The results of a study headed by researchers at the University of Chicago suggest that there may be a significant link between exposure to environmental pollution and the prevalence of neuropsychiatric disorders.

Analyses of large population data sets from the United States and Denmark linked poor air quality with increased rates of bipolar disorder and major depression in both countries. The association appeared stronger in Denmark, where exposure to air pollution during up to age 10 years life was predictive of a more than twofold increase in personality disorders and schizophrenia.

“Our studies in the United States and Denmark show that living in polluted areas, especially early in life, is predictive of mental disorders,” said computational biologist Atif Khan, PhD, lead author of study. “These neurological and psychiatric diseases—so costly in both financial and social terms—appear linked to the physical environment, particularly air quality.” Khan said that more research will be needed “to better understand how our environment is contributing to neurological and psychiatric disorders.” The researchers, including senior author Andrey Rzhetsky, PhD, the Edna K. Papazian professor of medicine and human genetics, reported their findings in PLoS Biology, in a paper titled, “Environmental pollution is associated with increased risk of psychiatric disorders in the U.S. and Denmark.”

Mental illnesses such as bipolar disorder and schizophrenia are caused by a complex interplay of genetic risk factors and life experiences or exposures, the authors explained. Although much work has been carried out to understand genetic factors that predispose to neuropsychiatric disorders, “genetics alone cannot account for full phenotypic variation in mental health and disease, and it has long been believed that genetic, neurochemical, and environmental factors interact at many different levels to play a role in the onset, severity and progression of these illnesses.”

Historically, studies of putative environmental factors that may play causal roles in neuropsychiatric disorders have focused on home or family environments, including childhood adversity and trauma, and prenatal influences. In contrast, the investigators noted, “far fewer studies have explored the links between physical environments and mental illnesses.” In fact, only a small number of studies have focused on environmental pollution, despite the fact that there is increasing concern about the many adverse effects of air pollution, “raising the possibility that air quality may play an important role in mental health and cognitive function.” As the team noted, laboratory research and studies in animal models are generating new insights into the mechanisms by which components of air pollution may be neurotoxic. “We hypothesized that pollutants might affect our brains through neuroinflammatory pathways that have also been shown to cause depression-like signs in animal studies,” said Rzhetsky.

For their study Khan, Rzhetsky, and colleagues first analyzed information held in a U.S. health insurance database of 151 million individuals, including 11 years of inpatient and of outpatient claims for neuropsychiatric diseases. They considered environmental factors—air quality, water, land, built environment, and weather conditions—and the psychiatric disorders such as bipolar disorder, major depression, personality disorder, and schizophrenia, as well as the neurological conditions epilepsy and Parkinson’s disease. The investigators’ computations also took into account factors such as population density, income, ethnic, and racial composition of the geographically defined counties. Their analyses compared the geo-incidence of claims to measurements of 87 potential air pollutants from the United States Environmental Protection Agency (EPA).

The results indicated that counties with the worst air quality had a 27% increase in bipolar disorder and 6% increase in major depression when compared to counties with the best air quality. The team also found that regions with the worst land quality were associated with an estimated 19.2% increased risk in the apparent rate of personality disorder.

Given the apparently strong correlations between environmental pollution and some mental illnesses, the team looked to validate their findings by applying their methods to data from another country. In the U.S. study, exposure measurements were confined to the county level, but in Denmark environmental quality indicators are monitored over much smaller areas, of something just over one-quarter of a mile. Individuals living in Denmark are also assigned unique identification numbers that can link information from various national registries, and this allowed the researchers to estimate exposure to air pollution at the individual level. “We strived to provide validation of association results in independent large datasets,” said Rzhetsky.

The University of Chicago team collaborated with researchers at the University of Aarhus to analyze Danish national treatment registers encompassing data from 1.4 million people who had been born in Denmark between 1979 and 2002. They evaluated the incidence of neuropsychiatric disease in Danish adults who had lived in areas with poor environmental quality up to their tenth birthdays. “The datasets representing U.S. and Denmark populations in this study have different strengths,” the authors added. “The U.S. dataset is two orders of magnitude larger than the Danish dataset but is at a county level, whereas the Danish dataset allows for the computation of individual-level pollutant exposure during the first years of a patient’s life with a spatial resolution of one square kilometer.”

The results showed a 29% increase in the incidence of bipolar disorder among people in areas with the worst air quality—a result similar to that from the U.S. cohort study. Analysis of the Danish data also indicated that early childhood exposure to air pollution correlated with a 50% increase in major depression, a 147% increase in schizophrenia, and a 162% increase in personality disorders when compared with individuals who grew up in areas with the highest quality air.

Khan, Rzhetsky, and the team worked on the project for more than two years, to improve their models with additional mathematical analyses and data sources. Their results have sparked controversy, with other researchers noting that the correlations don’t confirm that pollution actually triggers the diseases. “This study on psychiatric disorders is counterintuitive and generated considerable resistance from reviewers,” Rzhetsky acknowledged.

In a companion article commissioned by PLoS Biology, Stanford University’s John Ioannidis, PhD, who worked with the journal on the editorial process, commented, “A causal association of air pollution with mental diseases is an intriguing possibility. Despite analyses involving large datasets, the available evidence has substantial shortcomings and a long series of potential biases may invalidate the observed associations. More analyses by multiple investigators, including contrarians, are necessary.” Nevertheless, Ioannidis noted, “Khan and colleagues have offered a brilliant exploratory analysis with interesting hypothesis-generating hints for bipolar disorder and possibly other psychiatric diagnoses. Now, these leads need to be rigorously prospectively evaluated in other data sets.”

The authors also acknowledged that their study findings don’t necessarily point to causation, and the research wasn’t designed to show how air pollution might trigger neural effects. Even so, Rzhetsky noted that experiments on animals exposed to pollution have demonstrated signs of cognitive impairment and depression-like behavioral symptoms. “Growing evidence from human, animal, and in vitro studies demonstrates that airborne pollutants target the brain and are implicated in neurological and psychiatric disorders etiology,” the researchers commented. “Significantly, a growing number of experimental animal studies tie environmental factors to inflammatory and cytotoxic damage to neural tissues and to psychiatric disorders.” The team concluded, “Converging data points to neuroinflammatory mechanisms linking environmental compounds to their putative psychiatric consequences. However, these strong associations do not necessarily mean causation; further research will be needed to assess whether air pollution’s neuroinflammatory impacts share common pathways with other stress-induced conditions.”

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