ReviewExposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence
Section snippets
Global usage of glyphosate-based herbicides
Glyphosate is a highly effective broad spectrum herbicide that is typically applied in mixtures known as glyphosate-based herbicides (GBHs) and commonly sold under the trade names of Roundup® and Ranger Pro®. Use of GBHs has dramatically increased worldwide in recent decades (Fig. 1). In the United States alone, usage increased nearly sixteen-fold between 1992 and 2009 [1]. Most of this increase occurred after the introduction of genetically modified glyphosate-resistant “Roundup-ready” crops
Meta-analysis objective
Epidemiological studies may vary in several ways, such as by study design, sample size, and exposure assessment methods. Results among individual studies vary and may appear to conflict, which poses challenges in drawing an overall conclusion. Meta-analysis is a quantitative statistical tool that is frequently applied to consolidate the results from similar but separate individual studies so that an overall conclusion about the effects of exposure can be drawn. Here, we conducted a
Increased meta-relative risk of NHL
Table 5 reports the results from our two meta-analyses, which included the primary analysis using the most recently updated AHS cohort [25] and the secondary comparison analysis using the original study [20]. With the AHS results [25], we observed a meta-RR of 1.41 (95% CI: 1.13–1.75), which indicates a statistically significant increased risk (41%) of NHL following high cumulative GBH exposure. Although our results focus on the fixed-effects model, using the random-effects model resulted in a
Comparison with previous meta-analyses
Three meta-analyses of NHL in relation to GBH exposure have been published [23,26,27], all of which report lower, albeit also positive, risk estimates. In contrast to our work, these analyses did not focus on the highest exposed groups. Table 7 summarizes the major results from all GBH-NHL meta-analyses conducted to date, including the current one.
Schinasi and Leon [26] first reported a meta-RR of 1.45 (95% CI: 1.08–1.95). Although their selection criteria stated that they used the most
Strengths and limitations
In this section, we evaluate the strengths and limitations of our meta-analysis, as well as of the cohort and the case-control studies utilized.
Summary of the GBH and NHL association in humans
Overall, the results from our new meta-analysis employing the a priori hypothesis and including the updated AHS 2018 study (1) demonstrate a statistically significant increased NHL risk in highly GBH-exposed individuals (meta-RR = 1.41, 95% CI: 1.13–1.75; Table 5 and Fig. 3A), (2) are aligned with findings from previous meta-analyses [23,26,27] (Table 7), and (3) reveal an additional 11–14% and 15–18% increase in NHL relative risk due to high levels of GBH exposure (Table 7) when using the AHS
Animal data: lymphoma prevalence in glyphosate-exposed mice
The animal study outcome most closely linked to human NHL is malignant lymphoma. We identified six unpublished glyphosate and lymphoma studies in mice that are in the public domain from two sources: a presentation by the European Food Safety Authority (EFSA) [71] at the EPA FIFRA Scientific Advisory Panel on Carcinogenic Potential of Glyphosate and a report by The Food and Agriculture Organization of the United Nations and World Health Organization Joint Meeting on Pesticide Residues (JMPR) [22
Potential mechanistic context
There are several possible mechanistic explanations for the increased NHL risk in humans and lymphomas in animals. The etiology of NHL remains largely unknown; however, potential risk factors include autoimmune diseases, infection with viruses and/or bacteria, immunosuppressant medications, and exposures to some pesticides [83,84]. Although not a formally recognized risk factor for NHL, endocrine disruptors have been associated recently with risk of B-cell neoplasms [85], most of which are NHL [
Conclusions and future directions
The rise of GBHs as the most widely used herbicide raises serious health concerns, given its potential links with NHL. Using our a priori hypothesis and including the recently updated AHS cohort in a meta-analysis for the first time, we report that GBH exposure is associated with increased risk of NHL in humans. Our findings are consistent with results reported from prior meta-analyses but show higher risk for NHL because of our focus on the highest exposure groups. However, given the
Declaration of interest
All authors have no financial conflicts of interest to declare. We disclose Drs. Zhang, Taioli, and Sheppard served as Science Review Board Members of the US EPA FIFRA Scientific Advisory Panel (SAP) Meeting that evaluated glyphosate in December 2016.
Acknowledgements
The authors thank Christina Gillezeau, MPH from Icahn School of Medicine at Mount Sinai, New York for carefully checking epidemiological data and Phum Tachachartvanich, PhD for intellectual review and discussion on mechanisms of endocrine disruption. We also thank the anonymous reviewers for their helpful comments. R.M.S. was supported by National Institutes of Environmental Health Sciences (NIEHS) award T32ES015459 and the University of Washington Retirement Association Aging Fellowship. The
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