VPTD; gestational age < 30 weeks). Results We observed elevated risks for preeclampsia and preterm birth from maternal exposure to local traffic-generated NOx and PM2.5. The risk of preeclampsia increased 33% [odds ratio (OR) = 1.33; 95% confidence interval (CI), 1.18–1.49] and 42% (OR = 1.42; 95% CI, 1.26–1.59) for the highest NOx and PM2.5 exposure quartiles, respectively. The risk of VPTD increased 128% (OR = 2.28; 95% CI, 2.15–2.42) and 81% (OR = 1.81; 95% CI, 1.71–1.92) for women in the highest NOx and PM2.5 exposure quartiles, respectively. Conclusion Exposure to local traffic-generated air pollution during pregnancy increases the risk of preeclampsia and preterm birth in Southern California women. These results provide further evidence that air pollution is associated with adverse reproductive outcomes.

We examined the association of infant bronchiolitis with acute exposure to ambient air pollutants. Design We employed a time-stratified case–crossover method and based the exposure windows on a priori, biologically based hypotheses. Participants We evaluated effects in 19,901 infants in the South Coast Air Basin of California in 1995–2000 with a hospital discharge record for bronchiolitis in the first year of life (International Classification of Diseases, 9th Revision, CM466.1). Evaluations/Measurements Study subjects’ ZIP code was linked to ambient air pollution monitors to derive exposures. We estimated the risk of bronchiolitis hospitalization associated with increases in wintertime ambient air pollutants using conditional logistic regression. Results We observed no increased risk after acute exposure to particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5), carbon monoxide, or nitrogen dioxide. PM2.5 exposure models suggested a 26–41% increased risk in the most premature infants born at gestational ages between 25 and 29 weeks; however, these findings were based on very small numbers. Conclusions We found little support for a link between acute increases in ambient air pollution and infant bronchiolitis except modestly increased risk for PM2.5 exposure among infants born very prematurely. In these infants, the periods of viral acquisition and incubation concurred with the time of increased risk. Relevance to Professional Practice We present novel data for the infant period and the key respiratory disease of infancy, bronchiolitis. Incompletely explained trends in rising bronchiolitis hospitalization rates and increasing number of infants born prematurely underscore the importance of evaluating the impact of ambient air pollution in this age group in other populations and studies.

Disease surveillance has a century-long tradition in public health, and environmental data have been collected at a national level by the U.S. Environmental Protection Agency for several decades. Recently, the Centers for Disease Control and Prevention announced an initiative to develop a national environmental public health tracking (EPHT) network with "linkage" of existing environmental and chronic disease data as a central goal. On the basis of experience with long-established disease surveillance systems, in this article we suggest how a system capable of linking routinely collected disease and exposure data should be developed, but caution that formal linkage of data is not the only approach required for an effective EPHT program. The primary operational goal of EPHT has to be the "treatment" of the environment to prevent and/or reduce exposures and minimize population risk for developing chronic diseases. Chronic, multifactorial diseases do not lend themselves to data-driven evaluations of intervention strategies, time trends, exposure patterns, or identification of at-risk populations based only on routinely collected surveillance data. Thus, EPHT should be synonymous with a dynamic process requiring regular system updates to a) incorporate new technologies to improve population-level exposure and disease assessment, b) allow public dissemination of new data that become available, c) allow the policy community to address new and emerging exposures and disease "threads," and d) evaluate the effectiveness of EPHT over some appropriate time interval. It will be necessary to weigh the benefits of surveillance against its costs, but the major challenge will be to maintain support for this important new system. Key words: environmental health, evaluation, intervention, registries, surveillance.