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      A Systematic Review and Meta-Analysis of Multiple Airborne Pollutants and Autism Spectrum Disorder

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          Abstract

          Background

          Exposure to ambient air pollution is widespread and may be detrimental to human brain development and a potential risk factor for Autism Spectrum Disorder (ASD). We conducted a systematic review of the human evidence on the relationship between ASD and exposure to all airborne pollutants, including particulate matter air pollutants and others (e.g. pesticides and metals).

          Objective

          To answer the question: “is developmental exposure to air pollution associated with ASD?”

          Methods

          We conducted a comprehensive search of the literature, identified relevant studies using inclusion/exclusion criteria pre-specified in our protocol (registered in PROSPERO, CRD # 42015017890), evaluated the potential risk of bias for each included study and identified an appropriate subset of studies to combine in a meta-analysis. We then rated the overall quality and strength of the evidence collectively across all air pollutants.

          Results

          Of 1,158 total references identified, 23 human studies met our inclusion criteria (17 case-control, 4 ecological, 2 cohort). Risk of bias was generally low across studies for most domains; study limitations were related to potential confounding and accuracy of exposure assessment methods. We rated the quality of the body of evidence across all air pollutants as “moderate.” From our meta-analysis, we found statistically significant summary odds ratios (ORs) of 1.07 (95% CI: 1.06, 1.08) per 10-μg/m 3 increase in PM 10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-μg/m 3 increase in PM 2.5 exposure (n = 3 studies). For pollutants not included in a meta-analysis, we collectively evaluated evidence from each study in rating the strength and quality of overall evidence considering factors such as inconsistency, imprecision, and evidence of dose-response. All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components.

          Conclusion

          After considering strengths and limitations of the body of research, we concluded that there is “limited evidence of toxicity” for the association between early life exposure to air pollution as a whole and diagnosis of ASD. The strongest evidence was between prenatal exposure to particulate matter and ASD. However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate. Our research supports the need for health protective public policy to reduce exposures to harmful airborne contaminants among pregnant women and children and suggests opportunities for optimizing future research.

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          Most cited references52

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          Traffic-related air pollution, particulate matter, and autism.

          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 the etiology of autism, yet little research has examined its association with local levels of air pollution using residence-specific exposure assignments. To examine the relationship between traffic-related air pollution, air quality, and autism. This population-based case-control study includes data obtained from children with autism and control children with typical development who were enrolled in the Childhood Autism Risks from Genetics and the Environment 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. Traffic-related air pollution 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 children with autism and for control children with typical development. Case-control study from California. A total of 279 children with autism and a total of 245 control children with typical development. Crude and multivariable adjusted odds ratios (AORs) for autism. Children with autism were more likely to live at residences that had the highest quartile of exposure to traffic-related air pollution, during gestation (AOR, 1.98 [95% CI, 1.20-3.31]) and during the first year of life (AOR, 3.10 [95% CI, 1.76-5.57]), compared with control children. Regional exposure measures of nitrogen dioxide and particulate matter less than 2.5 and 10 μm in diameter (PM2.5 and PM10) were also associated with autism during gestation (exposure to nitrogen dioxide: AOR, 1.81 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.08 [95% CI, 1.93-2.25]; exposure to PM10: AOR, 2.17 [95% CI, 1.49-3.16) and during the first year of life (exposure to nitrogen dioxide: AOR, 2.06 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.12 [95% CI, 1.45-3.10]; exposure to PM10: AOR, 2.14 [95% CI, 1.46-3.12]). All regional pollutant estimates were scaled to twice the standard deviation of the distribution for all pregnancy estimates. Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10 during pregnancy and during the first year of life was associated with autism. Further epidemiological and toxicological examinations of likely biological pathways will help determine whether these associations are causal.
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            Adverse cardiovascular effects of air pollution.

            Air pollution is increasingly recognized as an important and modifiable determinant of cardiovascular disease in urban communities. Acute exposure has been linked to a range of adverse cardiovascular events including hospital admissions with angina, myocardial infarction, and heart failure. Long-term exposure increases an individual's lifetime risk of death from coronary heart disease. The main arbiter of these adverse health effects seems to be combustion-derived nanoparticles that incorporate reactive organic and transition metal components. Inhalation of this particulate matter leads to pulmonary inflammation with secondary systemic effects or, after translocation from the lung into the circulation, to direct toxic cardiovascular effects. Through the induction of cellular oxidative stress and proinflammatory pathways, particulate matter augments the development and progression of atherosclerosis via detrimental effects on platelets, vascular tissue, and the myocardium. These effects seem to underpin the atherothrombotic consequences of acute and chronic exposure to air pollution. An increased understanding of the mediators and mechanisms of these processes is necessary if we are to develop strategies to protect individuals at risk and reduce the effect of air pollution on cardiovascular disease.
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              Is Open Access

              The Navigation Guide Systematic Review Methodology: A Rigorous and Transparent Method for Translating Environmental Health Science into Better Health Outcomes

              Background: Synthesizing what is known about the environmental drivers of health is instrumental to taking prevention-oriented action. Methods of research synthesis commonly used in environmental health lag behind systematic review methods developed in the clinical sciences over the past 20 years. Objectives: We sought to develop a proof of concept of the “Navigation Guide,” a systematic and transparent method of research synthesis in environmental health. Discussion: The Navigation Guide methodology builds on best practices in research synthesis in evidence-based medicine and environmental health. Key points of departure from current methods of expert-based narrative review prevalent in environmental health include a prespecified protocol, standardized and transparent documentation including expert judgment, a comprehensive search strategy, assessment of “risk of bias,” and separation of the science from values and preferences. Key points of departure from evidence-based medicine include assigning a “moderate” quality rating to human observational studies and combining diverse evidence streams. Conclusions: The Navigation Guide methodology is a systematic and rigorous approach to research synthesis that has been developed to reduce bias and maximize transparency in the evaluation of environmental health information. Although novel aspects of the method will require further development and validation, our findings demonstrated that improved methods of research synthesis under development at the National Toxicology Program and under consideration by the U.S. Environmental Protection Agency are fully achievable. The institutionalization of robust methods of systematic and transparent review would provide a concrete mechanism for linking science to timely action to prevent harm. Citation: Woodruff TJ, Sutton P. 2014. The Navigation Guide systematic review methodology: a rigorous and transparent method for translating environmental health science into better health outcomes. Environ Health Perspect 122:1007–1014; http://dx.doi.org/10.1289/ehp.1307175
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 September 2016
                2016
                : 11
                : 9
                : e0161851
                Affiliations
                [1 ]Department of Obstetrics, Gynecology & Reproductive Sciences, Program on Reproductive Health and the Environment, University of California, San Francisco, CA, United States of America
                [2 ]Department of Obstetrics, Gynecology & Reproductive Sciences, Program on Reproductive Health and the Environment, University of California, San Francisco, CA, United States of America
                [3 ]Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milkwaukee, WI, United States of America
                [4 ]Division of Environmental and Occupational Disease Control, California Department of Public Health, Richmond, CA, United States of America
                [5 ]Autism Science Foundation, New York, NY, United States of America
                [6 ]Department of Pharmacology and Toxicology, Rutgers University, New Brunswick, NJ, United States of America
                [7 ]Scientific consultant to the University of California, San Francisco, CA, United States of America
                [8 ]Division of Extramural Research and Training, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States of America
                [9 ]Department of Obstetrics and Gynecology, Kaiser Permanente, Oakland, CA, United States of America
                [10 ]Department of Obstetrics, Gynecology & Reproductive Sciences, Program on Reproductive Health and the Environment, University of California, San Francisco, CA, United States of America
                [11 ]Department of Epidemiology and Biostatistics, Drexel University, Philadelphia, PA, United States of America
                [12 ]Department of Obstetrics, Gynecology & Reproductive Sciences, Program on Reproductive Health and the Environment, University of California, San Francisco, CA, United States of America
                CSIR-Indian Institute of Toxicology Research, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: JL PS AH TW GW.

                • Data curation: JL.

                • Formal analysis: JL TW.

                • Funding acquisition: JL PS AH ND TW.

                • Investigation: JL PS AK AH EK CL LD ND CN TW GW.

                • Methodology: JL PS AK AH CL CN TW GW.

                • Project administration: JL PS TW.

                • Software: JL.

                • Supervision: JL PS TW.

                • Validation: JL PS EK LD ND.

                • Visualization: JL.

                • Writing – original draft: JL.

                • Writing – review & editing: JL PS AK AH EK CL LD ND CN TW GW.

                Article
                PONE-D-16-21803
                10.1371/journal.pone.0161851
                5031428
                27653281
                34f674bc-aca5-4073-bad8-a3a8cc7dd12a

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 31 May 2016
                : 14 August 2016
                Page count
                Figures: 4, Tables: 3, Pages: 27
                Funding
                Funded by: United States Environmental Protection Agency
                Award ID: P01 83543301
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000073, Autism Speaks;
                Award ID: 9337
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000066, National Institute of Environmental Health Sciences;
                Award ID: PO1ES022841
                Award Recipient :
                The work of JL, PS, ND, TW was supported in part by a grant from Autism Speaks ( https://www.autismspeaks.org/) and by a P01 grant from the US Environmental Protection Agency and National Institute of Environmental Health Sciences ( https://www3.epa.gov/; http://www.niehs.nih.gov/). NIEHS grant number: PO1ES022841; USEPA grant number: 83543301. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Engineering and Technology
                Environmental Engineering
                Pollution
                Air Pollution
                Biology and Life Sciences
                Psychology
                Developmental Psychology
                Autism Spectrum Disorder
                Social Sciences
                Psychology
                Developmental Psychology
                Autism Spectrum Disorder
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Physical Sciences
                Chemistry
                Environmental Chemistry
                Pollutants
                Ecology and Environmental Sciences
                Environmental Chemistry
                Pollutants
                People and Places
                Population Groupings
                Age Groups
                Children
                People and Places
                Population Groupings
                Families
                Children
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Biology and Life Sciences
                Toxicology
                Toxicity
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Toxicology
                Toxicity
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                All relevant data are within the paper and its Supporting Information files.

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