Genotoxicity Assays Published since 2016 Shed New Light on the Oncogenic Potential of Glyphosate-Based Herbicides
Abstract
:1. Introduction
2. Methods
- “Glyphosate. Study summaries for genotoxicity studies” issued by OPP [143].
- Descriptions of Monsanto and other registrant-commissioned genotoxicity assays contained in expert reports, depositions and documents generated as a result of ongoing Roundup-NHL litigation.
3. Results
“The overall weight of evidence indicates that there is no convincing evidence that glyphosate induces mutations in vivo via the oral route.”
4. Discussion
- Proven carcinogen or oncogenic;
- Probable carcinogen or probably oncogenic;
- Possible or possibly carcinogenic or oncogenic;
- Not likely to be carcinogenic or oncogenic;
- Inadequate data to support or reach a classification decision.
- 3 studies were judged to be “High” quality;
- 21 were regarded as “Moderate” quality; and
- 34 were determined to be of “low” quality.
“Based on the weight-of-the-evidence, the agency cannot exclude chance or bias as an explanation for the observed associations in the database… A conclusion regarding the association between glyphosate exposure and risk of NHL cannot be determined based on available data”.
“ORD’s epidemiologists agree with IARC that there is ‘limited evidence’ of carcinogenicity in humans and understands IARC’s definition of ‘limited evidence’ as ‘a positive association has been observed’ for which a causal association is ‘credible, but chance, bias, or confounding could not be ruled out with reasonable confidence’” [43].
Starkly Divergent Assessments of the Genotoxicity Database
“… there is strong evidence that glyphosate can operate through two key [mechanistic] characteristics of known human carcinogens”. Specifically:
“There is strong evidence that exposure to glyphosate or glyphosate-based formulations is genotox based on studies in humans in vitro and studies in experimental animals…”; “There is strong evidence that glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid [AMPA] can act to induce oxidative stress…” [30].
- OPP focused on studies conducted testing technical glyphosate, while IARC placed considerable weight on in vivo GBH studies focused on biomarkers of genotoxicity in exposed human populations and experimental animals.
- The significant potentiation of GBH genotoxicity caused by the coformulants in GBHs, coupled with the enhancement of dermal penetration brought about by the most common GBH surfactants (POEAs).
- OPP/EPA relied predominantly on inappropriate bacterial genotoxicity assays conducted by or for GBH registrants, almost all of which were negative, while the IARC Working Group relied on a larger body of mostly published genotoxicity assays, of which over 70% reported one or more positive response.
5. Conclusions
- In accord with US federal law, the OPP focused its review on dietary exposures to technical glyphosate (i.e., the “oral route” of exposure), and largely ignored dermal exposures to GBHs and the ways that the surfactants in GBHs increase applicator exposures and, consequently, increase cancer risk.
- The IARC Working Group placed heavy weight on published epidemiology and genotoxicity studies in human populations exposed to formulated GBHs, and especially studies involving people exposed to GBHs over a span of years. Conversely, OPP placed little or no weight on these key studies and/or raised questions over the conclusions articulated by study authors.
- GBH applicators are exposed to far more glyphosate in a day of spraying GBHs than from glyphosate residues in their diet. This is especially the case among applicators who apply a GBH with small-scale, handheld spray equipment.
- The OPP relied mostly on purportedly negative studies done by GBH registrants, while IARC relied primarily on published studies not commissioned or sponsored by manufacturers, of which more than 70% reported positive results.
- (1)
- The identity and concentrations of all inert ingredients should be disclosed and listed on pesticide labels;
- (2)
- Applicator and farmworker dermal-exposure risk assessments should be markedly improved and new risk-mitigation measures and requirements codified in law;
- (3)
- The majority of the toxicological and exposure studies required by EPA prior to approval of new pesticide uses, or reregistration of existing uses, should be carried out on both active ingredients and selected, widely-sold formulated products; and
- (4)
- Most foundational pesticide toxicity and risk assessment studies should be conducted by scientists independent of the pesticide industry.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Glyphosate Technical | Number of Assays | 5 |
Positive | 4 | |
Percent Positive | 80% | |
Formulated GBHs | Number of Assays | 11 |
Positive | 9 | |
Percent Positive | 82% | |
All New Studies | Number of Assays | 16 |
Positive | 13 | |
Percent Positive | 81% |
Author & Date | Study Design | Methodology | Reported Results | Result |
---|---|---|---|---|
Bolognesi et al., 2009 [144] | Before v. after exposure | MN * frequency in peripheral leukocytes | There were significant increases in MN frequency after glyphosate exposure. | Positive |
Hutter, 2018 [66] | Exposed v. unexposed pesticide workers | Buccal micronucleus cytome assay (MN frequency and nuclear anomalies) | There were statistically significant nuclear anomalies in pesticide-exposed (primarily glyphosate) workers. | Positive |
Kupske, 2021 [67] | Before v. after exposure | MN frequency and other cellular alterations in buccal cells | There were significant increases in MN frequency, broken egg cells, binucleation, and karyolysis after glyphosate exposure. | Positive |
Leite, 2019 [68] | Exposed v. unexposed children | Buccal micronucleus Comet assay | The study found higher frequency of all damages analyzed (MN, binucleation, broken egg, karyorrhexis, karyolysis, pyknosis, and condensed chromatin). | Positive |
Lucia, 2022 [69] | Post-menopausal women | Differentially methylated probes (DNA methylation was measured at over 850,000 CpG sites) Biomonitoring methodology | The study identified 17 CpG sites (probes) at which a decrease in methylation was associated with increasing levels of urinary glyphosate. Four genomic regions, all located within gene promoters, were significantly associated with glyphosate levels in >90% of subsamples. | Positive |
Makris, 2020 [70] | Children 10–11 years old | Oxidative stress was assessed with immunoassay measurements of marker 8-iso-PGF2a for lipid damage and 8-OHdG as a DNA oxidative damage marker. Biomonitoring methodology | The DNA oxidative damage marker (8-OHdG) was positively associated with AMPA (beta = 0.17; 95% CI: 0.02, 0.31, p = 0.03 cr2, and beta = 0.12; 95% CI: 0.0, 0.24, p = 0.06, cr1), but not with GLY (p > 0.05). | Positive |
Paz-y-Miño, 2007 [145] | Exposed v. unexposed | Comet assay | The results showed a higher degree of DNA damage in the exposed group (comet length = 35.5 pm) compared to the control group (comet length = 25.9 4 pm), suggesting that the formulation used during aerial spraying glyphosate had a genotoxic effect on the exposed individuals. | Positive |
Glyphosate Technical | Number of Assays | 19 |
Positive | 13 | |
Percent Positive | 68% | |
Formulated GBHs | Number of Assays | 12 |
Positive | 12 | |
Percent Positive | 100% | |
All New Studies | Number of Assays | 31 |
Positive | 25 | |
Percent Positive | 81% |
Glyphosate Technical | Number of Assays | 6 |
Positive | 6 | |
Percent Positive | 100% | |
Formulated GBHs | Number of Assays | 33 |
Positive | 33 | |
Percent Positive | 100% | |
All New Studies | Number of Assays | 39 |
Positive | 39 | |
Percent Positive | 100% |
Glyphosate Technical | Number of Assays | 3 |
Positive | 1 | |
Percent Positive | 33% | |
Formulated GBHs | Number of Assays | 5 |
Positive | 4 | |
Percent Positive | 80% | |
All New Studies | Number of Assays | 8 |
Positive | 5 | |
Percent Positive | 63% |
Glyphosate Technical | Number of Assays | 33 |
Positive | 24 | |
Percent Positive | 73% | |
Formulated GBHs | Number of Assays | 61 |
Positive | 58 | |
Percent Positive | 95% | |
All New Studies | Number of Assays | 94 |
Positive | 82 | |
Percent Positive | 87% |
Registrant Studies | Type | Number of Assays | Number Positive |
BRM | 14 | 0 | |
MN | 9 | 1 | |
Gene mutations and other | 9 | 0 | |
Chrom aberration | 5 | 0 | |
Totals | 37 | 1 | |
Percent Positive | 2.7% | ||
BRM as % All | 37.8% | ||
% Since 2000 | 21.6% | ||
Published Studies | Type | Number of Assays | Number Positive |
BRM | 4 | 0 | |
MN | 8 | 7 | |
SCE | 4 | 4 | |
Comet | 5 | 5 | |
Chrom aberration | 4 | 2 | |
Oxidative stress & other | 3 | 2 | |
Totals | 28 | 20 | |
Percent Positive | 71.4% | ||
BRM as % All | 14.3% | ||
% Since 2000 | 35.7% |
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Benbrook, C.; Mesnage, R.; Sawyer, W. Genotoxicity Assays Published since 2016 Shed New Light on the Oncogenic Potential of Glyphosate-Based Herbicides. Agrochemicals 2023, 2, 47-68. https://doi.org/10.3390/agrochemicals2010005
Benbrook C, Mesnage R, Sawyer W. Genotoxicity Assays Published since 2016 Shed New Light on the Oncogenic Potential of Glyphosate-Based Herbicides. Agrochemicals. 2023; 2(1):47-68. https://doi.org/10.3390/agrochemicals2010005
Chicago/Turabian StyleBenbrook, Charles, Robin Mesnage, and William Sawyer. 2023. "Genotoxicity Assays Published since 2016 Shed New Light on the Oncogenic Potential of Glyphosate-Based Herbicides" Agrochemicals 2, no. 1: 47-68. https://doi.org/10.3390/agrochemicals2010005