Elsevier

Environmental Pollution

Volume 285, 15 September 2021, 117376
Environmental Pollution

Review
Exposure to pesticides and childhood leukemia risk: A systematic review and meta-analysis

https://doi.org/10.1016/j.envpol.2021.117376Get rights and content

Highlights

  • Evidence on pesticide exposures and childhood leukemia risk remains inconsistent.

  • Environmental exposure to pesticides increases the risk of childhood leukemia.

  • The association is stronger for exposure during pregnancy, and for infant leukemia.

  • Insecticides and herbicides are both associated with higher risk of childhood ALL.

Abstract

Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15–3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39–4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00–1.99) and insecticide (OR: 1.60, 95%CI: 1.11–2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12–0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44–3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98–5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (ORparental: 1.75, 95%CI: 1.08–2.85; ORpaternal: 1.20, 95%CI: 1.07–1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.

Introduction

Acute leukemia (AL) is the most common type of childhood cancer (0–14 years) accounting for up to 40% of pediatric cancer cases (Noone et al., 2017). Though the disease is rare at population level with an annual incidence of approximately 39 cases per million children, a small, but steady increase in the incidence of AL has been reported over the past three decades (Noone et al., 1975–2015). Despite striking advances in disease survival, childhood AL remains the second leading cause of death worldwide following physical injury; childhood AL deaths are responsible for around 131,000 years of life lost (YLL) in the USA (Collaborators, 2019). Long-term AL survivors are likely to experience severe adverse health outcomes throughout their adulthood (Erdmann et al., 2019; Landier et al., 2015). In particular, it is estimated that 40% of adults older than 35 years who have been diagnosed with pediatric cancer will experience life-threatening complications with mortality rates up to five times higher compared to their healthy counterparts (Armenian and Robison, 2013). Thus, primary prevention of this disease remains an utmost priority (Metayer et al., 2016).

Extensive research has focused on the multifactorial etiology of childhood AL involving an intricate interaction between a strong genetic component and many lifestyle influences (Buffler et al., 2005; Wiemels, 2012). The increasing incidence of the disease could be attributed, among others, to environmental determinants. Emerging evidence suggests that environmental contaminants may also play a crucial role. Pesticides represent an increasingly widespread environmental exposure and some specific compounds have the potential to accumulate in human tissues. This is a concern especially in children whose enzymatic and metabolic systems limits their ability to detoxify and excrete pesticides; in addition to this, the greater cellular division in children renders them more vulnerable to hazardous complications including acute toxic effects on their respiratory, gastrointestinal, nervous, and endocrine systems (Sheets, 2000; Infante-Rivard and Weichenthal, 2007). In recent years, there have been growing concerns about possible adverse health effects of low-level pesticide exposure during pregnancy or childhood generating a substantial number of epidemiologic studies (Panel on Plant Prote, 2017). Several of these studies have examined the association between environmental or occupational pesticide exposure and risk of childhood cancer, specifically focusing on leukemia (Infante-Rivard and Weichenthal, 2007; Bailey et al., 2014; Bailey et al., 2015; Patel et al., 2020a; Zahm, 1999; Meinert et al., 2000). Various systematic reviews and meta-analyses have also studied the association between environmental or occupational pesticide exposure and childhood AL risk (Turner et al., 2010; Van Maele-Fabry et al., 2019; Van Maele-Fabry et al., 2010; Van Maele-Fabry et al., 2011; Chen et al., 2015; Wigle et al., 2009). Overall, to-date evidence remains inconclusive and is inherently limited by heterogeneous exposure and outcome assessment (type of pesticides, exposed individual, window of exposure, type of leukemia), which, by necessity, result in multiple statistical testing that increase the probability of chance findings (Turner et al., 2010; Van Maele-Fabry et al., 2019; Metayer and Buffler, 2008).

Acknowledging these inherent limitations, in the present study, we aimed to comprehensively and systematically appraise the currently available epidemiological evidence on the association of exposure to pesticides with different types of childhood AL, including acute lymphoblastic (ALL), acute myeloid (AML) and infant leukemia, with a special focus on the methodological issues of literature.

Section snippets

Data sources and search

The present systematic review and meta-analysis adheres to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Supplementary Table 1) (Welch et al., 2016).

We searched for peer-reviewed original epidemiological research pertaining to pesticide exposure and risk of childhood AL. Our previous systematic literature search was conducted between January 1, 2006 and July 5, 2019 for the European Food and Safety Authority (EFSA). In the present systematic review

Study characteristics and quality evaluation

The initial literature search in MEDLINE and EMBASE databases retrieved 205,290 articles, of which 83 were evaluated for eligibility following the titles-first and title-and-abstract approaches as shown in the flow chart of the study selection process (Fig. 1). Twenty-seven publications (Noone et al., 1975–2015; Zahm, 1999; Alderton et al., 2006; Canalle et al., 2004; Flower et al., 2004; Kaatsch et al., 1996; Kishi et al., 1993; Kristensen et al., 1996; Maskarinec, 2005; Monge et al., 2004;

Principal findings

To our knowledge, this is the largest comprehensive systematic review and meta-analysis including all types of pesticide exposures and all types of childhood leukemia. Despite the large volume of available evidence stemming from 52 studies, a combined quantitative synthesis of all eligible studies was not feasible owing to the large variability in definitions of pesticide exposure, outcomes and windows of exposure (preconception, pregnancy or postnatal). Acknowledging this variability in study

Credit author statement

Maria A. Karalexi: Conceptualization, Data extraction and Quality Assessment, Statistical analysis, Writing – original draft, Final approval before submission Christos F. Tagkas: Data extraction and Quality Assessment, Statistical Analysis, Reviewing and Editing, Final approval before submission Georgios Markozannes: Statistical Analysis, Validation, Reviewing and Editing, Final approval before submission Xanthippi Tseretopoulou: Data extraction and Quality Assessment, Reviewing and Editing,

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments/Funding

This research is based on, and extends the publicly available results of a project outsourced by the United Nations Environment Program (UNEP). The present document has been produced and adopted by the bodies identified above as author(s). It does not necessarily reflect the position, policy and views of the United Nations Environment Program. The present study is co-financed by Greece and the European Union (European Social Fund- ESF) through the Operational Programme « Human Resources

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