Long-Term Exposure to Low-Level PM2.5 and Mortality: Investigation of Heterogeneity by Harmonizing Analyses in Large Cohort Studies in Canada, United States, and Europe.

BACKGROUND: Studies across the globe generally reported increased mortality risks associated with particulate matter with aerodynamic diameter ≤2.5µm (PM2.5) exposure with large heterogeneity in the magnitude of reported associations and the shape of concentration-response functions (CRFs). We aimed to evaluate the impact of key study design factors (including confounders, applied exposure model, population age, and outcome definition) on PM2.5 effect estimates by harmonizing analyses on three previously published large studies in Canada [Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE), 1991-2016], the United States (Medicare, 2000-2016), and Europe [Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), 2000-2016] as much as possible. METHODS: We harmonized the study populations to individuals 65+ years of age, applied the same satellite-derived PM2.5 exposure estimates, and selected the same sets of potential confounders and the same outcome. We evaluated whether differences in previously published effect estimates across cohorts were reduced after harmonization among these factors. Additional analyses were conducted to assess the influence of key design features on estimated risks, including adjusted covariates and exposure assessment method. A combined CRF was assessed with meta-analysis based on the extended shape-constrained health impact function (eSCHIF). RESULTS: More than 81 million participants were included, contributing 692 million person-years of follow-up. Hazard ratios and 95% confidence intervals (CIs) for all-cause mortality associated with a 5-µg/m3 increase in PM2.5 were 1.039 (1.032, 1.046) in MAPLE, 1.025 (1.021, 1.029) in Medicare, and 1.041 (1.014, 1.069) in ELAPSE. Applying a harmonized analytical approach marginally reduced difference in the observed associations across the three studies. Magnitude of the association was affected by the adjusted covariates, exposure assessment methodology, age of the population, and marginally by outcome definition. Shape of the CRFs differed across cohorts but generally showed associations down to the lowest observed PM2.5 levels. A common CRF suggested a monotonically increased risk down to the lowest exposure level. https://doi.org/10.1289/EHP12141.

Mortality and Morbidity Effects of Long-Term Exposure to Low-Level PM2.5, BC, NO2, and O3: An Analysis of European Cohorts in the ELAPSE Project.

INTRODUCTION: Epidemiological cohort studies have consistently found associations between long-term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that these associations may be nonlinear and may persist at very low concentrations. Studies conducted in North America in particular have suggested that associations with mortality persisted at concentrations of particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) well below current air quality standards and guidelines. The uncertainty about the shape of the concentration-response function at the low end of the concentration distribution, related to the scarcity of observations in the lowest range, was the basis of the current project. Previous studies have focused on PM2.5, but increasingly associations with nitrogen dioxide (NO2) are being reported, particularly in studies that accounted for the fine spatial scale variation of NO2. Very few studies have evaluated the effects of long-term exposure to low concentrations of ozone (O3). Health effects of black carbon (BC), representing primary combustion particles, have not been studied in most large cohort studies of PM2.5. Cohort studies assessing health effects of particle composition, including elements from nontailpipe traffic emissions (iron, copper, and zinc) and secondary aerosol (sulfur) have been few in number and reported inconsistent results. The overall objective of our study was to investigate the shape of the relationship between long-term exposure to four pollutants (PM2.5, NO2, BC, and O3) and four broad health effect categories using a number of different methods to characterize the concentration-response function (i.e., linear, nonlinear, or threshold). The four health effect categories were (1) natural- and cause-specific mortality including cardiovascular and nonmalignant as well as malignant respiratory and diabetes mortality; and morbidity measured as (2) coronary and cerebrovascular events; (3) lung cancer incidence; and (4) asthma and chronic obstructive pulmonary disease (COPD) incidence. We additionally assessed health effects of PM2.5 composition, specifically the copper, iron, zinc, and sulfur content of PM2,5. METHODS: We focused on analyses of health effects of air pollutants at low concentrations, defined as less than current European Union (EU) Limit Values, U.S. Environmental Protection Agency (U.S. EPA), National Ambient Air Quality Standards (NAAQS), and/or World Health Organization (WHO) Air Quality Guideline values for PM2.5, NO2, and O3. We address the health effects at low air pollution levels by performing new analyses within selected cohorts of the ESCAPE study (European Study of Cohorts for Air Pollution Effects; Beelen et al. 2014a) and within seven very large European administrative cohorts. By combining well-characterized ESCAPE cohorts and large administrative cohorts in one study the strengths and weaknesses of each approach can be addressed. The large administrative cohorts are more representative of national or citywide populations, have higher statistical power, and can efficiently control for area-level confounders, but have fewer possibilities to control for individual-level confounders. The ESCAPE cohorts have detailed information on individual confounders, as well as country-specific information on area-level confounding. The data from the seven included ESCAPE cohorts and one additional non-ESCAPE cohort have been pooled and analyzed centrally. More than 300,000 adults were included in the pooled cohort from existing cohorts in Sweden, Denmark, Germany, the Netherlands, Austria, France, and Italy. Data from the administrative cohorts have been analyzed locally, without transfer to a central database. Privacy regulations prevented transfer of data from administrative cohorts to a central database. More than 28 million adults were included from national administrative cohorts in Belgium, Denmark, England, the Netherlands, Norway, and Switzerland as well as an administrative cohort in Rome, Italy. We developed central exposure assessment using Europewide hybrid land use regression (LUR) models, which incorporated European routine monitoring data for PM2.5, NO2, and O3, and ESCAPE monitoring data for BC and PM2.5 composition, land use, and traffic data supplemented with satellite observations and chemical transport model estimates. For all pollutants, we assessed exposure at a fine spatial scale, 100 × 100 m grids. These models have been applied to individual addresses of all cohorts including the administrative cohorts. In sensitivity analyses, we applied the PM2.5 models developed within the companion HEI-funded Canadian MAPLE study (Brauer et al. 2019) and O3 exposures on a larger spatial scale for comparison with previous studies. Identification of outcomes included linkage with mortality, cancer incidence, hospital discharge registries, and physician-based adjudication of cases. We analyzed natural-cause, cardiovascular, ischemic heart disease, stroke, diabetes, cardiometabolic, respiratory, and COPD mortality. We also analyzed lung cancer incidence, incidence of coronary and cerebrovascular events, and incidence of asthma and COPD (pooled cohort only). We applied the Cox proportional hazard model with increasing control for individual- and area-level covariates to analyze the associations between air pollution and mortality and/or morbidity for both the pooled cohort and the individual administrative cohorts. Age was used as the timescale because of evidence that this results in better adjustment for potential confounding by age. Censoring occurred at the time of the event of interest, death from other causes, emigration, loss to follow-up for other reasons, or at the end of follow-up, whichever came first. A priori we specified three confounder models, following the modeling methods of the ESCAPE study. Model 1 included only age (time axis), sex (as strata), and calendar year of enrollment. Model 2 added individual-level variables that were consistently available in the cohorts contributing to the pooled cohort or all variables available in the administrative cohorts, respectively. Model 3 further added area-level socioeconomic status (SES) variables. A priori model 3 was selected as the main model. All analyses in the pooled cohort were stratified by subcohort. All analyses in the administrative cohorts accounted for clustering of the data in neighborhoods by adjusting the variance of the effect estimates. The main exposure variable we analyzed was derived from the Europewide hybrid models based on 2010 monitoring data. Sensitivity analyses were conducted using earlier time periods, time-varying exposure analyses, local exposure models, and the PM2.5 models from the Canadian MAPLE project. We first specified linear single-pollutant models. Two-pollutant models were specified for all combinations of the four main pollutants. Two-pollutant models for particle composition were analyzed with PM2.5 and NO2 as the second pollutant. We then investigated the shape of the concentration-response function using natural splines with two, three, and four degrees of freedom; penalized splines with the degrees of freedom determined by the algorithm and shape-constrained health impact functions (SCHIF) using confounder model 3. Additionally, we specified linear models in subsets of the concentration range, defined by removing concentrations above a certain value from the analysis, such as for PM2.5 25 µg/m3 (EU limit value), 20, 15, 12 µg/m3 (U.S. EPA National Ambient Air Quality Standard), and 10 µg/m3 (WHO Air Quality Guideline value). Finally, threshold models were evaluated to investigate whether the associations persisted below specific concentration values. For PM2.5, we evaluated 10, 7.5, and 5 µg/m3 as potential thresholds. Performance of threshold models versus the corresponding no-threshold linear model were evaluated using the Akaike information criterion (AIC). RESULTS: In the pooled cohort, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values (25 µg/m3 and 40 µg/m3, respectively). More than 50,000 had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3). More than 25,000 subjects had a residential PM2.5 exposure below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and diabetes mortality. In our main model, the hazard ratios (HRs) (95% [confidence interval] CI) were 1.13 (CI = 1.11, 1.16) for an increase of 5 µg/m3 PM2.5, 1.09 (CI = 1.07, 1.10) for an increase of 10 µg/m3 NO2, and 1.08 (CI = 1.06, 1.10) for an increase of 0.5 × 10-5/m BC for natural-cause mortality. The highest HRs were found for diabetes mortality. Associations with O3 were negative, both in the fine spatial scale of the main ELAPSE model and in large spatial scale exposure models. For PM2.5, NO2, and BC, we generally observed a supralinear association with steeper slopes at low exposures and no evidence of a concentration below which no association was found. Subset analyses further confirmed that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. HRs were similar to the full cohort HRs for subjects with exposures below the EU limit values for PM2.5 and NO2, the U.S. NAAQS values for PM2.5, and the WHO guidelines for PM2.5 and NO2. The mortality associations were robust to alternative specifications of exposure, including different time periods, PM2.5 from the MAPLE project, and estimates from the local ESCAPE model. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. HRs in two-pollutant models were attenuated but remained elevated and statistically significant forPM2.5 and NO2. In two-pollutant models of PM2.5 and NO2 HRs for natural-cause mortality were 1.08 (CI = 1.05, 1.11) for PM2.5 and 1.05 (CI = 1.03, 1.07) for NO2. Associations with O3 were attenuated but remained negative in two-pollutant models with NO2, BC, and PM2.5. We found significant positive associations between PM2.5, NO2, and BC and incidence of stroke and asthma and COPD hospital admissions. Furthermore, NO2 was significantly related to acute coronary heart disease and PM2.5 was significantly related to lung cancer incidence. We generally observed linear to supralinear associations with no evidence of a threshold, with the exception of the association between NO2 and acute coronary heart disease, which was sublinear. Subset analyses documented that associations remained even with PM2.5 below 20 µg/m3 and possibly 12 µg/m3. Associations remained even when NO2 was below 30 µg/m3 and in some cases 20 µg/m3. In two-pollutant models, NO2 was most consistently associated with acute coronary heart disease, stroke, asthma, and COPD hospital admissions. PM2.5 was not associated with these outcomes in two-pollutant models with NO2. PM2.5 was the only pollutant that was associated with lung cancer incidence in two-pollutant models. Associations with O3 were negative though generally not statistically significant. In the administrative cohorts, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values. More than 3.9 million subjects had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3) and more than 1.9 million had residential PM2.5 exposures below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and lung cancer mortality, with moderate to high heterogeneity between cohorts. We found positive but statistically nonsignificant associations with diabetes mortality. In our main model meta-analysis, the HRs (95% CI) for natural-cause mortality were 1.05 (CI = 1.02, 1.09) for an increase of 5 µg/m3 PM2.5, 1.04 (CI = 1.02, 1.07) for an increase of 10 µg/m3 NO2, and 1.04 (CI = 1.02, 1.06) for an increase of 0.5 × 10-5/m BC, and 0.95 (CI = 0.93, 0.98) for an increase of 10 µg/m3 O3. The shape of the concentration-response functions differed between cohorts, though the associations were generally linear to supralinear, with no indication of a level below which no associations were found. Subset analyses documented that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. BC and NO2 remained significantly associated with mortality in two-pollutant models with PM2.5 and O3. The PM2.5 HR attenuated to unity in a two-pollutant model with NO2. The negative O3 association was attenuated to unity and became nonsignificant. The mortality associations were robust to alternative specifications of exposure, including time-varying exposure analyses. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. Effect estimates in the youngest participants (<65 years at baseline) were much larger than in the elderly (>65 years at baseline). Effect estimates obtained with the ELAPSE PM2.5 model did not differ from the MAPLE PM2.5 model on average, but in individual cohorts, substantial differences were found. CONCLUSIONS: Long-term exposure to PM2.5, NO2, and BC was positively associated with natural-cause and cause-specific mortality in the pooled cohort and the administrative cohorts. Associations were found well below current limit values and guidelines for PM2.5 and NO2. Associations tended to be supralinear, with steeper slopes at low exposures with no indication of a threshold. Two-pollutant models documented the importance of characterizing the ambient mixture with both NO2 and PM2.5. We mostly found negative associations with O3. In two-pollutant models with NO2, the negative associations with O3 were attenuated to essentially unity in the mortality analysis of the administrative cohorts and the incidence analyses in the pooled cohort. In the mortality analysis of the pooled cohort, significant negative associations with O3 remained in two-pollutant models. Long-term exposure to PM2.5, NO2, and BC was also positively associated with morbidity outcomes in the pooled cohort. For stroke, asthma, and COPD, positive associations were found for PM2.5, NO2, and BC. For acute coronary heart disease, an increased HR was observed for NO2. For lung cancer, an increased HR was found only for PM2.5. Associations mostly showed steeper slopes at low exposures with no indication of a threshold.

Green Space Visits among Adolescents: Frequency and Predictors in the PIAMA Birth Cohort Study.

BACKGROUND: Green space may influence health through several pathways, for example, increased physical activity, enhanced social cohesion, reduced stress, and improved air quality. For green space to increase physical activity and social cohesion, spending time in green spaces is likely to be important. OBJECTIVES: We examined whether adolescents visit green spaces and for what purposes. Furthermore, we assessed the predictors of green space visits. METHODS: In this cross-sectional study, data for 1911 participants of the Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort were analyzed. At age 17, adolescents reported how often they visited green spaces for physical activities, social activities, relaxation, and to experience nature and quietness. We assessed the predictors of green space visits altogether and for different purposes by log-binomial regression. RESULTS: Fifty-three percent of the adolescents visited green spaces at least once a week in summer, mostly for physical and social activities. Adolescents reporting that a green environment was (very) important to them visited green spaces most frequently {adjusted prevalence ratio (PR) [95% confidence interval (CI)] very vs. not important: 6.84 (5.10, 9.17) for physical activities and 4.76 (3.72, 6.09) for social activities}. Boys and adolescents with highly educated fathers visited green spaces more often for physical and social activities. Adolescents who own a dog visited green spaces more often to experience nature and quietness. Green space visits were not associated with the objectively measured quantity of residential green space, i.e., the average normalized difference vegetation index (NDVI) and percentages of urban, agricultural, and natural green space in circular buffers around the adolescents' homes. CONCLUSIONS: Subjective variables are stronger predictors of green space visits in adolescents than the objectively measured quantity of residential green space. https://doi.org/10.1289/EHP2429.

Daily changes of peak expiratory flow and respiratory symptom occurrence around a soy processing factory.

OBJECTIVES: To evaluate sensitization and acute respiratory health effects in inhabitants living in the vicinity of a factory producing soy oil. METHODS: Two panels of potential responders were created on the basis of a response to a short screening questionnaire sent to random samples of 1,000 exposed and 1,000 non-exposed individuals living around the factory and a control area. Individuals responding to the questionnaire were invited for a medical evaluation, including a respiratory symptom questionnaire and skin prick testing, for a panel of common allergens and a soy allergen extract. This resulted in 53 atopic and/or asthmatic inhabitants from the area surrounding the factory and 30 comparable control subjects. In these subjects, morning and evening Peak Expiratory Flow (PEF), respiratory symptoms and medication use were recorded daily during a 10-week period in the autumn. At the same time, soy allergen and endotoxin concentrations were determined in airborne dust in the exposed and the control area. The wind direction relative to the location of a subjects' house and the factory was used to determine whether an individual was exposed on a particular day. RESULTS: Only few of the atopic subjects were sensitized to soy. PEF showed a decrease, respiratory symptoms and bronchodilator use, an increase among soy sensitized subjects after having been downwind from the factory. Airborne soy allergen was found more frequently in the area surrounding the factory and levels were higher than in the control area. Highest levels were found on the factory premises. Only a weak association was found with wind direction. Airborne endotoxin concentrations did not show a consistent pattern with distance, but levels were clearly higher on the factory premises. CONCLUSION: Sensitization to soy allergen was not increased among the population sample living in the vicinity of the factory. Soy sensitized individuals living in the surroundings of the factory reported more respiratory symptoms, used bronchodilators more often and had a lower PEF after having been downwind of the factory.

Blood pressure in 12-year-old children is associated with fatty acid composition of human milk: the prevention and incidence of asthma and mite allergy birth cohort.

Breastfed individuals have a lower blood pressure than formula-fed individuals. Supplementation with n-3 long-chain polyunsaturated fatty acids in adults is also associated with a lower blood pressure. We studied whether children receiving human milk with a relatively high content of n-3 long-chain polyunsaturated fatty acids have a lower blood pressure at age 12 years, and, if so, whether this association is explained by the n-3 long-chain polyunsaturated fatty acids content in erythrocyte membranes at age 12 years. Within a 12-year follow-up of a population-based birth cohort, we compared blood pressure of 205 never-breastfed children and 109 children who had fatty acid composition of their mothers' breast milk measured during lactation. In addition, 973 children had information on erythrocyte fatty acid composition and blood pressure at age 12 years. Children who received human milk with an n-3 long-chain polyunsaturated fatty acids content above the median (ie, 0.51 weight percentage) had a 4.79-mm Hg lower systolic (95% CI, -7.64 to -1.94) and a 2.47-mm Hg lower diastolic (95% CI, -4.45 to -0.49) blood pressure at age 12 years than never-breastfed children. N-3 long-chain polyunsaturated fatty acids levels in human milk below the median value and current n-3 long-chain polyunsaturated fatty acid status were not associated with blood pressure at age 12 years. Thus, a relatively high content of n-3 long-chain polyunsaturated fatty acids in human milk is associated with a lower blood pressure in children at age 12 years, a finding not explained by current n-3 long-chain polyunsaturated fatty acids status.

Commuters' exposure to particulate matter air pollution is affected by mode of transport, fuel type, and route.

BACKGROUND: Commuters are exposed to high concentrations of air pollutants, but little quantitative information is currently available on differences in exposure between different modes of transport, routes, and fuel types. OBJECTIVES: The aim of our study was to assess differences in commuters' exposure to traffic-related air pollution related to transport mode, route, and fuel type. METHODS: We measured particle number counts (PNCs) and concentrations of PM2.5 (particulate matter

Allergic disease and atopic sensitization in children in relation to measles vaccination and measles infection.

OBJECTIVE: Our aim was to investigate the role of measles vaccination and measles infection in the development of allergic disease and atopic sensitization. METHODS: A total of 14 893 children were included from the cross-sectional, multicenter Prevention of Allergy-Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle study, conducted in 5 European countries (Austria, Germany, the Netherlands, Sweden, and Switzerland). The children were between 5 and 13 years of age and represented farm children, Steiner-school children, and 2 reference groups. Children attending Steiner schools often have an anthroposophic (holistic) lifestyle in which some immunizations are avoided or postponed. Parental questionnaires provided information on exposure and lifestyle factors as well as symptoms and diagnoses in the children. A sample of the children was invited for additional tests, and 4049 children provided a blood sample for immunoglobulin E analyses. Only children with complete information on measles vaccination and infection were included in the analyses (84%). RESULTS: In the whole group of children, atopic sensitization was inversely associated with measles infection, and a similar tendency was seen for measles vaccination. To reduce risks of disease-related modification of exposure, children who reported symptoms of wheezing and/or eczema debuting during first year of life were excluded from some analyses. After this exclusion, inverse associations were observed between measles infection and "any allergic symptom" and "any diagnosis of allergy by a physician." However, no associations were found between measles vaccination and allergic disease. CONCLUSION: Our data suggest that measles infection may protect against allergic disease in children.

Long-chain polyunsaturated fatty acids in breast milk and early weight gain in breast-fed infants.

The long-chain PUFA (LCPUFA) content of an infant's diet might affect early weight gain. In early trials on supplementation of formula feeding n-3 LCPUFA affected weight gain adversely. n-6 LCPUFA are thought to promote adipose tissue development and might be associated with higher weight gain. We studied the association between the natural n-3 and n-6 LCPUFA content of breast milk of Dutch women and weight and BMI gain of their breast-fed infants in the first year of life. The children in this study were enrolled in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study and were born in 1996-1997 in The Netherlands. Parents reported their child's weight and length in a questionnaire. Of a subgroup of the total population breast-milk samples were collected (n 244). The fatty acid composition of breast milk was determined by GLC and expressed as weight percentages. Linear regression was used for data analysis. Mean gain in weight, length and BMI per week from birth to 1 year of age was 119.5 (SD 16.1) g, 0.48 (SD 0.05) cm and 0.06 (SD 0.03) kg/m2, respectively. The associations between n-6 and n-3 LCPUFA in breast milk, and infant weight, length and BMI gain were weak and inconsistent. The n-3 and n-6 LCPUFA content in breast milk did not affect weight or BMI gain in the first year of life in breast-fed term infants.

The role of atopic sensitization in flexural eczema: findings from the International Study of Asthma and Allergies in Childhood Phase Two.

BACKGROUND: The association between allergic sensitization and eczema has been debated for years. OBJECTIVE: We sought to determine and compare the strength of the association between allergen skin sensitization and eczema in both developing and industrialized countries. METHODS: Twenty-eight thousand five hundred ninety-one randomly selected 8- to 12-year-old schoolchildren in 20 countries were physically examined for flexural eczema and received skin prick testing to Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat hair, Alternaria tenuis, mixed tree and grass pollen, and allergens of local relevance. RESULTS: The age- and sex-adjusted odds ratios (ORs) for a positive association between flexural eczema and atopy ranged between 0.74 (95% CI, 0.31-1.81) and 4.53 (95% CI, 1.72-11.93), with a significantly stronger association in affluent compared with nonaffluent countries (combined age- and sex-adjusted OR(affluent) = 2.69 [95% CI, 2.31-3.13] and OR(nonaffluent) = 1.17 [95% CI, 0.81-1.70]). The combined population attributable fraction for atopy in flexural eczema was 27.9% for affluent and 1.2% for nonaffluent-country centers. Correlating gross national per-capita income with either ORs or population attributable fractions for atopy in flexural eczema confirmed a highly significant positive association (P = .006 and P < .001, respectively). CONCLUSIONS: The association between atopy and flexural eczema is weak and more variable than previously suggested, and the strength of this association is positively linked to gross national income.

Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children.

BACKGROUND: There is increasing evidence that environmental exposures determining childhood illnesses operate early in life. Prenatal exposure to a farming environment through the mother might also play an important role. OBJECTIVE: We sought to investigate the role of maternal exposures to environments rich in microbial compounds for the development of atopic sensitization, asthma, and corresponding alterations in the innate immune system in offspring. METHODS: In the children of the cross-sectional Prevention of Allergy Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Life Style study, asthma and atopy were assessed by means of standardized questionnaires (n = 8263) and serum IgE measurements (n = 2086). In a subsample (n = 322) gene expression of Toll-like receptors (TLR2 and TLR4) and CD14 was assessed. Maternal exposures were defined through questionnaire information. RESULTS: Both atopic sensitization (adjusted odds ratio, 0.58; 95% CI, 0.39-0.86) and the gene expression of receptors of innate immunity were strongly determined by maternal exposure to stables during pregnancy, whereas current exposures had much weaker or no effects. A dose-response relation was found between the extent of upregulation of these genes and the number of different farm animal species the mother had encountered in her pregnancy. Each additional farm animal species increased the expression of TLR2, TLR4, and CD14 by a factor of 1.16 (95% CI, 1.07-1.26), 1.12 (95% CI, 1.04-1.2), and 1.10 (95% CI, 1.03-1.23), respectively. CONCLUSION: Maternal exposure to an environment rich in microbial compounds might protect against the development of atopic sensitization and lead to upregulation of receptors of the innate immune system. The underlying mechanisms potentially operating through the intrauterine milieu or epigenetic inheritance await further elucidation. CLINICAL IMPLICATIONS: When assessing risk factors of allergies in an infant's medical history, attention must also be paid to environmental exposures affecting the mother.

The relationship between air pollution from heavy traffic and allergic sensitization, bronchial hyperresponsiveness, and respiratory symptoms in Dutch schoolchildren.

Studies have suggested that children living close to busy roads may have impaired respiratory health. This study was designed to test the hypothesis that exposure to exhaust from heavy traffic in particular is related to childhood respiratory health. Children attending 24 schools located within 400 m from busy motorways were investigated. The motorways carried between 5,190 and 22,326 trucks per weekday and between 30,399 and 155,656 cars per day. Locations were chosen so that the correlation between truck and car traffic counts was low. Air pollution measurements were performed at the schools for 1 year. Respiratory symptoms were collected by parent-completed questionnaire. Sensitization to common allergens was measured by serum immunoglobulin E and skin prick tests. Bronchial hyperresponsiveness (BHR) was measured with a hypertonic saline challenge. Respiratory symptoms were increased near motorways with high truck but not high car traffic counts. They were also related to air pollutants that increased near motorways with high truck traffic counts. Lung function and BHR were not related to pollution. Sensitization to pollen increased in relation to truck but not car traffic counts. The relation between symptoms and measures of exposure to (truck) traffic-related air pollution were almost entirely restricted to children with BHR and/or sensitization to common allergens, indicating that these are a sensitive subgroup among all children for these effects.