Does socioeconomic and environmental burden affect vulnerability to extreme air pollution and heat? A case-crossover study of mortality in California.

BACKGROUND: Extreme heat and air pollution is associated with increased mortality. Recent evidence suggests the combined effects of both is greater than the effects of each individual exposure. Low neighborhood socioeconomic status ("socioeconomic burden") has also been associated with increased exposure and vulnerability to both heat and air pollution. We investigated if neighborhood socioeconomic burden or the combination of socioeconomic and environmental exposures ("socioenvironmental burden") modified the effect of combined exposure to extreme heat and particulate air pollution on mortality in California. METHODS: We used a time-stratified case-crossover design to assess the impact of daily exposure to extreme particulate matter <2.5 µm (PM2.5) and heat on cardiovascular, respiratory, and all-cause mortality in California 2014-2019. Daily average PM2.5 and maximum temperatures based on decedent's residential census tract were dichotomized as extreme or not. Census tract-level socioenvironmental and socioeconomic burden was assessed with the CalEnviroScreen (CES) score and a social deprivation index (SDI), and individual educational attainment was derived from death certificates. Conditional logistic regression was used to estimate associations of heat and PM2.5 with mortality with a product term used to evaluate effect measure modification. RESULTS: During the study period 1,514,292 all-cause deaths could be assigned residential exposures. Extreme heat and air pollution alone and combined were associated with increased mortality, matching prior reports. Decedents in census tracts with higher socioenvironmental and socioeconomic burden experienced more days with extreme PM2.5 exposure. However, we found no consistent effect measure modification by CES or SDI on combined or separate extreme heat and PM2.5 exposure on odds of total, cardiovascular or respiratory mortality. No effect measure modification was observed for individual education attainment. CONCLUSION: We did not find evidence that neighborhood socioenvironmental- or socioeconomic burden significantly influenced the individual or combined impact of extreme exposures to heat and PM2.5 on mortality in California. IMPACT: We investigated the effect measure modification by socioeconomic and socioenvironmental of the co-occurrence of heat and PM2.5, which adds support to the limited previous literature on effect measure modification by socioeconomic and socioenvironmental burden of heat alone and PM2.5 alone. We found no consistent effect measure modification by neighborhood socioenvironmental and socioeconomic burden or individual level SES of the mortality association with extreme heat and PM2.5 co-exposure. However, we did find increased number of days with extreme PM2.5 exposure in neighborhoods with high socioenvironmental and socioeconomic burden. We evaluated multiple area-level and an individual-level SES and socioenvironmental burden metrics, each estimating socioenvironmental factors differently, making our conclusion more robust.

Neighborhood Disadvantage and Autism Spectrum Disorder in a Population With Health Insurance.

Importance: Family socioeconomic status has been associated with autism spectrum disorder (ASD) diagnoses. Less is known regarding the role of neighborhood disadvantage in the United States, particularly when children have similar access to health insurance. Objective: To evaluate the association between neighborhood disadvantage and the diagnosis of ASD and potential effect modification by maternal and child demographic characteristics. Design, Setting, and Participants: This cohort study examined a retrospective birth cohort from Kaiser Permanente Southern California (KPSC), an integrated health care system. Children born in 2001 to 2014 at KPSC were followed up through KPSC membership records. Electronic medical records were used to obtain an ASD diagnosis up to December 31, 2019, or the last follow-up. Data were analyzed from February 2022 to September 2023. Exposure: Socioeconomic disadvantage at the neighborhood level, an index derived from 7 US census tract characteristics using principal component analysis. Main Outcomes and Measures: Clinical ASD diagnosis based on electronic medical records. Associations between neighborhood disadvantage and ASD diagnosis were determined by hazard ratios (HRs) from Cox regression models adjusted for birth year, child sex, maternal age at delivery, parity, severe prepregnancy health conditions, maternal race and ethnicity, and maternal education. Effect modification by maternal race and ethnicity, maternal education, and child sex was assessed. Results: Among 318 372 mothers with singleton deliveries during the study period, 6357 children had ASD diagnoses during follow-up; their median age at diagnosis was 3.53 years (IQR, 2.57-5.34 years). Neighborhood disadvantage was associated with a higher likelihood of ASD diagnosis (HR, 1.07; 95% CI, 1.02-1.11, per IQR = 2.70 increase). Children of mothers from minoritized racial and ethnic groups (African American or Black, Asian or Pacific Islander, Hispanic or Latinx groups) had increased likelihood of ASD diagnosis compared with children of White mothers. There was an interaction between maternal race and ethnicity and neighborhood disadvantage (difference in log-likelihood = 21.88; P < .001 for interaction under χ24); neighborhood disadvantage was only associated with ASD among children of White mothers (HR, 1.17; 95% CI, 1.09-1.26, per IQR = 2.00 increase). Maternal education and child sex did not significantly modify the neighborhood-ASD association. Conclusions and Relevance: In this study, children residing in more disadvantaged neighborhoods at birth had higher likelihood of ASD diagnosis among a population with health insurance. Future research is warranted to investigate the mechanisms behind the neighborhood-related disparities in ASD diagnosis, alongside efforts to provide resources for early intervention and family support in communities with a higher likelihood of ASD.

Evidence Synthesis of Observational Studies in Environmental Health: Lessons Learned from a Systematic Review on Traffic-Related Air Pollution.

BACKGROUND: There is a long tradition in environmental health of using frameworks for evidence synthesis, such as those of the U.S. Environmental Protection Agency for its Integrated Science Assessments and the International Agency for Research on Cancer Monographs. The framework, Grading of Recommendations Assessment, Development, and Evaluation (GRADE), was developed for evidence synthesis in clinical medicine. The U.S. Office of Health Assessment and Translation (OHAT) elaborated an approach for evidence synthesis in environmental health building on GRADE. METHODS: We applied a modified OHAT approach and a broader "narrative" assessment to assess the level of confidence in a large systematic review on traffic-related air pollution and health outcomes. DISCUSSION: We discuss several challenges with the OHAT approach and its implementation and suggest improvements for synthesizing evidence from observational studies in environmental health. We consider the determination of confidence using a formal rating scheme of up- and downgrading of certain factors, the treatment of every factor as equally important, and the lower initial confidence rating of observational studies to be fundamental issues in the OHAT approach. We argue that some observational studies can offer high-confidence evidence in environmental health. We note that heterogeneity in magnitude of effect estimates should generally not weaken the confidence in the evidence, and consistency of associations across study designs, populations, and exposure assessment methods may strengthen confidence in the evidence. We mention that publication bias should be explored beyond statistical methods and is likely limited when large and collaborative studies comprise most of the evidence and when accrued over several decades. We propose to identify possible key biases, their most likely direction, and their potential impacts on the results. We think that the OHAT approach and other GRADE-type frameworks require substantial modification to align better with features of environmental health questions and the studies that address them. We emphasize that a broader, "narrative" evidence assessment based on the systematic review may complement a formal GRADE-type evaluation. https://doi.org/10.1289/EHP11532.

Prenatal air pollution, maternal immune activation, and autism spectrum disorder.

BACKGROUND: Autism Spectrum Disorder (ASD) risk is highly heritable, with potential additional non-genetic factors, such as prenatal exposure to ambient particulate matter with aerodynamic diameter < 2.5 µm (PM2.5) and maternal immune activation (MIA) conditions. Because these exposures may share common biological effect pathways, we hypothesized that synergistic associations of prenatal air pollution and MIA-related conditions would increase ASD risk in children. OBJECTIVES: This study examined interactions between MIA-related conditions and prenatal PM2.5 or major PM2.5 components on ASD risk. METHODS: In a population-based pregnancy cohort of children born between 2001 and 2014 in Southern California, 318,751 mother-child pairs were followed through electronic medical records (EMR); 4,559 children were diagnosed with ASD before age 5. Four broad categories of MIA-related conditions were classified, including infection, hypertension, maternal asthma, and autoimmune conditions. Average exposures to PM2.5 and four PM2.5 components, black carbon (BC), organic matter (OM), nitrate (NO3-), and sulfate (SO42-), were estimated at maternal residential addresses during pregnancy. We estimated the ASD risk associated with MIA-related conditions, air pollution, and their interactions, using Cox regression models to adjust for covariates. RESULTS: ASD risk was associated with MIA-related conditions [infection (hazard ratio 1.11; 95% confidence interval 1.05-1.18), hypertension (1.30; 1.19-1.42), maternal asthma (1.22; 1.08-1.38), autoimmune disease (1.19; 1.09-1.30)], with higher pregnancy PM2.5 [1.07; 1.03-1.12 per interquartile (3.73 µg/m3) increase] and with all four PM2.5 components. However, there were no interactions of each category of MIA-related conditions with PM2.5 or its components on either multiplicative or additive scales. CONCLUSIONS: MIA-related conditions and pregnancy PM2.5 were independently associations with ASD risk. There were no statistically significant interactions of MIA conditions and prenatal PM2.5 exposure with ASD risk.

Maternal exposure to aircraft emitted ultrafine particles during pregnancy and likelihood of ASD in children.

BACKGROUND: There is increasing evidence for adverse health effects associated with aircraft-emitted particulate matter (PM) exposures, which are largely in the ultrafine (PM0.1) size fraction, but no previous study has examined neurodevelopmental outcomes. OBJECTIVE: To assess associations between maternal exposure to aircraft ultrafine particles (UFP) during pregnancy and offspring autism spectrum disorder (ASD) diagnosis. METHODS: This large, representative cohort study included 370,723 singletons born in a single healthcare system. Demographic data, maternal health information, and child's ASD diagnosis by age 5 were extracted from electronic medical records. Aircraft exposure estimates for PM0.1 were generated by the University of California Davis/California Institute of Technology Source Oriented Chemical Transport model. Cox proportional hazard models were used to assess associations between maternal exposure to aircraft PM0·1 in pregnancy and ASD diagnosis, controlling for covariates. RESULTS: Over the course of follow-up, 4,554 children (1.4 %) were diagnosed with ASD. Increased risk of ASD was associated with maternal exposure to aircraft PM0.1 [hazard ratio, HR: 1.02, (95 % confidence interval (CI): 1.01-1.03) per IQR = 0.02 µg/m3 increase during pregnancy. Associations were robust to adjustment for total PM0.1 and fine particulate matter (PM2.5), near-roadway air pollution, and other covariates. Noise adjustment modestly attenuated estimates of UFP effects, which remained statistically significant. DISCUSSION: The results strengthen the emerging evidence that maternal particulate matter exposure during pregnancy is associated with offspring ASD diagnosis and identify aircraft-derived PM0.1 as novel targets for further study and potential regulation.

Prenatal exposure to tailpipe and non-tailpipe tracers of particulate matter pollution and autism spectrum disorders.

BACKGROUND: Traffic-related air pollution exposure is associated with increased risk of autism spectrum disorder (ASD). It is unknown whether carbonaceous material from vehicular tailpipe emissions or redox-active non-tailpipe metals, eg. from tire and brake wear, are responsible. We assessed ASD associations with fine particulate matter (PM2.5) tracers of tailpipe (elemental carbon [EC] and organic carbon [OC]) and non-tailpipe (copper [Cu]; iron [Fe] and manganese [Mn]) sources during pregnancy in a large cohort. METHODS: This retrospective cohort study included 318,750 children born in Kaiser Permanente Southern California (KPSC) hospitals during 2001-2014, followed until age 5. ASD cases were identified by ICD codes. Monthly estimates of PM2.5 and PM2.5 constituents EC, OC, Cu, Fe, and Mn with 4 km spatial resolution were obtained from a source-oriented chemical transport model. These exposures and NO2 were assigned to each maternal address during pregnancy, and associations with ASD were assessed using Cox regression models adjusted for covariates. PM constituent effect estimates were adjusted for PM2.5 and NO2 to assess independent effects. To distinguish ASD risk associated with non-tailpipe from tailpipe sources, the associations with Cu, Fe, and Mn were adjusted for EC and OC, and vice versa. RESULTS: There were 4559 children diagnosed with ASD. In single-pollutant models, increased ASD risk was associated with gestational exposures to tracers of both tailpipe and non-tailpipe emissions. The ASD hazard ratios (HRs) per inter-quartile increment of exposure) for EC, OC, Cu, Fe, and Mn were 1.11 (95% CI: 1.06-1.16), 1.09 (95% CI: 1.04-1.15), 1.09 (95% CI: 1.04-1.13), 1.14 (95% CI: 1.09-1.20), and 1.17 (95% CI: 1.12-1.22), respectively. Estimated effects of Cu, Fe, and Mn (reflecting non-tailpipe sources) were largely unchanged in two-pollutant models adjusting for PM2.5, NO2, EC or OC. In contrast, ASD associations with EC and OC were markedly attenuated by adjustment for non-tailpipe sources. CONCLUSION: Results suggest that non-tailpipe emissions may contribute to ASD. Implications are that reducing tailpipe emissions, especially from vehicles with internal combustion engines, may not eliminate ASD associations with traffic-related air pollution.

Prenatal exposure to ambient air pollution is associated with neurodevelopmental outcomes at 2 years of age.

BACKGROUND: Higher prenatal ambient air pollution exposure has been associated with impaired neurodevelopment in preschoolers and school-aged children. The purpose of this study was to explore the relationships between prenatal ambient air pollution exposure and neurodevelopment during infancy. METHODS: This study examined 161 Latino mother-infant pairs from the Southern California Mother's Milk Study. Exposure assessments included prenatal nitrogen dioxide (NO2) and particulate matter smaller than 2.5 and 10 microns in diameter (PM2.5 and PM10, respectively). The pregnancy period was also examined as three windows, early, mid, and late, which describe the first, middle, and last three months of pregnancy. Infant neurodevelopmental outcomes at 2 years of age were measured using the Bayley-III Scales of Infant and Toddler Development. Multivariable linear models and distributed lag linear models (DLM) were used to examine relationships between prenatal exposures and neurodevelopmental scores, adjusting for socioeconomic status, breastfeeding frequency, time of delivery, pre-pregnancy body mass index, and infant birthweight and sex. RESULTS: Higher prenatal exposure to PM10 and PM2.5 was negatively associated with composite cognitive score (ß = -2.01 [-3.89, -0.13] and ß = -1.97 [-3.83, -0.10], respectively). In addition, higher average prenatal exposure to PM10 was negatively associated with composite motor (ß = -2.35 [-3.95, -0.74]), scaled motor (ß = -0.77 [-1.30, -0.24]), gross motor (ß = -0.37 [-0.70, -0.04]), fine motor (ß = -0.40 [-0.71, -0.09]), composite language (ß = -1.87 [-3.52, -0.22]), scaled language (ß = -0.61 [-1.18, -0.05]) and expressive communication scaled scores (ß = -0.36 [-0.66, -0.05]). DLMs showed that higher prenatal air pollution exposure during mid and late pregnancy was inversely associated with motor, cognitive, and communication language scores. CONCLUSIONS: Higher exposure to air pollutants during pregnancy, particularly in the mid and late prenatal periods, was inversely associated with scaled and composite motor, cognitive, and language scores at 2 years. These results indicate that prenatal ambient air pollution may negatively impact neurodevelopment in early life.

Maternal obesity, diabetes, preeclampsia, and asthma during pregnancy and likelihood of autism spectrum disorder with gastrointestinal disturbances in offspring.

LAY ABSTRACT: Autism spectrum disorder is heterogeneous and often accompanied by co-occurring conditions. Previous studies have shown that maternal health conditions during pregnancy including obesity, diabetes, preeclampsia, and asthma were associated with increased likelihood of autism. However, little has been done examining the likelihood associated with autism with co-occurring conditions. This study assessed these maternal health conditions in relationship to autism and gastrointestinal disturbances, a common co-occurring condition in children diagnosed with autism. Data included 308,536 mother-child pairs from one integrated health care system with comprehensive electronic medical records. Among the study cohort, 5,131 (1.7%) children had a diagnosis of autism by age 5. Gastrointestinal disturbances were present in 35.4% of children diagnosed with autism and 25.1% of children without autism diagnoses. Our results showed that each of the four maternal health conditions during pregnancy was associated with increased likelihood of gastrointestinal disturbances, autism without gastrointestinal disturbances, and autism with gastrointestinal disturbances. For all four maternal health conditions, the association was greatest for likelihood of autism with gastrointestinal disturbances. Given that children diagnosed with autism are more likely to have gastrointestinal disturbances and over 80% of gastrointestinal disturbances in this cohort were diagnosed prior to autism diagnosis, this study suggests that there may be common biological pathways between autism and gastrointestinal disturbances impacted by these maternal exposures. Future studies are warranted to assess associations between different exposures and autism with other co-occurring conditions to increase our understanding of autism heterogeneity.

The Effects of Coexposure to Extremes of Heat and Particulate Air Pollution on Mortality in California: Implications for Climate Change.

Rationale: Extremes of heat and particulate air pollution threaten human health and are becoming more frequent because of climate change. Understanding the health impacts of coexposure to extreme heat and air pollution is urgent. Objectives: To estimate the association of acute coexposure to extreme heat and ambient fine particulate matter (PM2.5) with all-cause, cardiovascular, and respiratory mortality in California from 2014 to 2019. Methods: We used a case-crossover study design with time-stratified matching using conditional logistic regression to estimate mortality associations with acute coexposures to extreme heat and PM2.5. For each case day (date of death) and its control days, daily average PM2.5 and maximum and minimum temperatures were assigned (0- to 3-day lag) on the basis of the decedent's residence census tract. Measurements and Main Results: All-cause mortality risk increased 6.1% (95% confidence interval [CI], 4.1-8.1) on extreme maximum temperature-only days and 5.0% (95% CI, 3.0-8.0) on extreme PM2.5-only days, compared with nonextreme days. Risk increased by 21.0% (95% CI, 6.6-37.3) on days with exposure to both extreme maximum temperature and PM2.5. Increased risk of cardiovascular and respiratory mortality on extreme coexposure days was 29.9% (95% CI, 3.3-63.3) and 38.0% (95% CI, -12.5 to 117.7), respectively, and were more than the sum of individual effects of extreme temperature and PM2.5 only. A similar pattern was observed for coexposure to extreme PM2.5 and minimum temperature. Effect estimates were larger over age 75 years. Conclusions: Short-term exposure to extreme heat and air pollution alone were individually associated with increased risk of mortality, but their coexposure had larger effects beyond the sum of their individual effects.

Near-roadway air pollution, immune cells and adipokines among obese young adults.

BACKGROUND: Air pollution has been associated with metabolic disease and obesity. Adipokines are potential mediators of these effects, but studies of air pollution-adipokine relationships are inconclusive. Macrophage and T cells in adipose tissue (AT) and blood modulate inflammation; however, the role of immune cells in air pollution-induced dysregulation of adipokines has not been studied. We examined the association between air pollution exposure and circulating and AT adipokine concentrations, and whether these relationships were modified by macrophage and T cell numbers in the blood and AT. METHODS: Fasting blood and abdominal subcutaneous AT biopsies were collected from 30 overweight/obese 18-26 year-old volunteers. Flow cytometry was used to quantify T effector (Teff, inflammatory) and regulatory (Treg, anti-inflammatory) lymphocytes and M1 [inflammatory] and M2 [anti-inflammatory]) macrophage cell number. Serum and AT leptin and adiponectin were measured using enzyme-linked immunosorbent assay (ELISA). Exposure to near-roadway air pollution (NRAP) from freeway and non-freeway vehicular sources and to regional particulate matter, nitrogen dioxide and ozone were estimated for the year prior to biopsy, based on participants' residential addresses. Linear regression models were used to examine the association between air pollution exposures and adipokines and to evaluate effect modification by immune cell counts. RESULTS: An interquartile increase in non-freeway NRAP exposure during 1 year prior to biopsy was associated with higher leptin levels in both serum [31.7% (95% CI: 10.4, 52.9%)] and AT [19.4% (2.2, 36.6%)]. Non-freeway NRAP exposure effect estimates were greater among participants with greater than median Teff/Treg ratio and M1/M2 ratio in blood, and with greater M1 counts in AT. No adipokine associations with regional air pollutants were found. DISCUSSION: Our results suggest that NRAP may increase serum leptin levels in obese young adults, and this association may be promoted in a pro-inflammatory immune cell environment in blood and AT.

Prenatal Exposure to Air Pollution and Autism Spectrum Disorder: Sensitive Windows of Exposure and Sex Differences.

BACKGROUND: Studies have shown that air pollution exposures during pregnancy are associated with an increased risk of autism spectrum disorder (ASD) in children, and the risk appears to be greater for boys. However, studies assessing gestational windows of susceptibility have been mostly limited by trimesters. OBJECTIVE: We identified sensitive windows of exposure to regional air pollution and risk of ASD and examined sex differences in a large birth cohort. METHODS: This population-based retrospective cohort study included 294,937 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals from 2001 to 2014. Children were followed using electronic medical records until clinical ASD diagnosis, non-KPSC membership, death, or 31 December 2019, whichever came first. Weekly mean fine particulate matter [PM with an aerodynamic diameter of ≤2.5µm (PM2.5)], nitrogen dioxide (NO2), and ozone (O3) pregnancy exposures were estimated using spatiotemporal prediction models. Cox proportional hazard models with distributed lags were used to estimate weekly pollutant exposure associations with ASD risk for the entire cohort, and separately for boys and for girls. Models were adjusted for child sex (for full cohort), maternal race/ethnicity, maternal age at delivery, parity, maternal education, maternal comorbidities, medical center, census tract median household income, birth year, and season. RESULTS: There were 5,694 ASD diagnoses (4,636 boys, 1,058 girls). Sensitive PM2.5 exposure windows associated with ASD were found early in pregnancy, statistically significant throughout the first two trimesters [1-27 wk of gestation, cumulative hazard ratio (HR)=1.14 [95% confidence interval (CI): 1.06, 1.23] per interquartile range (IQR) (7.4-µg/m3) increase]. O3 exposure during 34-37 wk of gestation was associated with increased risk [HR=1.06 (95% CI: 1.01, 1.11) per IQR (17.4 ppb) increase] but with reduced risk during 20-28 wk of gestation [HR=0.93 (95% CI: 0.89, 0.98)]. No associations were observed with NO2. Sex-stratified early gestational PM2.5 associations were stronger among boys [boys HR=1.16 (95% CI: 1.08, 1.26); girls HR=1.06 (95% CI: 0.89, 1.26)]. O3 associations in later gestation were observed only in boys [boys HR=1.10 (95% CI: 1.04, 1.16); girls HR=0.94 (95% CI: 0.84, 1.05)]. CONCLUSIONS: Exposures to PM2.5 in the first two gestational trimesters were associated with increased ASD risk in children, with stronger associations observed for boys. The role of O3 exposure on ASD risk merits further investigation. https://doi.org/10.1289/EHP9509.

In utero exposure to near-roadway air pollution and autism spectrum disorder in children.

IMPORTANCE: Previous studies have reported associations between in utero exposure to regional air pollution and autism spectrum disorders (ASD). In utero exposure to components of near-roadway air pollution (NRAP) has been linked to adverse neurodevelopment in animal models, but few studies have investigated NRAP association with ASD risk. OBJECTIVE: To identify ASD risk associated with in utero exposure to NRAP in a large, representative birth cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective pregnancy cohort study included 314,391 mother-child pairs of singletons born between 2001 and 2014 at Kaiser Permanente Southern California (KPSC) hospitals. Maternal and child data were extracted from KPSC electronic medical records. Children were followed until: clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Exposure to the complex NRAP mixture during pregnancy was assessed using line-source dispersion models to estimate fresh vehicle emissions from freeway and non-freeway sources at maternal addresses during pregnancy. Vehicular traffic load exposure was characterized using advanced telematic models combining traditional traffic counts and travel-demand models with cell phone and vehicle GPS data. Cox proportional-hazard models estimated hazard ratios (HR) of ASD associated with near-roadway traffic load and dispersion-modeled NRAP during pregnancy, adjusted for covariates. Non-freeway NRAP was analyzed using quintile distribution due to nonlinear associations with ASD. EXPOSURES: Average NRAP and traffic load exposure during pregnancy at maternal residential addresses. MAIN OUTCOMES: Clinical diagnosis of ASD. RESULTS: A total of 6,291 children (5,114 boys, 1,177 girls) were diagnosed with ASD. The risk of ASD was associated with pregnancy-average exposure to total NRAP [HR(95% CI): 1.03(1.00,1.05) per 5 ppb increase in dispersion-modeled NOx] and to non-freeway NRAP [HR(95% CI) comparing the highest to the lowest quintile: 1.19(1.11, 1.27)]. Total NRAP had a stronger association in boys than in girls, but the association with non-freeway NRAP did not differ by sex. The association of freeway NRAP with ASD risk was not statistically significant. Non-freeway traffic load exposure demonstrated associations with ASD consistent with those of NRAP and ASD. CONCLUSIONS: In utero exposure to near-roadway air pollution, particularly from non-freeway sources, may increase ASD risk in children.

Gestational diabetes mellitus, prenatal air pollution exposure, and autism spectrum disorder.

BACKGROUND: Ambient air pollution and maternal diabetes may affect common biological pathways underlying adverse neurodevelopmental effects. However, joint effects of maternal diabetes and air pollution on autism spectrum disorder (ASD) have not been studied. OBJECTIVE: We evaluated whether prenatal and early-life air pollution exposure interacts with maternal diabetes status to affect ASD risk. METHODS: This retrospective cohort study included 246,420 singleton children born in Kaiser Permanente Southern California hospitals in 1999-2009. Children were followed from birth until age 5, during which 2471 ASD cases were diagnosed. Ozone (O3), particulate matter < 2.5 µm (PM2.5) and <10 µm in aerodynamic diameter, and nitrogen dioxide measured at regulatory air monitoring stations were interpolated to estimate exposures during preconception and each pregnancy trimester, and first year of life at each child's birth address. Hazard ratios (HRs) for ASD were estimated adjusting for birth year, KPSC service areas, and relevant maternal and child characteristics. For each exposure window, interactions were tested between pollutants and a 4-category maternal diabetes variable (none, GDM ≥ 24 and <24 weeks' gestation, and pre-existing type 2 diabetes). For an exposure window with statistically significant global interaction between pollutant and diabetes (p < 0.05), pollutant-associated HRs were estimated separately for each category of maternal diabetes. RESULTS: There were associations of ASD with preconception, first and third trimesters, and first year of life PM2.5, but not with other pollutants. There were, however, interactions of maternal diabetes with first trimester and first year of life O3. Increased ASD risk was associated with first trimester O3 among mothers with GDM < 24 weeks' gestation [adjusted HR 1.50 per 15.7 ppb O3 (95% CI: 1.08-2.09)]. No O3 associations with ASD were observed in other categories of maternal diabetes. CONCLUSIONS: GDM onset early in pregnancy may increase children's susceptibility to prenatal O3-associated ASD risk. These novel findings merit further investigation.

Sex-specific associations of autism spectrum disorder with residential air pollution exposure in a large Southern California pregnancy cohort.

Autism spectrum disorder (ASD) affects more boys than girls. Recent animal studies found that early life exposure to ambient particles caused autism-like behaviors only in males. However, there has been little study of sex-specificity of effects on ASD in humans. We evaluated ASD risk associated with prenatal and first year of life exposures to particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5) by child sex. This retrospective cohort study included 246,420 singleton children born in Kaiser Permanente Southern California (KPSC) hospitals between 1999 and 2009. The cohort was followed from birth through age five to identify 2471 ASD cases from the electronic medical record. Ambient PM2.5 and other regional air pollution measurements (PM less than 10 µm, ozone, nitrogen dioxide) from regulatory air monitoring stations were interpolated to estimate exposure during each trimester and first year of life at each geocoded birth address. Hazard ratios (HRs) were estimated using Cox regression models to adjust for birth year, KPSC medical center service areas, and relevant maternal and child characteristics. Adjusted HRs per 6.5 µg/m3 PM2.5 were elevated during entire pregnancy [1.17 (95% confidence interval (CI), 1.04-1.33)]; first trimester [1.10 (95% CI, 1.02-1.19)]; third trimester [1.08 (1.00-1.18)]; and first year of life [1.21 (95% CI, 1.05-1.40)]. Only the first trimester association remained robust to adjustment for other exposure windows, and was specific to boys only (HR = 1.18; 95% CI, 1.08-1.27); there was no association in girls (HR = 0.90; 95% CI, 0.76-1.07; interaction p-value 0.03). There were no statistically significant associations with other pollutants. PM2.5-associated ASD risk was stronger in boys, consistent with findings from recent animal studies. Further studies are needed to better understand these sexually dimorphic neurodevelopmental associations.

Epigenetic marks of prenatal air pollution exposure found in multiple tissues relevant for child health.

BACKGROUND: Prenatal air pollution exposure has been linked to many adverse health conditions in the offspring. However, little is known about the mechanisms underlying these associations. Epigenetics may be one plausible biologic link. Here, we sought to identify site-specific and global DNA methylation (DNAm) changes, in developmentally relevant tissues, associated with prenatal exposure to nitrogen dioxide (NO2) and ozone (O3). Additionally, we assessed whether sex-specific changes in methylation exist and whether DNAm changes are consistently observed across tissues. METHODS: Genome-scale DNAm measurements were obtained using the Infinium HumanMethylation450k platform for 133 placenta and 175 cord blood specimens from Early Autism Risk Longitudinal Investigation (EARLI) neonates. Ambient NO2 and O3 exposure levels were based on prenatal address locations of EARLI mothers and the Environmental Protection Agency's AirNOW monitoring network using inverse distance weighting. We computed sample-level aggregate methylation measures for each of 5 types of genomic regions including genome-wide, open sea, shelf, shore, and island regions. Linear regression was performed for each genomic region; per-sample aggregate methylation measures were modeled as a function of quantitative exposure level with covariate adjustment. In addition, bumphunting was performed to identify differentially methylated regions (DMRs) associated with prenatal O3 and NO2 exposures in each tissue and by sex, with adjustment for technical and biological sources of variation. RESULTS: We identified global and locus-specific changes in DNA methylation related to prenatal exposure to NO2 and O3 in 2 developmentally relevant tissues. Neonates with increased prenatal O3 exposure had lower aggregate levels of DNAm at CpGs located in open sea and shelf regions of the genome. We identified 6 DMRs associated with prenatal NO2 exposure, including 3 sex-specific. An additional 3 sex-specific DMRs were associated with prenatal O3 exposure levels. DMRs initially detected in cord blood samples (n = 4) showed consistent exposure-related changes in DNAm in placenta. However, the DMRs initially detected in placenta (n = 5) did not show DNAm differences in cord blood and, thus, they appear to be tissue-specific. CONCLUSIONS: We observed global, locus, and sex-specific methylation changes associated with prenatal NO2 and O3 exposures. Our findings support DNAm is a biologic target of prenatal air pollutant exposures and highlight epigenetic involvement in sex-specific differential susceptibility to environmental exposure effects in 2 developmentally relevant tissues.

Association of Prenatal Exposure to Ambient and Traffic-Related Air Pollution With Newborn Thyroid Function: Findings From the Children's Health Study.

Importance: Thyroid hormones are critical for fetal growth and development. Prenatal particulate matter (PM) air pollution exposure has been associated with altered newborn thyroid function, but other air pollutants have not been evaluated, and critical windows of exposure are unknown. Objectives: To investigate the association of prenatal exposure to ambient and traffic-related air pollutants with newborn thyroid function and identify critical windows of exposure. Design, Setting, and Participants: This cohort study used data from 2050 participants in the Children's Health Study. Statistical analyses were conducted from 2017 to 2018 using pregnancy and birth data from 1994 to 1997 for a subset of participants recruited from schools in 13 southern California communities in 2002 to 2003 when participants were 5 to 7 years of age. Participants were included in statistical analyses if they could be linked to their newborn blood spot and had complete monthly exposure measures for at least 1 air pollutant across pregnancy. Exposures: Prenatal monthly averages of ambient (PM diameter <2.5 µm [PM2.5] or <10 µm [PM10], nitrogen dioxide, and ozone) and traffic-related (freeway, nonfreeway, and total nitrogen oxides) air pollutant exposures were determined using inverse distance-squared weighting of central monitoring data and the California Line Source Dispersion model, respectively. Main Outcomes and Measures: Newborn heel-stick blood spot total thyroxine (TT4) measures were acquired retrospectively from the California Department of Public Health. Results: Participants included 2050 newborns (50.5% male), with a median (interquartile range) age of 20 (15-29) hours. The majority of newborns were Hispanic white (1202 [58.6%]) or non-Hispanic white (638 [31.1%]). Sixty-six (3.2%) were black and 144 (7.0%) were from other racial/ethnic groups. The mean (SD) newborn TT4 measure was 16.2 (4.3) µg/dL. A 2-SD increase in prenatal PM2.5 (16.3 µg/m3) and PM10 (22.2 µg/m3) was associated with a 1.2-µg/dL (95% CI, 0.5-1.8 µg/dL) and 1.5-µg/dL (95% CI, 0.9-2.1 µg/dL) higher TT4 measure, respectively, in covariate-adjusted linear regression models. Other pollutants were not consistently associated with newborn TT4. Distributed lag models revealed that PM2.5 exposure during months 3 to 7 of pregnancy and PM10 exposure during months 1 to 8 of pregnancy were associated with significantly higher newborn TT4 concentrations (P < .05). Conclusions and Relevance: Prenatal PM exposure, particularly in early pregnancy and midpregnancy, is associated with higher newborn TT4 concentrations. Future studies should assess the health implications of PM-associated differences in newborn TT4 concentrations.

Particulate matter air pollution and liver cancer survival.

Particulate matter (PM) air pollution exposure has been associated with cancer incidence and mortality especially with lung cancer. The liver is another organ possibly affected by PM due to its role in detoxifying xenobiotics absorbed from PM. Various studies have investigated the mechanistic pathways between inhaled pollutants and liver damage, cancer incidence, and tumor progression. However, little is known about the effects of PM on liver cancer survival. Twenty thousand, two hundred and twenty-one California Cancer Registry patients with hepatocellular carcinoma (HCC) diagnosed between 2000 and 2009 were used to examine the effect of exposure to ambient PM with diameter <2.5 µm (PM2.5 ) on HCC survival. Cox proportional hazards models were used to estimate hazard ratios (HRs) relating PM2.5 to all-cause and liver cancer-specific mortality linearly and nonlinearly-overall and stratified by stage at diagnosis (local, regional and distant)-adjusting for potential individual and geospatial confounders.PM2.5 exposure after diagnosis was statistically significantly associated with HCC survival. After adjustment for potential confounders, the all-cause mortality HR associated with a 1 standard deviation (5.0 µg/m3 ) increase in PM2.5 was 1.18 (95% CI: 1.16-1.20); 1.31 (95% CI:1.26-1.35) for local stage, 1.19 (95% CI:1.14-1.23) for regional stage, and 1.05 (95% CI:1.01-1.10) for distant stage. These associations were nonlinear, with substantially larger HRs at higher exposures. The associations between liver cancer-specific mortality and PM2.5 were slightly attenuated compared to all-cause mortality, but with the same patterns.Exposure to elevated PM2.5 after the diagnosis of HCC may shorten survival, with larger effects at higher concentrations.

Longitudinal Associations Between Ambient Air Pollution With Insulin Sensitivity, ß-Cell Function, and Adiposity in Los Angeles Latino Children.

Evidence suggests that ambient air pollution (AAP) exposure may contribute to the development of obesity and type 2 diabetes. The objective of this study was to determine whether exposure to elevated concentrations of nitrogen dioxide (NO2) and particulate matter with aerodynamic diameter <2.5 (PM2.5) had adverse effects on longitudinal measures of insulin sensitivity (SI), ß-cell function, and obesity in children at high risk for developing diabetes. Overweight and obese Latino children (8-15 years; n = 314) were enrolled between 2001 and 2012 from Los Angeles, CA, and followed for an average of 3.4 years (SD 3.1 years). Linear mixed-effects models were fitted to assess relationships between AAP exposure and outcomes after adjusting for covariates including body fat percent. Higher NO2 and PM2.5 were associated with a faster decline in SI and a lower SI at age 18 years, independent of adiposity. NO2 exposure negatively affected ß-cell function, evidenced by a faster decline in disposition index (DI) and a lower DI at age 18 years. Higher NO2 and PM2.5 exposures over follow-up were also associated with a higher BMI at age 18 years. AAP exposure may contribute to development of type 2 diabetes through direct effects on SI and ß-cell function.

Air pollution affects lung cancer survival.

RATIONALE: Exposure to ambient air pollutants has been associated with increased lung cancer incidence and mortality, but due to the high case fatality rate, little is known about the impacts of air pollution exposures on survival after diagnosis. This study aimed to determine whether ambient air pollutant exposures are associated with the survival of patients with lung cancer. METHODS: Participants were 352 053 patients with newly diagnosed lung cancer during 1988-2009 in California, ascertained by the California Cancer Registry. Average residential ambient air pollutant concentrations were estimated for each participant's follow-up period. Cox proportional hazards models were used to estimate HRs relating air pollutant exposures to all-cause mortality overall and stratified by stage (localised only, regional and distant site) and histology (squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma and others) at diagnosis, adjusting for potential individual and area-level confounders. RESULTS: Adjusting for histology and other potential confounders, the HRs associated with 1 SD increases in NO2, O3, PM10, PM2.5 for patients with localised stage at diagnosis were 1.30 (95% CI 1.28 to 1.32), 1.04 (95% CI 1.02 to 1.05), 1.26 (95% CI 1.25 to 1.28) and 1.38 (95% CI 1.35 to 1.41), respectively. Adjusted HRs were smaller in later stages and varied by histological type within stage (p<0.01, except O3). The largest associations were for patients with early-stage non-small cell cancers, particularly adenocarcinomas. CONCLUSIONS: These epidemiological findings support the hypothesis that air pollution exposures after lung cancer diagnosis shorten survival. Future studies should evaluate the impacts of exposure reduction.

Ambient polycyclic aromatic hydrocarbons and pulmonary function in children.

Few studies have examined the relationship between ambient polycyclic aromatic hydrocarbons (PAHs) and pulmonary function in children. Major sources include vehicular emissions, home heating, wildland fires, agricultural burning, and power plants. PAHs are an important component of fine particulate matter that has been linked to respiratory health. This cross-sectional study examines the relationship between estimated individual exposures to the sum of PAHs with 4, 5, or 6 rings (PAH456) and pulmonary function tests (forced expiratory volume in one second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity) in asthmatic and non-asthmatic children. We applied land-use regression to estimate individual exposures to ambient PAHs for averaging periods ranging from 1 week to 1 year. We used linear regression to estimate the relationship between exposure to PAH456 with pre- and postbronchodilator pulmonary function tests in children in Fresno, California (N=297). Among non-asthmatics, there was a statistically significant association between PAH456 during the previous 3 months, 6 months, and 1 year and postbronchodilator FEV1. The magnitude of the association increased with the length of the averaging period ranging from 60 to 110 ml decrease in FEV1 for each 1 ng/m(3) increase in PAH456. There were no associations with PAH456 observed among asthmatic children. We identified an association between annual PAHs and chronic pulmonary function in children without asthma. Additional studies are needed to further explore the association between exposure to PAHs and pulmonary function, especially with regard to differential effects between asthmatic and non-asthmatic children.