Cindy P. Lawler

The outdoor air pollution and brain health workshop

Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications

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

Elucidating the Links Between Endocrine Disruptors and Neurodevelopment

Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes.

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

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/m3 increase in PM10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-μg/m3 increase in PM2.5 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.

The “Environment” for Autism Research: Signs of Improvement?

Once thought to be rare, autism spectrum disorders (ASD) have gained increasing public attention as prevalence studies have revealed sharp increases over the past two decades. ASD now represents the second most common category of neurodevelopmental disorders. The prevalence data have been instrumental in mobilizing parents to act on behalf of their affected family members for better services and treatments and for greater research investments aimed at understanding what causes these disorders and how they can be prevented.

Strength in numbers: three separate studies link in utero organophosphate pesticide exposure and cognitive development.

Children entering classrooms for the first time this fall can be seen carrying backpacks filled with school supplies, yet each new student brings something less obvious but more important—a legacy of their earlier experiences and environment. Three studies published in this issue of Environmental Health Perspectives (Bouchard et al. 2011; Engel et al. 2011; Rauh et al. 2011) deliver compelling new data linking one aspect of a child’s history—in utero exposure to organophosphates (OP), a commonly used class of pesticides—and early cognitive development. Working memory, perceptual reasoning, and IQ were among the measures of intellectual development associated with prenatal OP exposure. Bouchard et al. (2011) found that children in the category corresponding to the highest 20% of maternal urinary levels of OP metabolites during pregnancy showed a 7-point decrease in full scale IQ compared with children of mothers in the lowest 20%, an association of magnitude similar to that observed with an increase in blood lead concentrations from 1 to 10 µg/dL (Canfield et al. 2003). The strength of evidence arising from these studies reflects, in part, their rigorous study design. Each used a longitudinal birth cohort, a design well suited to detect the evolution of exposure effects over time. Accordingly, the latest findings build on previous data from these birth cohorts showing relationships between prenatal OP pesticide exposure levels and developmental end points in the first 3 years of life (e.g., Engel et al. 2007; Eskenazi et al. 2004; Rauh et al. 2006). Decrements in full-scale IQ, working memory, and perceptual reasoning showed the most consistent associations with prenatal exposure biomarkers across studies. Comparability of these results, despite differences in populations and exposure metrics, underscores the robustness of this latest group of findings. Two of the birth cohorts represent multiethnic inner city populations in New York City, while the third cohort comprises low-income families living in California’s Salinas Valley, an agricultural area. Rauh et al. (2011) measured chlorpyrifos in cord blood, whereas Engel et al. (2011) and Bouchard et al. (2011) relied on measurement of nonspecific OP metabolites in maternal urine samples collected during pregnancy. A primary limitation of these three studies relates to exposure assessment. One study measured chlorpyrifos and diazinon in blood (Rauh et al. 2011), but the other studies (Bouchard et al. 2011; Engel et al. 2011) measured OP pesticide breakdown products in urine. Some of these breakdown products can also be found pre-formed in food; thus, measurements in urine do not show how much exposure was due to the parent pesticide compounds or the preformed breakdown product. Another complication is that measurement of the breakdown products reflects exposure to many different OP pesticides, some that are much more toxic than others. For many OP pesticides, however, there are no laboratory methods to measure the parent pesticides in blood or specific breakdown products in urine at levels needed for epidemiologic research. The National Institute of Environmental Health Sciences (NIEHS), through the Exposure Biology Program, is supporting efforts to improve exposure assessment for epidemiological research. The three birth cohort studies highlighted here were initiated in the first phase of the Children’s Centers for Environmental Health and Disease Prevention Research Program. This program was developed jointly by the NIEHS and the U.S. Environmental Protection Agency (EPA) in response to a 1997 Executive Order that charged agencies to prioritize the identification and assessment of environmental health risks to children and to ensure that policies, programs, activities, and standards address these risks (Clinton 1997). At present, six full centers and six developmental/formative Children’s Centers, each comprised of interdisciplinary research teams, receive support through this program. Collectively, these centers are addressing a range of established and emerging priority issues in the environmental health of children, including neurodevelopment, respiratory health, and endocrine function. An important component of these NIEHS/U.S. EPA Children’s Centers is meaningful engagement of affected communities. Although not the focus of the articles in this issue of EHP, all three research teams have community outreach and translation cores whose primary objective is to rapidly and effectively translate the center study findings at local, state, and national levels to communities and stakeholders. These efforts have taken various forms, from hosting town hall meetings, developing community advisory boards, and encouraging integrated pest management solutions in New York City to outreach efforts to reduce take home exposures among farm workers in the Salinas Valley. The present findings in young children are likely to have implications for longer-term learning and academic success. Determining the persistence of these associations, and their generalizability to other populations, requires additional study. The U.S. EPA began a phase-out of the residential use of chlorpyrifos and diazinon in 2001 and 2004, respectively, which led to a marked reduction of markers of chlorpyrifos exposure in the United States, yet exposure to children continues due to use of organophosphate pesticides on crops and residues on foods. Spurred by recent advances in mechanistic toxicology and exposure science, efforts to improve identification of neurodevelopmental toxicity of new and existing industrial compounds are under way (e.g., U.S. Senate Committee on Environment & Public Works 2009). The findings of Bouchard et al. (2011), Engel et al. (2011), and Rauh et al. (2011) should stimulate renewed efforts to develop and fully implement measures that can identify threats before widespread exposure occurs and harms pregnant women and children.

Meeting report: Identification of biomarkers for early detection of mitochondrial dysfunction.

In addition to their central role in cellular bioenergetics, mitochondria also play a major role in apoptosis, control of cytosolic calcium concentrations, and metabolic cell signaling. Through normal energy production by oxidative phosphorylation and the electron transport chain, mitochondrial proteins and mtDNA are vulnerable to damage from reactive oxygen species (ROS). Mitochondria are also a target for over 60 natural and synthetic compounds that exert their toxicity by affecting the integrity of mtDNA, inhibiting complexes in the electron transport chain, altering membrane potential, affecting calcium homeostasis, and by modulating induction of apoptosis. Mitochondrial dysfunction is associated with numerous chronic diseases including Type II diabetes, neurodegenerative diseases, blindness, cardiovascular disease, and cancer. This may reflect, in part, the vulnerability of mitochondria to environmental influences. For example, the organic pesticide rotenone is a potent Complex I inhibitor, exhibits selective toxicity for dopaminergic neurons, and is associated in human studies with increased risk of Parkinson’s disease (PD). The identification of mitochondrial impairment in clinical settings is challenging. Acute exposure to mitochondrial poisons causes short-term and nonspecific clinical symptoms that include muscle weakness, fatigue, hypotension and shortness of breath. The effects of drugs or environmental mitochondrial toxicants are often detected by lactic acidosis in which a large percentage of mitochondria have already been affected. Such markers have limited utility for detecting individuals at risk of developing disease or in the early stages of a disease. There is an urgent need for reliable, informative markers of early mitochondrial dysfunction associated with environmental stressors, as these could enable intervention in the subclinical stages of disease. In the case of PD, such markers could enable interventions aimed at preserving dopamine neurons.

Laying a Community-Based Foundation for Data-Driven Semantic Standards in Environmental Health Sciences.

Background: Despite increasing availability of environmental health science (EHS) data, development, and implementation of relevant semantic standards, such as ontologies or hierarchical vocabularies, has lagged. Consequently, integration and analysis of information needed to better model environmental influences on human health remains a significant challenge. Objectives: We aimed to identify a committed community and mechanisms needed to develop EHS semantic standards that will advance understanding about the impacts of environmental exposures on human disease. Methods: The National Institute of Environmental Health Sciences sponsored the “Workshop for the Development of a Framework for Environmental Health Science Language” hosted at North Carolina State University on 15–16 September 2014. Through the assembly of data generators, users, publishers, and funders, we aimed to develop a foundation for enabling the development of community-based and data-driven standards that will ultimately improve standardization, sharing, and interoperability of EHS information. Discussion: Creating and maintaining an EHS common language is a continuous and iterative process, requiring community building around research interests and needs, enabling integration and reuse of existing data, and providing a low barrier of access for researchers needing to use or extend such a resource. Conclusions: Recommendations included developing a community-supported web-based toolkit that would enable a) collaborative development of EHS research questions and use cases, b) construction of user-friendly tools for searching and extending existing semantic resources, c) education and guidance about standards and their implementation, and d) creation of a plan for governance and sustainability. Citation: Mattingly CJ, Boyles R, Lawler CP, Haugen AC, Dearry A, Haendel M. 2016. Laying a community-based foundation for data-driven semantic standards in environmental health sciences. Environ Health Perspect 124:1136–1140; http://dx.doi.org/10.1289/ehp.1510438