Overlooking relevant confounders in the assessment

Authors: Keith Fluegge

Publish Date: 2016/12/28

Volume: 91, Issue: 2, Pages: 601-602

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Abstract

Mostafalou and Abdollahi Arch Toxicol 2016 doi 101007/s002040161849x have recently conducted a review exploring human exposure to pesticides and systematically highlighting known toxic mechanisms from these exposures Their review is extensive and appraises the literature on pesticide toxicity in a number of domains including neurotoxicity and developmental toxicity However as important as it may be to understand the toxicological potential of these chemicals in humans and other species the role of these chemicals as proxies for other environmental exposures should not be excluded Recently we published evidence suggesting use of the herbicide glyphosate may predict health care utilization for attentiondeficit hyperactivity disorder ADHD a neurodevelopmental disorder that is characterized by cognitive impairments leading to attention deficits impulsivity and hyperactivity Given that the finding appeared to be landdependent we concluded that glyphosate may be an instrumental variable that predicts severe ADHD mostly through its inseparableness from nitrogen fertilizers at a county level and increasing agricultural air emissions of the compound nitrous oxide N2O Since the WHO designates N2O as an important modern health medicine its environmental imprint is largely thought to be inconsequential in a human health context and unfortunately not worthy of further consideration Our findings and subsequent review on the topic are not amenable to this complacency We argue that future pesticide risk assessments be made more comprehensive insofar as identifying not only critical direct routes of toxicity as extensively reviewed by Mostafalou and Abdollahi 2016 but also indirect toxicological mechanisms such as the one presented in this correspondenceMostafalou and Abdollahi 2016 have recently conducted a review exploring human exposure to pesticides and systematically highlighting known toxic mechanisms from these exposures Their review is extensive and appraises the literature on pesticide toxicity in a number of domains including neurotoxicity and developmental toxicity The publication of the review comes at a time when the WHO has recently classified glyphosate an organophosphorus compound used in agriculture as a probable human carcinogen That classification has spurred intense interest in restricting the use of glyphosate internationally However as important as it may be to understand the toxicological potential of these chemicals in humans and other species the role of these chemicals as proxies for other environmental exposures should not be excludedRecently we published evidence suggesting use of the herbicide glyphosate may predict health care utilization for attentiondeficit hyperactivity disorder ADHD a neurodevelopmental disorder that is characterized by cognitive impairments leading to attention deficits impulsivity and hyperactivity Fluegge and Fluegge 2016 In the study we employed a twoway fixedeffects regression analysis to identify the relationship between statewide glyphosate use and hospital discharge diagnoses for ADHD A valid criticism of this methodology is that hospital discharges do not necessarily represent prevalent ADHD cases However ADHD is a condition that is often overdiagnosed which complicates prevalence accuracy and the presence of mental health comorbidities may be an important diagnostic facet of the disorder that necessitates health care utilization Indeed our data may be representing “severe ADHD” and this is a limitation that has been recently identified in other published epidemiological studies When we became aware that glyphosate use predicted alllisted ADHD hospital discharge diagnoses the following year we wanted to know whether the relationship was dependent upon land usage We hypothesized a null relationship here given that glyphosate is used in every urbanization category that was studied ie metropolitan urban and rural However our analysis did reveal an unexpected marginal association in urban areas after multiple comparison correction We suspected that glyphosate’s relationship with nitrogen fertilizers may be a dynamic that alters the land to induce the association between glyphosate use and severe ADHD We confirmed using a countylevel analysis that glyphosate and nitrogen fertilizers were inextricably positively linked in some urbanization levels and negatively linked in othersOur study led us to conclude that glyphosate may be an instrumental variable that predicts severe ADHD mostly through its inseparableness from nitrogen fertilizers at a county level and increasing agricultural air emissions of the compound nitrous oxide N2O This supposition was corroborated with data from independent government agencies on agricultural emissions of N2O making the study the first to suggest that the use of synthetic nitrogen fertilizers in modern agricultural systems may be a significant confounder to the proposed relationship between glyphosate and neuropsychiatric disease in human populations We have expounded on these conclusions in a recent review proposing potential mechanisms underlying the role of environmental N2O in the etiology of neurodevelopmental disorders like ADHD and autism spectrum disorders Fluegge 2016 However the WHO designates N2O as an important modern health medicine so its environmental imprint is largely thought to be inconsequential in a human health context and unfortunately not worthy of much consideration Our findings are not amenable to this complacency We argue that future pesticide risk assessments be made more comprehensive insofar as identifying not only critical direct routes of toxicity but also indirect toxicological mechanisms such as the one presented in this correspondenceThe author contributed to the following 1 substantial contributions to conception and design or acquisition of data or analysis and interpretation of data 2 drafting the article or revising it critically for important intellectual content and 3 final approval of the version to be published

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