Exploring the potential confounder of nitrogen fertilizers in the relationship between pesticide exposures and risk of leukemia: a Poisson regression with two-way fixed-effects analysis

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Dear Editor, Research discussing potential environmental toxins that may be related to the etiology of childhood leukemia has been growing. The suspected environmental contaminants include solvents, air pollutants, pesticides, and tobacco smoke. Exposure to various pesticides has come under particular scrutiny, with positive associations with childhood leukemia [1]. Poynter et al. [2] conducted a population-based study assessing the association between self-reported chemical exposures and odds of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The authors found no clear association between pesticides and AML or MDS; however, they did report significant associations of AML and MDS with other chemicals, including benzene, vinyl chloride, and fertilizers [2]. While it is certainly important to identify exposure to pesticides as a potential etiological factor in leukemia onset, it is also important to address confounding variables, such as fertilizers, that may be both strongly associated with pesticide use and empirically associated with leukemic outcomes. We have previously identified environmental exposure to nitrous oxide (N2O), an agricultural and combustion pollutant, as a likely effect modifier to the proposed relationship between the use of the herbicide, glyphosate, and neurodevelopmental outcomes like attention-deficit hyperactivity disorder (ADHD) [3]. We found that use of glyphosate was closely tied to the use of nitrogen fertilizers in agriculture at a county urbanization level [3]. Therefore, it is possible that pesticide exposures may act as a proxy for air pollutants (i.e., N2O) directly related to the use of anthropogenic nitrogen in agriculture. Prior studies have identified pre-morbid ADHD and other developmental abnormality in children newly diagnosed with leukemia [4]. Therefore, if environmental N2O is a trigger for neurodevelopmental disorders, as we have suggested, and developmental abnormalities may precede childhood leukemia, we hypothesize that chronic exposure to N2O in the environment, and not necessarily pesticide exposures, may foster both neurodevelopmental and hematologic abnormalities. To investigate the possible association between farm use of nitrogen fertilizers—as the most relevant environmental proxy for N2O emissions—and hospitalization for blood-related cancers, we have replicated our earlier work [3] using the database from the Healthcare Cost and Utilization Project (HCUP). We conducted a Poisson regression analysis using a two-way fixed-effects model. This approach minimizes the likelihood of omitted variable bias due to unobserved or unmeasured factors that influence the outcome. Briefly, a random variable Y is said to have a Poisson distribution with parameter μ if it takes integer values y = 0, 1, 2, ... with probability.