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1.  ASTHMA AND SCHOOL COMMUTING TIME 
Objectives
This study examined associations of asthma with school commuting time.
Methods
Time on likely school commute route was used as a proxy for on-road air pollution exposure among 4741 elementary school children at enrollment into the Children's Health Study. Lifetime asthma and severe wheeze (including multiple attacks, nocturnal or with shortness of breath) were reported by parents.
Results
In asthmatic children, severe wheeze was associated with commuting time (odds ratio (OR) 1.54 across the 9-minute 5%-95% exposure distribution; 95% confidence interval (CI) 1.01,2.36). The association was stronger in analysis restricted to asthmatic children with commuting times five minutes or longer (OR 1.97; 95% CI 1.02,3.77). No significant associations were observed with asthma prevalence.
Conclusions
Among asthmatics, severe wheeze was associated with relatively short school commuting times. Further investigation of effects of on-road pollutant exposure is warranted.
doi:10.1097/JOM.0b013e3181ebf1a9
PMCID: PMC4083079  PMID: 20657304
air pollution; asthma; child; epidemiology; traffic; commuting
3.  Exhaled Nitric Oxide, Susceptibility and New-Onset Asthma in the Children’s Health Study 
The European respiratory journal  2010;37(3):523-531.
A substantial body of evidence suggests an etiologic role of inflammation and oxidative/nitrosative stress in asthma pathogenesis. Fractional concentration of nitric oxide in exhaled air (FeNO) may provide a non-invasive marker of oxidative/nitrosative stress and aspects of airway inflammation. We examined whether children with elevated FeNO are at increased risk for new-onset asthma.
We prospectively followed 2206 asthma-free children (age 7–10 years) who participated in the Children’s Health Study. We measured FeNO and followed these children for three years to ascertain incident asthma cases. Cox proportional hazard models were fitted to examine the association between FeNO and new-onset asthma.
We found that FeNO was associated with increased risk of new-onset asthma. Children with the highest quartile of FeNO had more than a two-fold increased risk of new-onset asthma compared to those with the lowest quartile (hazard ratio: 2.1; 95% confidence interval: 1.3–3.5). This effect did not vary by child’s history of respiratory allergic symptoms. However, the effect of elevated FeNO on new-onset asthma was most apparent among those without a parental history of asthma.
Our results indicate that children with elevated FeNO are at increased risk for new-onset asthma, especially if they have no parental history of asthma.
doi:10.1183/09031936.00021210
PMCID: PMC4020940  PMID: 20634264
Incident Asthma; Exhaled Nitric Oxide; Airway Inflammation
4.  Traffic Related Air Pollution, Particulate Matter, and Autism 
JAMA psychiatry  2013;70(1):71-77.
Context
Autism is a heterogeneous disorder with genetic and environmental factors likely contributing to its origins. Examination of hazardous pollutants has suggested the importance of air toxics in autism etiology, yet little research has examined local level air pollution associations using residence-specific exposure assignments.
Objective
To examine the relationship between traffic-related air pollution (TRP), air quality, and autism.
Design, Setting and Population
This study includes data on 279 autism cases and 245 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study in California. The mother’s address from the birth certificate and addresses reported from a residential history questionnaire were used to estimate exposure for each trimester of pregnancy and first year of life. TRP was assigned to each location using a line-source air-quality dispersion model. Regional air pollutant measures were based on the Environmental Protection Agency’s Air Quality System data. Logistic regression models compared estimated and measured pollutant levels for autism cases and typically developing controls.
Main Outcome Measures
Crude and multivariable-adjusted odds ratios (OR) for autism.
Results
Cases were more likely to live at residences in the highest quartile TRP exposure during pregnancy (OR=1.98, 95%CI 1.20–3.31) and the first year of life (OR=3.10, 1.76–5.57) compared to controls. Regional exposure measures of nitrogen dioxide (NO2) and particulate matter less than 2.5 and 10 microns in diameter (PM2.5 and PM10) were also associated with autism during gestation (NO2 OR=1.81/2SD, 95%CI 1.37–3.09; PM2.5 OR=2.08/2SD, 95%CI 1.93–2.25; PM10 OR=2.17/2SD, 95%CI 1.49–3.16) and the first year of life (NO2 OR=2.06, 95%CI 1.37–3.09; PM2.5 OR=2.12, 95%CI 1.45–3.10; PM10 OR=2.14, 95%CI 1.46–3.12).
Conclusions
Exposure to TRP, NO2, PM2.5, and PM10 during pregnancy and the first year of life was associated with autism. Further epidemiological and toxicological examination of likely biological pathways will help determine whether these associations are causal.
doi:10.1001/jamapsychiatry.2013.266
PMCID: PMC4019010  PMID: 23404082
5.  Interaction of the MET Receptor Tyrosine Kinase Gene and Air Pollution Exposure in Autism Spectrum Disorder 
Background
Independent studies report association of autism spectrum disorder with air pollution exposure and a functional promoter variant (rs1858830) in the MET receptor tyrosine kinase (MET) gene. Toxicologic data find altered brain Met expression in mice after prenatal exposure to a model air pollutant. Our objective was to investigate whether air pollution exposure and MET rs1858830 genotype interact to alter ASD risk.
Methods
We studied 252 cases of autism spectrum disorder and 156 typically developing controls the Childhood Autism Risk from Genetics and the Environment Study. Air pollution exposure was assigned for local traffic-related sources and regional sources (particulate matter, nitrogen dioxide and ozone). MET genotype was determined by direct re-sequencing.
Results
Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower pollutant exposures. A statistical test of multiplicative interaction identified a statistically significant effect between NO2 and MET CC genotype (p=0.03)
Conclusions
MET rs1858830 CC genotype and air pollutant exposure may interact to increase autism spectrum disorder risk.
doi:10.1097/EDE.0000000000000030
PMCID: PMC4019012  PMID: 24240654
6.  Inflammatory Cytokine Response to Ambient Particles Varies due to Field Collection Procedures 
In vitro assays of biological activity induced by particulate matter (PM) are a tool for investigating mechanisms of PM health effects. They have potential application to exposure assessment in chronic disease epidemiology. However, there has been little reporting of the impact of real-world PM collection techniques on assay results. Therefore, we examined the effect of sampling duration and postsampling delays in freezing on PM-induced biological activity. Duplicate samples of respirable ambient Los Angeles PM were collected on polyurethane foam filters during 17 days and during three contemporaneous consecutive shorter periods. After collection, one duplicate was stored at ambient temperature for 24 hours before freezing; the other was frozen immediately. Cytokine response (IL-1β, IL-6, IL-8, and TNF-α) to PM aqueous extract was assessed in THP-1 cells, a model for evaluating monocyte/macrophage lineage cell responses. There was consistent 3- to 4-fold variation in PM-induced cytokine levels across the three collection intervals. Compared with levels induced by PM pooled across the three periods, continuously collected PM-induced levels were reduced by 25% (IL-6) to 39% (IL-8). The pattern of cytokine gene expression response was similar. Cytokine level variation by time to freezing was not statistically significant. PM-induced inflammatory response varied substantially over a weekly time scale. We conclude that long PM sampling interval induced less activity than the average of equivalent shorter consecutive sampling intervals. Time to freezing was less important. Implications for development of metrics of long-term spatial variation in biological exposure metrics for study of chronic disease merit further investigation.
doi:10.1165/rcmb.2012-0320OC
PMCID: PMC3653609  PMID: 23306836
air pollution; toxicology; exposure assessment; epidemiology
7.  Childhood Air Pollutant Exposure and Carotid Artery Intima-Media Thickness in Young Adults 
Circulation  2012;126(13):1614-1620.
Background
Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.
Methods and results
The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007–2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and socio-demographic characteristics and a 12-hr fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency’s Air Quality System (AQS) database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (± 54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12) O3 exposure was associated with a 7.8 μm (95% CI −0.3, 15.9) or 10.1 μm (95% CI 1.8, 18.5) higher CIMT, respectively. Lifetime exposure to O3 showed similar but non-significant associations. No associations were observed for PM2.5, PM10 or NO2 although adjustment for these pollutants strengthened the childhood O3 associations.
Conclusion
Childhood exposure to O3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
doi:10.1161/CIRCULATIONAHA.112.096164
PMCID: PMC3474843  PMID: 22896588
atherosclerosis; cardiovascular diseases; carotid arteries; epidemiology; pediatrics
8.  Organized Physical Activity in Young School Children Predicts Subsequent 4-Year Change in Body Mass Index 
Objective
To determine whether participation in organized outdoor team sports and structured indoor non-school activity programs in kindergarten and first grade predicted subsequent 4-year change in Body Mass Index (BMI) across the adiposity rebound period of childhood.
Design
Longitudinal cohort study.
Setting
Forty-five schools in 13 communities across Southern California.
Participants
Largely Hispanic and non-Hispanic white children (N = 4,550; average age at study entry 6.60 years, standard deviation 0.65).
Main Exposures
Parents completed questionnaires assessing physical activity, demographic characteristics and other relevant covariates at baseline. Data on built and social environmental variables were linked to the neighborhood around children’s homes using geographical information systems (GIS).
Main Outcome Measures
Each child’s height and weight were measured annually during 4-years of follow-up.
Results
After adjusting for several confounders, BMI increased at a 0.05 unit per year slower rate for children who participated in outdoor organized team sports at least twice per week as compared to children who did not. For participation in each additional indoor non-school structured activity classes, lessons, and program, BMI increased at a 0.05 unit per year slower rate, and the attained BMI level at age 10 was 0.48 units lower.
Conclusions
Engagement in organized sports and activity programs as early as kindergarten and the first grade may result in smaller increases in BMI during the adiposity rebound period of childhood.
doi:10.1001/archpediatrics.2012.20
PMCID: PMC3415326  PMID: 22869403
9.  Prenatal Exposure to Urban Air Nanoparticles in Mice Causes Altered Neuronal Differentiation and Depression-Like Responses 
PLoS ONE  2013;8(5):e64128.
Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m3) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.
doi:10.1371/journal.pone.0064128
PMCID: PMC3667185  PMID: 23734187
10.  Near-Roadway Pollution and Childhood Asthma: Implications for Developing “Win–Win” Compact Urban Development and Clean Vehicle Strategies 
Environmental Health Perspectives  2012;120(11):1619-1626.
Background: The emerging consensus that exposure to near-roadway traffic-related pollution causes asthma has implications for compact urban development policies designed to reduce driving and greenhouse gases.
Objectives: We estimated the current burden of childhood asthma-related disease attributable to near-roadway and regional air pollution in Los Angeles County (LAC) and the potential health impact of regional pollution reduction associated with changes in population along major traffic corridors.
Methods: The burden of asthma attributable to the dual effects of near-roadway and regional air pollution was estimated, using nitrogen dioxide and ozone as markers of urban combustion-related and secondary oxidant pollution, respectively. We also estimated the impact of alternative scenarios that assumed a 20% reduction in regional pollution in combination with a 3.6% reduction or 3.6% increase in the proportion of the total population living near major roads, a proxy for near-roadway exposure.
Results: We estimated that 27,100 cases of childhood asthma (8% of total) in LAC were at least partly attributable to pollution associated with residential location within 75 m of a major road. As a result, a substantial proportion of asthma-related morbidity is a consequence of near-roadway pollution, even if symptoms are triggered by other factors. Benefits resulting from a 20% regional pollution reduction varied markedly depending on the associated change in near-roadway proximity.
Conclusions: Our findings suggest that there are large and previously unappreciated public health consequences of air pollution in LAC and probably in other metropolitan areas with dense traffic corridors. To maximize health benefits, compact urban development strategies should be coupled with policies to reduce near-roadway pollution exposure.
doi:10.1289/ehp.1104785
PMCID: PMC3556611  PMID: 23008270
air pollution; asthma; burden of disease; children; compact urban growth; risk assessment; vehicle emissions
11.  Parental Stress Increases the Detrimental Effect of Traffic Exposure on Children's Lung Function 
Rationale: Emerging evidence indicates that psychosocial stress enhances the effect of traffic exposure on the development of asthma.
Objectives: We hypothesized that psychosocial stress would also modify the effect of traffic exposure on lung function deficits.
Methods: We studied 1,399 participants in the Southern California Children's Health Study undergoing lung function testing (mean age, 11.2 yr). We used hierarchical mixed models to assess the joint effect of traffic-related air pollution and stress on lung function.
Measurements and Main Results: Psychosocial stress in each child's household was assessed based on parental response to the perceived stress scale (range, 0–16) at study entry. Exposures to nitric oxide, nitrogen dioxide, and total oxides of nitrogen (NOx), surrogates of the traffic-related pollution mixture, were estimated at schools and residences based on a land-use regression model. Among children from high-stress households (parental perceived stress scale >4) deficits in FEV1 of 4.5 (95% confidence interval, −6.5 to −2.4) and of 2.8% (−5.7 to 0.3) were associated with each 21.8 ppb increase in NOx at homes and schools, respectively. These pollutant effects were significantly larger in the high-stress compared with lower-stress households (interaction P value 0.007 and 0.05 for residential and school NOx, respectively). No significant NOx effects were observed in children from low-stress households. A similar pattern of association was observed for FVC. The observed associations for FEV1 and FVC remained after adjusting for sociodemographic factors and after restricting the analysis to children who do not have asthma.
Conclusions: A high-stress home environment is associated with increased susceptibility to lung function effects of air pollution both at home and at school.
doi:10.1164/rccm.201104-0720OC
PMCID: PMC3208647  PMID: 21700914
parental stress; traffic exposure; lung function; children
12.  Glutathione-S-transferase M1 regulation of diesel exhaust particle-induced pro-inflammatory mediator expression in normal human bronchial epithelial cells 
Background
Diesel exhaust particles (DEP) contribute substantially to ambient particulate matter (PM) air pollution in urban areas. Inhalation of PM has been associated with increased incidence of lung disease in susceptible populations. We have demonstrated that the glutathione S-transferase M1 (GSTM1) null genotype could aggravate DEP-induced airway inflammation in human subjects. Given the critical role airway epithelial cells play in the pathogenesis of airway inflammation, we established the GSTM1 deficiency condition in primary bronchial epithelial cells from human volunteers with GSTM1 sufficient genotype (GSTM1+) using GSTM1 shRNA to determine whether GSTM1 deficiency could exaggerate DEP-induced expression of interleukin-8 (IL-8) and IL-1β proteins. Furthermore, the mechanisms underlying GSTM1 regulation of DEP-induced IL-8 and IL-1β expression were also investigated.
Methods
IL-8 and IL-1β protein levels were measured using enzyme-linked immunosorbent assay. GSTM1 deficiency in primary human bronchial epithelial cells was achieved using lentiviral GSTM1 shRNA particles and verified using real-time polymerase chain reaction and immunoblotting. Intracellular reactive oxygen species (ROS) production was evaluated using flow cytometry. Phosphorylation of protein kinases was detected using immunoblotting.
Results
Exposure of primary human bronchial epithelial cells (GSTM1+) to 25-100 μg/ml DEP for 24 h significantly increased IL-8 and IL-1β protein expression. Knockdown of GSTM1 in these cells further elevated DEP-induced IL-8 and IL-1β expression, implying that GSTM1 deficiency aggravated DEP-induced pro-inflammatory response. DEP stimulation induced the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, the downstream kinase of phosphoinositide 3-kinase (PI3K), in GSTM1+ bronchial epithelial cells. Pharmacological inhibition of ERK kinase and PI3K activity blocked DEP-induced IL-8 and IL-1β expression. DEP-induced ERK and Akt phosphorylation could be increased by GSTM1 knockdown. In addition, pretreatment of HBEC with the antioxidant N-acetyl cysteine significantly inhibited DEP-induced ERK and Akt phosphorylation, and subsequent IL-8 and IL-1β expression.
Conclusion
GSTM1 regulates DEP-induced IL-8 and IL-1β expression in primary human bronchial epithelial cells by modulation of ROS, ERK and Akt signaling.
doi:10.1186/1743-8977-9-31
PMCID: PMC3480908  PMID: 22867088
Diesel exhaust particles; ROS; GSTM1; ERK; Akt
13.  Ethnic Differences in the Effect of Asthma on Pulmonary Function in Children 
Rationale: The impact of asthma on chronic lung function deficits is well known. However, there has been little study of ethnic differences in these asthma-associated deficits.
Objectives: To examine whether there are ethnic differences in the effects of asthma on children's lung function.
Methods: We evaluated the impact of asthma on lung function in 3,245 Hispanic and non-Hispanic white school children (age 10–18 yr) in a longitudinal analysis of the Southern California Children's Health Study. Sex-specific mixed-effects regression spline models were fitted separately for each ethnic group.
Measurements and Main Results: Large deficits in flows were observed among children with asthma diagnosed before age 4 years regardless of ethnicity. Hispanic girls with asthma had greater deficits in flows than non-Hispanic girls and were largest for maximal midexpiratory flow (−5.13% compared with −0.58%, respectively). A bigger impact of asthma in Hispanic girls was also found for FEV1, FEF75, and PEF (P value 0.04, 0.07, and 0.005, respectively). These ethnic differences were limited to girls diagnosed after age 4 years. In boys, asthma was also associated with greater deficits in flows among Hispanic than in non-Hispanic white children (differences that were not statistically significant). Ethnic differences in prevalence of pets and pests in the home, health insurance coverage, parental education, and smoking did not explain the pattern of lung function differences.
Conclusions: Larger asthma-associated lung function deficits in Hispanics, especially among girls, merit further investigation to determine public health implications and to identify causes amenable to intervention.
doi:10.1164/rccm.200912-1863OC
PMCID: PMC3081280  PMID: 20889910
Hispanics; non-Hispanic whites; pulmonary function; asthma
14.  Residential Proximity to Freeways and Autism in the CHARGE Study 
Environmental Health Perspectives  2010;119(6):873-877.
Background
Little is known about environmental causes and contributing factors for autism. Basic science and epidemiologic research suggest that oxidative stress and inflammation may play a role in disease development. Traffic-related air pollution, a common exposure with established effects on these pathways, contains substances found to have adverse prenatal effects.
Objectives
We examined the association between autism and proximity of residence to freeways and major roadways during pregnancy and near the time of delivery, as a surrogate for air pollution exposure.
Methods
Data were from 304 autism cases and 259 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. The mother’s address recorded on the birth certificate and trimester-specific addresses derived from a residential history obtained by questionnaire were geocoded, and measures of distance to freeways and major roads were calculated using ArcGIS software. Logistic regression models compared residential proximity to freeways and major roads for autism cases and typically developing controls.
Results
Adjusting for sociodemographic factors and maternal smoking, maternal residence at the time of delivery was more likely be near a freeway (≤ 309 m) for cases than for controls [odds ratio (OR) = 1.86; 95% confidence interval (CI), 1.04–3.45]. Autism was also associated with residential proximity to a freeway during the third trimester (OR = 2.22; CI, 1.16–4.42). After adjustment for socioeconomic and sociodemographic characteristics, these associations were unchanged. Living near other major roads at birth was not associated with autism.
Conclusions
Living near a freeway was associated with autism. Examination of associations with measured air pollutants is needed.
doi:10.1289/ehp.1002835
PMCID: PMC3114825  PMID: 21156395
autism; epidemiology; gene-environment interaction; roadway proximity; traffic emissions
15.  Performances of Different Global Positioning System Devices for Time-Location Tracking in Air Pollution Epidemiological Studies 
Background:
People’s time-location patterns are important in air pollution exposure assessment because pollution levels may vary considerably by location. A growing number of studies are using global positioning systems (GPS) to track people’s time-location patterns. Many portable GPS units that archive location are commercially available at a cost that makes their use feasible for epidemiological studies.
Methods:
We evaluated the performance of five portable GPS data loggers and two GPS cell phones by examining positional accuracy in typical locations (indoor, outdoor, in-vehicle) and factors that influence satellite reception (building material, building type), acquisition time (cold and warm start), battery life, and adequacy of memory for data storage. We examined stationary locations (eg, indoor, outdoor) and mobile environments (eg, walking, traveling by vehicle or bus) and compared GPS locations to highly-resolved US Geological Survey (USGS) and Digital Orthophoto Quarter Quadrangle (DOQQ) maps.
Results:
The battery life of our tested instruments ranged from <9 hours to 48 hours. The acquisition of location time after startup ranged from a few seconds to >20 minutes and varied significantly by building structure type and by cold or warm start. No GPS device was found to have consistently superior performance with regard to spatial accuracy and signal loss. At fixed outdoor locations, 65%–95% of GPS points fell within 20-m of the corresponding DOQQ locations for all the devices. At fixed indoor locations, 50%–80% of GPS points fell within 20-m of the corresponding DOQQ locations for all the devices except one. Most of the GPS devices performed well during commuting on a freeway, with >80% of points within 10-m of the DOQQ route, but the performance was significantly impacted by surrounding structures on surface streets in highly urbanized areas.
Conclusions:
All the tested GPS devices had limitations, but we identified several devices which showed promising performance for tracking subjects’ time location patterns in epidemiological studies.
doi:10.4137/EHI.S6246
PMCID: PMC3000001  PMID: 21151593
global positioning systems; GPS; time activity
16.  Relationship between air pollution, lung function and asthma in adolescents 
Thorax  2007;62(11):957-963.
Background
The interrelationships between air pollution, lung function and the incidence of childhood asthma have yet to be established. A study was undertaken to determine whether lung function is associated with new onset asthma and whether this relationship varies by exposure to ambient air pollutants.
Methods
A cohort of children aged 9–10 years without asthma or wheeze at study entry were identified from the Children's Health Study and followed for 8 years. The participants resided in 12 communities with a wide range of ambient air pollutants that were measured continuously. Spirometric testing was performed and a medical diagnosis of asthma was ascertained annually. Proportional hazard regression models were fitted to investigate the relationship between lung function at study entry and the subsequent development of asthma and to determine whether air pollutants modify these associations.
Results
The level of airway flow was associated with new onset asthma. Over the 10th–90th percentile range of forced expiratory flow over the mid‐range of expiration (FEF25–75, 57.1%), the hazard ratio (HR) of new onset asthma was 0.50 (95% CI 0.35 to 0.71). This protective effect of better lung function was reduced in children exposed to higher levels of particulate matter with an aerodynamic diameter <2.5 μm (PM2.5). Over the 10th–90th percentile range of FEF25–75, the HR of new onset asthma was 0.34 (95% CI 0.21 to 0.56) in communities with low PM2.5 (<13.7 μg/m3) and 0.76 (95% CI 0.45 to 1.26) in communities with high PM2.5 (⩾13.7 μg/m3). A similar pattern was observed for forced expiratory volume in 1 s. Little variation in HR was observed for ozone.
Conclusion
Exposure to high levels of PM2.5 attenuates the protective effect of better lung function against new onset asthma.
doi:10.1136/thx.2007.078964
PMCID: PMC2117135  PMID: 17517830
17.  Obesity, Waist Size, and Prevalence of Current Asthma in the California Teachers Study Cohort 
Thorax  2009;64(10):889.
Obesity is a risk factor for asthma, particularly in women, but few cohort studies have evaluated abdominal obesity, which reflects metabolic differences in visceral fat known to influence systemic inflammation. We examined the relationships of asthma prevalence with measures of abdominal obesity and adult weight gain, in addition to body mass index (BMI), in a large cohort of female teachers. We calculated prevalence odds ratios (ORs) for current asthma using multivariable linear modeling, adjusting for age, smoking, and race/ethnicity. Of the 88,304 women in the analyses, 13% (11,500) were obese (BMI ≥ 30 kg/m2) at baseline; 1,334 were extremely obese (BMI ≥ 40). Compared to those of normal weight, the adjusted OR for adult-onset asthma increased from 1.40 (95% confidence interval (CI): 1.31, 1.49) for overweight women to 3.30 (95% CI: 2.85, 3.82) for extremely obese women. Large waist circumference (> 88 cm) was associated with increased asthma prevalence even among women with a normal BMI (OR = 1.37, 95% CI: 1.18, 1.59). Among obese women, the OR for asthma was greater among those who were also abdominally obese compared to women whose waist was ≤ 88 cm (2.36 vs. 1.57). Obese and overweight women were at greater risk of severe asthma episodes, measured by urgent medical visits and hospitalizations. This study confirms the association between excess weight and asthma severity and prevalence, and showed that a large waist was associated with increased asthma prevalence even among women considered to have normal body weight.
doi:10.1136/thx.2009.114579
PMCID: PMC2813683  PMID: 19706838
Asthma; Body Fat Distribution; Body Mass Index; Cohort Studies; Obesity; Prevalence
18.  Childhood Incident Asthma and Traffic-Related Air Pollution at Home and School 
Environmental Health Perspectives  2010;118(7):1021-1026.
Background
Traffic-related air pollution has been associated with adverse cardiorespiratory effects, including increased asthma prevalence. However, there has been little study of effects of traffic exposure at school on new-onset asthma.
Objectives
We evaluated the relationship of new-onset asthma with traffic-related pollution near homes and schools.
Methods
Parent-reported physician diagnosis of new-onset asthma (n = 120) was identified during 3 years of follow-up of a cohort of 2,497 kindergarten and first-grade children who were asthma- and wheezing-free at study entry into the Southern California Children’s Health Study. We assessed traffic-related pollution exposure based on a line source dispersion model of traffic volume, distance from home and school, and local meteorology. Regional ambient ozone, nitrogen dioxide (NO2), and particulate matter were measured continuously at one central site monitor in each of 13 study communities. Hazard ratios (HRs) for new-onset asthma were scaled to the range of ambient central site pollutants and to the residential interquartile range for each traffic exposure metric.
Results
Asthma risk increased with modeled traffic-related pollution exposure from roadways near homes [HR 1.51; 95% confidence interval (CI), 1.25–1.82] and near schools (HR 1.45; 95% CI, 1.06–1.98). Ambient NO2 measured at a central site in each community was also associated with increased risk (HR 2.18; 95% CI, 1.18–4.01). In models with both NO2 and modeled traffic exposures, there were independent associations of asthma with traffic-related pollution at school and home, whereas the estimate for NO2 was attenuated (HR 1.37; 95% CI, 0.69–2.71).
Conclusions
Traffic-related pollution exposure at school and homes may both contribute to the development of asthma.
doi:10.1289/ehp.0901232
PMCID: PMC2920902  PMID: 20371422
air pollution; asthma; child; epidemiology; vehicular traffic
19.  Glutathione-S-Transferase (GST) P1, GSTM1, Exercise, Ozone and Asthma Incidence in School Children 
Thorax  2008;64(3):197-202.
Background
Because asthma has been associated with exercise and ozone exposure, an association likely mediated by oxidative stress, we hypothesized that GSTP1, GSTM1, exercise and ozone exposure have inter-related effects on asthma pathogenesis.
Methods
We examined associations of the well characterized null variant of GSTM1 and four SNPs that characterized common variation in GSTP1 with new-onset asthma in a cohort of 1,610 school children. Children’s exercise and ozone-exposure status were classified using participation in team sports and community-specific ozone levels, respectively.
Results
A two SNP model (rs6591255, rs1695 [Ile105Val]) best captured the association between GSTP1 and asthma. Compared to children with common alleles for both the SNPs, the risk of asthma was lower for those with the Val allele of Ile105Val (HR 0.60, 95% CI 0.4, 0.8) and higher for the variant allele of rs6591255 (HR 1.40, 95%CI 1.1–1.9). Asthma risk increased with level of exercise among ile105 homozygotes but not among those with at least one val105 allele (interaction p-value=0.02). Risk was highest among ile105 homozygotes who participated in ≥3 sports in the high-ozone communities (HR: 6.15, 95%CI: 2.2–7.4). GSTM1 null was independently associated with asthma and showed little variation with air pollution or GSTP1 genotype. These results were consistent in two independent fourth-grade cohorts in the study population recruited in 1993 and 1996.
Conclusion
Children who inherit a val105 variant allele may be protected from the increased risk of asthma associated with exercise, especially in high-ozone communities. GSTM1 null genotype was associated with increased risk of asthma.
doi:10.1136/thx.2008.099366
PMCID: PMC2738935  PMID: 18988661
Oxidative stress; Candidate gene; Asthma genetics; Gene-environmental interaction; Air pollution
20.  Spatial analysis of air pollution and childhood asthma in Hamilton, Canada: comparing exposure methods in sensitive subgroups 
Environmental Health  2009;8:14.
Background
Variations in air pollution exposure within a community may be associated with asthma prevalence. However, studies conducted to date have produced inconsistent results, possibly due to errors in measurement of the exposures.
Methods
A standardized asthma survey was administered to children in grades one and eight in Hamilton, Canada, in 1994–95 (N ~1467). Exposure to air pollution was estimated in four ways: (1) distance from roadways; (2) interpolated surfaces for ozone, sulfur dioxide, particulate matter and nitrous oxides from seven to nine governmental monitoring stations; (3) a kriged nitrogen dioxide (NO2) surface based on a network of 100 passive NO2 monitors; and (4) a land use regression (LUR) model derived from the same monitoring network. Logistic regressions were used to test associations between asthma and air pollution, controlling for variables including neighbourhood income, dwelling value, state of housing, a deprivation index and smoking.
Results
There were no significant associations between any of the exposure estimates and asthma in the whole population, but large effects were detected the subgroup of children without hayfever (predominately in girls). The most robust effects were observed for the association of asthma without hayfever and NO2LUR OR = 1.86 (95%CI, 1.59–2.16) in all girls and OR = 2.98 (95%CI, 0.98–9.06) for older girls, over an interquartile range increase and controlling for confounders.
Conclusion
Our findings indicate that traffic-related pollutants, such as NO2, are associated with asthma without overt evidence of other atopic disorders among female children living in a medium-sized Canadian city. The effects were sensitive to the method of exposure estimation. More refined exposure models produced the most robust associations.
doi:10.1186/1476-069X-8-14
PMCID: PMC2669065  PMID: 19338672
21.  Ozone, Oxidant Defense Genes, and Risk of Asthma during Adolescence 
Rationale: Although oxidative stress is a cardinal feature of asthma, the roles of oxidant air pollutants and antioxidant genes heme oxygenase 1 (HMOX-1), catalase (CAT), and manganese superoxide dismutase (MNSOD) in asthma pathogenesis have yet to be determined.
Objectives: We hypothesized that the functional polymorphisms of HMOX-1 ([GT]n repeat), CAT (−262C>T −844C>T), and MNSOD (Ala-9Val) are associated with new-onset asthma, and the effects of these variants vary by exposure to ozone, a potent oxidant air pollutant.
Methods: We assessed this hypothesis in a population-based cohort of non-Hispanic (n = 1,125) and Hispanic white (n = 586) children who resided in 12 California communities and who were followed annually for 8 years to ascertain new-onset asthma.
Measurements and Main Results: Air pollutants were continuously measured in each of the study communities during the 8 years of study follow-up. HMOX-1 “short” alleles (<23 repeats) were associated with a reduced risk for new-onset asthma among non-Hispanic whites (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41–0.99). This protective effect was largest in children residing in low-ozone communities (HR, 0.48; 95% CI, 0.25–0.91) (interaction P value = 0.003). Little evidence for an association with HMOX-1 was observed among Hispanic children. In contrast, Hispanic children with a variant of the CAT-262 “T” allele (CT or TT) had an increased risk for asthma (HR, 1.78; P value = 0.01). The effects of these polymorphisms were not modified by personal smoking or secondhand-smoke exposure.
Conclusions: Functional promoter variants in CAT and HMOX-1 showed ethnicity-specific associations with new-onset asthma. Oxidant gene protection was restricted to children living in low-ozone communities.
doi:10.1164/rccm.200706-863OC
PMCID: PMC2258440  PMID: 18048809
asthma; catalase; heme oxygenase-1; MnSOD; oxidative stress; ozone
22.  Rodent Allergen in Los Angeles Inner City Homes of Children with Asthma 
Journal of Urban Health   2007;85(1):52-61.
Recent studies have examined the presence of mouse allergen in inner city children with asthma. Researchers have found high levels of rodent allergen in homes sampled in the northeast and midwest United States, but there has been considerable variation between cities, and there have been few studies conducted in western states. We evaluated the frequency of rodent sightings and detectable mouse allergen and the housing conditions associated with these outcomes in inner city homes in Los Angeles. Two hundred and two families of school children, ages 6–16 living in inner city neighborhoods, participated in the study. Families were predominantly Latino (94%), and Spanish speaking (92%). At study entry, parents completed a home assessment questionnaire, and staff conducted a home evaluation and collected kitchen dust, which was analyzed for the presence of mouse allergen. Fifty-one percent of homes had detectable allergen in kitchen dust. All 33 families who reported the presence of rodents had detectable allergen in the home and were also more likely to have increased levels of allergen compared to those who did not report rodents. Unwashed dishes or food crumbs, lack of a working vacuum, and a caretaker report of a smoker in the home were all significantly associated with a greater risk of rodent sightings or detectable allergen (P < 0.05). Detached homes were significantly more likely to have detectable allergen. The prevalence of allergen is common enough that it may have public health implications for asthmatic children, and detectable allergen was not routinely identified based on rodent sightings. Many of the predictors of rodent allergen are amenable to low-cost interventions that can be integrated with other measures to reduce exposure to indoor allergens.
doi:10.1007/s11524-007-9232-0
PMCID: PMC2430140  PMID: 18004665
Asthma; Mouse allergen; House dust; Rodent; Environment
23.  Transforming Growth Factor-β1 C-509T Polymorphism, Oxidant Stress, and Early-Onset Childhood Asthma 
Rationale: Transforming growth factor (TGF)-β1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-β1 gene expression. We hypothesized that the effects of functional TGF-β1 variants on asthma occurrence vary by these exposures.
Objectives: We tested these hypotheses among 3,023 children who participated in the Children's Health Study.
Methods: Tagging single-nucleotide polymorphisms rs4803457 C>T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry.
Measurements and Main Results: Children with the −509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11–2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the −509CC/CT genotype with no in utero exposure to maternal smoking, those with the −509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46–7.80; interaction, P = 0.11). The association between TGF-β1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P = 0.02). Children with the −509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29–7.44) compared with children with CC/CT genotype living > 1500 m from a freeway.
Conclusions: Children with the TGF-β1 −509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.
doi:10.1164/rccm.200704-561OC
PMCID: PMC2176104  PMID: 17673695
maternal smoking; traffic; asthma; genetics; gene–environment interaction; association study
24.  Traffic-Related Air Pollution and Asthma Onset in Children: A Prospective Cohort Study with Individual Exposure Measurement 
Environmental Health Perspectives  2008;116(10):1433-1438.
Background
The question of whether air pollution contributes to asthma onset remains unresolved.
Objectives
In this study, we assessed the association between asthma onset in children and traffic-related air pollution.
Methods
We selected a sample of 217 children from participants in the Southern California Children’s Health Study, a prospective cohort designed to investigate associations between air pollution and respiratory health in children 10–18 years of age. Individual covariates and new asthma incidence (30 cases) were reported annually through questionnaires during 8 years of follow-up. Children had nitrogen dioxide monitors placed outside their home for 2 weeks in the summer and 2 weeks in the fall–winter season as a marker of traffic-related air pollution. We used multilevel Cox models to test the associations between asthma and air pollution.
Results
In models controlling for confounders, incident asthma was positively associated with traffic pollution, with a hazard ratio (HR) of 1.29 [95% confidence interval (CI), 1.07–1.56] across the average within-community interquartile range of 6.2 ppb in annual residential NO2. Using the total interquartile range for all measurements of 28.9 ppb increased the HR to 3.25 (95% CI, 1.35–7.85).
Conclusions
In this cohort, markers of traffic-related air pollution were associated with the onset of asthma. The risks observed suggest that air pollution exposure contributes to new-onset asthma.
doi:10.1289/ehp.10968
PMCID: PMC2569108  PMID: 18941591
air pollution; asthma onset; children; nitrogen dioxide
25.  Health Effects of the 2003 Southern California Wildfires on Children 
Rationale: In late October 2003, Southern California wildfires burned more than 3,000 km2. The wildfires produced heavy smoke that affected several communities participating in the University of Southern California Children's Health Study (CHS).
Objectives: To study the acute effects of fire smoke on the health of CHS participants.
Methods: A questionnaire was used to assess smoke exposure and occurrence of symptoms among CHS high-school students (n = 873; age, 17–18 yr) and elementary-school children (n = 5,551; age, 6–7 yr), in a total of 16 communities. Estimates of particulate matter (PM10) concentrations during the 5 d with the highest fire activity were used to characterize community smoke level.
Main Results: All symptoms (nose, eyes, and throat irritations; cough; bronchitis; cold; wheezing; asthma attacks), medication usage, and physician visits were associated with individually reported exposure differences within communities. Risks increased monotonically with the number of reported smoky days. For most outcomes, reporting rates between communities were also associated with the fire-related PM10 levels. Associations tended to be strongest among those without asthma. Individuals with asthma were more likely to take preventive action, such as wearing masks or staying indoors during the fire.
Conclusions: Exposure to wildfire smoke was associated with increased eye and respiratory symptoms, medication use, and physician visits.
doi:10.1164/rccm.200604-519OC
PMCID: PMC2648104  PMID: 16946126
air pollution; asthma; sore throat; wheezing

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