Autism in 2016: additional discovery

To the Editor,

Posar and Visconti¹ have recently published their narrative biomedical review on the developments in the field of autism research in 2016, with a particular focus on the hypothetical role of environmental factors, like air pollution. The authors searched the available recent literature using PubMed (United States National Library of Medicine) for interesting hypotheses published between January 1, 2013 and August 20, 2016 and relevant literature (case–control studies involving human participants were preferred) using a variety of selected keywords. Although the authors identified a search strategy, their review did not consider a recently published mini-review identifying the role of the specific agricultural air pollutant, nitrous oxide (N₂O), in autism etiopathogenesis and neurodevelopmental disorders more broadly.

Fluegge² has suggested repeatedly that exposure to environmental N₂O may increase susceptibility to a range of neurodevelopmental disorders, including autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD). An initial epidemiological analysis revealed an association between the use of the pesticide glyphosate and ADHD, but subsequent sensitivity analyses found that the association was likely dependent upon the level of land urbanization and glyphosate's strong county-specific association with nitrogen-based fertilizers and presumable emissions of N₂O.² These findings were replicated in an analysis of ASD hospitalizations (personal communication). Hypothesized mechanisms of interest underlying these associations included known pharmacological targets of low level N₂O exposure, including NMDA receptor antagonism (N-methyl-d-aspartate receptor), stimulation of central opioid peptide release, and suppression of cholinergic activity.³ The review is particularly notable since environmental N₂O has not been considered by either Posar and Visconti¹ or the studies that comprise their narrative review as an air pollutant capable of inducing adverse human health consequences and autism, in particular. It is, therefore, interesting to read the authors’ suggestion to investigate whether there is a difference in autism prevalence among nations exposed to low vs. high levels of pollution.

Tian et al.⁴ recently reported on the annual rates of change for a multitude of environmental factors for different continents, having found significant increases in nitrogen fertilizer use in North America from 1981 to 2010 and significant decreases in nitrogen fertilizer use in Europe during the same period. As the use of anthropogenic nitrogen sources is the most directly tied environmental contributor to N₂O emissions,⁵ this continental difference in nitrogen fertilizer use going back decades is particularly revealing and suggests higher U.S. emissions of N₂O derived from nitrogen fertilizers compared to Europe, a fact confirmed by the Intergovernmental Panel on Climate Change (IPCC, 2015).⁶ This geographical distinction could explain the differential dynamics in ASD prevalence.

Epidemiologic, population-based studies from Europe indicate that much of the increase in ASD prevalence between 1980 and 2003 can be accounted for by changes in administrative and reporting practices,^7,8 while ASD prevalence in the subsequent years in the UK may have plateaued.⁹ These data argue for the possibility that the increase in the registered prevalence of ASD may be driven more by administrative changes. However, the marked increase in ASD prevalence in the United States between 2000 and 2012, in particular, could not be readily accounted for by any evolution in diagnostic criteria since no formal changes were introduced or adopted during this time, although it cannot be discounted that the increasing prevalence of ASD during this time might be attributable to lingering diagnostic substitution or the accrual of practices started in the prior decades.¹⁰ This, therefore, leaves open the possibility that secular environmental contributors, like environmental N₂O, may play a role in ASD etiopathogenesis in a continentally distinct way. In light of this research, Posar and Visconti¹ may wish to expand their view on the role of air pollution as a risk factor in ASD. Considering that N₂O is not regarded as a human health pollutant in the literature or by government officials, a call for a re-evaluation of this particular environmental pollutant seems necessary.

Conflicts of interest

The author declares no conflicts of interest.