Genotoxic Potential of Glyphosate Formulations: Mode-of-Action Investigations

Heydens, William F.; Healy, Charles E.; Hotz, Kathy J.; Kier, Larry D.; Martens, Mark A.; Wilson, Alan G. E.; Farmer, Donna R.

doi:10.1021/jf072581i

Cited by 13 publications

(17 citation statements)

References 18 publications

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“…Glyphosate was reported to induce 8-OHdG adducts in liver but not kidney tissues whereas a GBF (with an equivalent level of glyphosate) was reported to induce 8-OHdG adducts in kidney but not in liver tissue. Results of the Bolognesi et al (1997) study are contradicted by another published study (Heydens et al 2008) that was not considered by IARC. In this study no statistically significant increases in 8-OHdG were observed in liver or kidneys of mice 24 h after treatment by i.p.…”

Section: Indirect Measures Of Oxidative Stress Vs Measures Of Oxidatmentioning

confidence: 90%

“…Moreover, the GBF was administered i.p. using dimethylsulfoxide (DMSO) as a vehicle and the use of this vehicle and route has unusual toxicity properties (Heydens et al 2008). This assay was also unusual in that doseresponsive increases were observed at multiple sampling times, which is difficult to explain since cells damaged at early sampling times have usually died and disappeared from the bone marrow by later sampling times.…”

Section: Chromosomal Effects In Vivomentioning

confidence: 99%

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Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Brusick¹,

Aardema²,

Kier

et al. 2016

Critical Reviews in Toxicology

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published a monograph concluding there was strong evidence for genotoxicity of glyphosate and glyphosate formulations and moderate evidence for genotoxicity of the metabolite aminomethylphosphonic acid (AMPA). These conclusions contradicted earlier extensive reviews supporting the lack of genotoxicity of glyphosate and glyphosate formulations. The IARC Monograph concluded there was strong evidence of induction of oxidative stress by glyphosate, glyphosate formulations, and AMPA. The Expert Panel reviewed the genotoxicity and oxidative stress data considered in the IARC Monograph, together with other available data not considered by IARC. The Expert Panel defined and used a weight of evidence (WoE) approach that included ranking of studies and endpoints by the strength of their linkage to events associated with carcinogenic mechanisms. Importantly, the Expert Panel concluded that there was sufficient information available from a very large number of regulatory genotoxicity studies that should have been considered by IARC. The WoE approach, the inclusion of all relevant regulatory studies, and some differences in interpretation of individual studies led to significantly different conclusions by the Expert Panel compared with the IARC Monograph. The Expert Panel concluded that glyphosate, glyphosate formulations, and AMPA do not pose a genotoxic hazard and the data do not support the IARC Monograph genotoxicity evaluation. With respect to carcinogenicity classification and mechanism, the Expert Panel concluded that evidence relating to an oxidative stress mechanism of carcinogenicity was largely unconvincing and that the data profiles were not consistent with the characteristics of genotoxic carcinogens. ARTICLE HISTORY

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Section: Indirect Measures Of Oxidative Stress Vs Measures Of Oxidatmentioning

confidence: 90%

Section: Chromosomal Effects In Vivomentioning

confidence: 99%

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Brusick¹,

Aardema²,

Kier

et al. 2016

Critical Reviews in Toxicology

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“…The authors suggested that subtoxic concentrations of H 2 O 2 that occur in the cell due to presence of xenobiotics may lead to the genotoxic effects. However, Heydens et al [2008] showed no significant increase in the amount of 8-OHdG, despite kidney values being 143% higher than control values. Comparing the tail intensity values for both comet assay versions (Table II and III), at all tested concentrations, we obtained higher statistical differences between treated and untreated cells for the alkaline comet assay than for the hOGG1 modified comet assay.…”

Section: Discussionmentioning

confidence: 63%

Evaluation of genome damage and its relation to oxidative stress induced by glyphosate in human lymphocytes in vitro

Mladinić

Berend

Vrdoljak

et al. 2009

Environ and Mol Mutagen

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In the present study we evaluated the genotoxic and oxidative potential of glyphosate on human lymphocytes at concentrations likely to be encountered in residential and occupational exposure. Testing was done with and without metabolic activation (S9). Ferric-reducing ability of plasma (FRAP), thiobarbituric acid reactive substances (TBARS) and the hOGG1 modified comet assay were used to measure glyphosate's oxidative potential and its impact on DNA. Genotoxicity was evaluated by alkaline comet and analysis of micronuclei and other nuclear instabilities applying centromere probes. The alkaline comet assay showed significantly increased tail length (20.39 microm) and intensity (2.19%) for 580 microg/ml, and increased tail intensity (1.88%) at 92.8 microg/ml, compared to control values of 18.15 mum for tail length and 1.14% for tail intensity. With S9, tail length was significantly increased for all concentrations tested: 3.5, 92.8, and 580 microg/ml. Using the hOGG1 comet assay, a significant increase in tail intensity was observed at 2.91 microg/ml with S9 and 580 microg/ml without S9. Without S9, the frequency of micronuclei, nuclear buds and nucleoplasmic bridges slightly increased at concentrations 3.5 microg/ml and higher. The presence of S9 significantly elevated the frequency of nuclear instabilities only for 580 microg/ml. FRAP values slightly increased only at 580 microg/ml regardless of metabolic activation, while TBARS values increased significantly. Since for any of the assays applied, no clear dose-dependent effect was observed, it indicates that glyphosate in concentrations relevant to human exposure do not pose significant health risk.

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“…A published toxicity study has reported that use of a DMSO/olive oil vehicle by the i.p. route dramatically enhanced the toxicity of glyphosate formulation or the formulation components without glyphosate compared to saline vehicle (Heydens et al, 2008). The enhanced toxicity observed with this vehicle was not observed when the oral route was used.…”

Section: Micronucleus and Chromosomal Aberrationmentioning

confidence: 94%

“…Heydens et al (2008) reported on studies in mice to further investigate toxic effects and 8-OHdG levels associated with the routes, vehicles and dose levels of the earlier studies. The Heydens et al (2008) publication reported significant GBF-induced liver and kidney toxicity for high i.p. doses but no liver or kidney toxicity for comparable oral doses.…”

Section: Glyphosate-based Formulationsmentioning

confidence: 99%

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

Kier

Kirkland²

2013

Critical Reviews in Toxicology

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120

102

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An earlier review of the toxicity of glyphosate and the original Roundupä-branded formulation concluded that neither glyphosate nor the formulation poses a risk for the production of heritable/somatic mutations in humans. The present review of subsequent genotoxicity publications and regulatory studies of glyphosate and glyphosate-based formulations (GBFs) incorporates all of the findings into a weight of evidence for genotoxicity. An overwhelming preponderance of negative results in well-conducted bacterial reversion and in vivo mammalian micronucleus and chromosomal aberration assays indicates that glyphosate and typical GBFs are not genotoxic in these core assays. Negative results for in vitro gene mutation and a majority of negative results for chromosomal effect assays in mammalian cells add to the weight of evidence that glyphosate is not typically genotoxic for these endpoints in mammalian systems. Mixed results were observed for micronucleus assays of GBFs in nonmammalian systems. Reports of positive results for DNA damage endpoints indicate that glyphosate and GBFs tend to elicit DNA damage effects at high or toxic dose levels, but the data suggest that this is due to cytotoxicity rather than DNA interaction with GBF activity perhaps associated with the surfactants present in many GBFs. Glyphosate and typical GBFs do not appear to present significant genotoxic risk under normal conditions of human or environmental exposures.

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Genotoxic Potential of Glyphosate Formulations: Mode-of-Action Investigations

Cited by 13 publications

References 18 publications

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Genotoxicity Expert Panel review: weight of evidence evaluation of the genotoxicity of glyphosate, glyphosate-based formulations, and aminomethylphosphonic acid

Evaluation of genome damage and its relation to oxidative stress induced by glyphosate in human lymphocytes in vitro

Review of genotoxicity studies of glyphosate and glyphosate-based formulations

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