Elsevier

Mutation Research/Reviews in Mutation Research

Volume 781, July–September 2019, Pages 186-206
Mutation Research/Reviews in Mutation Research

Review
Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence

https://doi.org/10.1016/j.mrrev.2019.02.001Get rights and content

Abstract

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13–1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11–1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.

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) awardT32ES015459 and the University of Washington Retirement Association Aging Fellowship. The

References (126)

  • K.R. Shankland et al.

    Non-Hodgkin lymphoma

    Lancet

    (2012)
  • Y. Aitbali et al.

    Glyphosate based-herbicide exposure affects gut microbiota, anxiety and depression-like behaviors in mice

    Neurotoxicol. Teratol.

    (2018)
  • J. Nardi et al.

    Prepubertal subchronic exposure to soy milk and glyphosate leads to endocrine disruption

    Food Chem. Toxicol. Int. J. Publ. For. Br. Ind. Biol. Res. Assoc.

    (2017)
  • A. Pandey et al.

    Analysis of endocrine disruption effect of Roundup® in adrenal gland of male rats

    Toxicol. Rep.

    (2015)
  • G.A. Altamirano et al.

    Postnatal exposure to a glyphosate-based herbicide modifies mammary gland growth and development in Wistar male rats

    Food Chem. Toxicol. Int. J. Publ. For. Br. Ind. Biol. Res. Assoc.

    (2018)
  • G. Thelin et al.

    Estimation of Annual Agricultural Pesticide Use for Counties of the Conterminous United States, 1992–2009: U.S. Geological Survey Scientific Investigations Report 2013-5009

    (2013)
  • C.M. Benbrook

    Trends in glyphosate herbicide use in the United States and globally

    Environ. Sci. Eur.

    (2016)
  • EPA

    Glyphosate Reregistration Eligibility Document (RED). Glyphosate. EPA-738-R-93-014.

    (1993)
  • EPA
  • Y. Wang et al.

    Accumulation of 2, 4-D and glyphosate in fish and water hyacinth

    Water Air Soil. Pollut.

    (1994)
  • D. Roy et al.

    Uptake and persistence of the herbicide glyphosate (vision®) in fruit of wild blueberry and red raspberry

    Can. J. For. Res.

    (1989)
  • N.R. Rodrigues et al.

    Occurrence of glyphosate and AMPA residues in soy-based infant formula sold in Brazil

    Food Addit. Contam. Part. A Chem. Anal. Control. Exp. Risk Assess.

    (2018)
  • P. Alferness et al.

    Determination of glyphosate and (aminomethyl)phosphonic acid in soil, plant and animal matrices, and Water by capillary gas chromatography with mass-selective detection

    J. Agric. Food. Chem.

    (1994)
  • K. Granby et al.

    Analysis of glyphosate residues in cereals using liquid chromatography-mass spectrometry (LC-MS/MS)

    Food Addit. Contam.

    (2003)
  • Cox Caroline

    Glyphosate, part 1: toxicology

    J. Pestic. Reform

    (1995)
  • C. Gillezeau et al.

    The evidence of human exposure to glyphosate: a review

    Environ. Health

    (2019)
  • P.J. Mills et al.

    Excretion of the herbicide glyphosate in older adults between 1993 and 2016

    JAMA

    (2017)
  • J.F. Villarreal-Chiu et al.

    Biological limitations on glyphosate biodegradation

  • A.J. De Roos et al.

    Integrative assessment of multiple pesticides as risk factors for non-Hodgkin’s lymphoma among men

    Occup. Environ. Med.

    (2003)
  • M. Eriksson et al.

    Pesticide exposure as risk factor for non-Hodgkin lymphoma including histopathological subgroup analysis

    Int. J. Cancer

    (2008)
  • L. Hardell et al.

    Exposure to pesticides as risk factor for non-Hodgkin’s lymphoma and hairy cell leukemia: pooled analysis of two Swedish case-control studies

    Leukemia Lymphoma

    (2002)
  • L. Orsi et al.

    Occupational exposure to pesticides and lymphoid neoplasms among men: results of a French case-control study

    Occup. Environ. Med.

    (2009)
  • A.J. De Roos et al.

    Cancer incidence among glyphosate-exposed pesticide applicators in the agricultural health study

    Environ. Health Perspect.

    (2005)
  • EPA

    Revised Glyphosate Issue Paper: Evaluation of Carcinogenic Potential

    (2017)
  • JMPR

    World Health Organization: Pesticide Residues in Food-2016: Toxicological Evaluations. Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues, Geneva, Switzerland

    (2017)
  • IARC
    (2015)
  • California Office of Environmental Health Hazard Assessment, Safe Drinking Water and Toxic Enforcement Act of 1986: The Proposition 65 List

    (1985)
  • G. Andreotti et al.

    Glyphosate use and cancer incidence in the agricultural health study

    J. Natl. Cancer Inst.

    (2018)
  • L. Schinasi et al.

    Non-Hodgkin lymphoma and occupational exposure to agricultural pesticide chemical groups and active ingredients: a systematic review and meta-analysis

    Int. J. Environ. Res. Public Health

    (2014)
  • E.T. Chang et al.

    Systematic review and meta-analysis of glyphosate exposure and risk of lymphohematopoietic cancers

    J. Environ. Sci. Health Part. B Pesticides Food Contam. Agric. Wastes

    (2016)
  • W.N. Rom et al.

    Environmental and Occupational Medicine

    (2007)
  • C. Steinmaus et al.

    Meta-analysis of benzene exposure and non-Hodgkin lymphoma: biases could mask an important association

    Occup. Environ. Med.

    (2008)
  • S. Greenland

    Meta-analysis

  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    PLoS Med.

    (2009)
  • S.K. Hoar et al.

    Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma

    JAMA

    (1986)
  • S.H. Zahm et al.

    A case-control study of non-Hodgkin’s lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska

    Epidemiology

    (1990)
  • L. Kachuri et al.

    Multiple pesticide exposures and the risk of multiple myeloma in Canadian men

    Int. J. Cancer

    (2013)
  • W.J. Lee et al.

    Non-Hodgkin’s lymphoma among asthmatics exposed to pesticides

    Int. J. Cancer

    (2004)
  • K.P. Cantor et al.

    Pesticides and other agricultural risk factors for non-Hodgkin’s lymphoma among men in Iowa and Minnesota

    Cancer Res.

    (1992)
  • L. Hardell et al.

    A case-control study of non-Hodgkin lymphoma and exposure to pesticides

    Cancer

    (1999)
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