Ethoxylated Adjuvants of Glyphosate-Based Herbicides Are Active Principles of Human Cell Toxicity

University of Caen, EA2608, Institute of Biology, Risk Pole CNRS, Esplanade de la Paix, 14032 Caen, Cedex, France
Toxicology (Impact Factor: 3.62). 09/2012; 313(2-3). DOI: 10.1016/j.tox.2012.09.006


Pesticides are always used in formulations as mixtures of an active principle with adjuvants. Glyphosate, the active ingredient of the major pesticide in the world, is an herbicide supposed to be specific on plant metabolism. Its adjuvants are generally considered as inert diluents. Since side effects for all these compounds have been claimed, we studied potential active principles for toxicity on human cells for 9 glyphosate-based formulations. For this we detailed their compositions and toxicities, and as controls we used a major adjuvant (the polyethoxylated tallowamine POE-15), glyphosate alone, and a total for-mulation without glyphosate. This was performed after 24 h exposures on hepatic (HepG2), embryonic (HEK293) and placental (JEG3) cell lines. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. The compositions in adjuvants were analyzed by mass spectrometry. Here we demonstrate that all formulations are more toxic than glyphosate, and we separated experimen-tally three groups of formulations differentially toxic according to their concentrations in ethoxylated adjuvants. Among them, POE-15 clearly appears to be the most toxic principle against human cells, even if others are not excluded. It begins to be active with negative dose-dependent effects on cellular respiration and membrane integrity between 1 and 3 ppm, at environmental/occupational doses. We demonstrate in addition that POE-15 induces necrosis when its first micellization process occurs, by contrast to glyphosate which is known to promote endocrine disrupting effects after entering cells. Alto-gether, these results challenge the establishment of guidance values such as the acceptable daily intake of glyphosate, when these are mostly based on a long term in vivo test of glyphosate alone. Since pesti-cides are always used with adjuvants that could change their toxicity, the necessity to assess their whole formulations as mixtures becomes obvious. This challenges the concept of active principle of pesticides for non-target species.

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    • "The major formulated preparation among glyphosate-based herbicides is Roundup ® , in which glyphosate is formulated as isopropylamine salt and POEA is added to enhance herbicidal efficacy by providing better penetrability to plant tissues via its detergent effect [1]. Although glyphosate presents lower acute toxicity on vertebrates than other herbicides, it has been evidenced to cause toxicity and genotoxicity in many taxonomic groups, especially in aquatic organisms and amphibians [6]; and to induce endocrine disrupting effects [7], the latter effect being highly synergized by POEA and other surfactants [8], [9] commonly used formulating agents in glyphosate-based herbicide preparations. "
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    ABSTRACT: Environmental and toxicological characteristics of formulated pesticides may substantially differ from those of their active ingredients or other components alone. This phenomenon is demonstrated in the case of the herbicide active ingredient glyphosate. Due to its extensive application, this active ingredient was found in surface and ground water samples collected in Békés County, Hungary, in the concentration range of 0.54–0.98 ng/ml. The occurrence of glyphosate appeared to be somewhat higher at areas under intensive agriculture, industrial activities and public road services, but the compound was detected at areas under organic (ecological) farming or natural grasslands, indicating environmental mobility. Increased toxicity of the formulated herbicide product Roundup compared to that of glyphosate was observed on the indicator aquatic organism Daphnia magna Straus. Acute LC50 values of Roundup and its formulating adjuvant polyethoxylated tallowamine (POEA) exceeded 20 and 3.1 μg/ml, respectively, while that of glyphosate (as isopropyl salt) was found to be substantially lower (690-900 μg/ml) showing good agreement with literature data. Cytotoxicity of Roundup, POEA and glyphosate has been determined on the neuroectodermal cell line, NE-4C measured both by cell viability test and holographic microscopy. Acute toxicity (LC50) of Roundup, POEA and glyphosate on NE-4C cells was found to be 0.013±0.002%, 0.017±0.009% and 6.46±2.25%, respectively (in equivalents of diluted Roundup solution), corresponding to 0.022±0.003 and 53.1±18.5 mg/ml for POEA and glyphosate, respectively, indicating no statistical difference between Roundup and POEA and 2.5 orders of magnitude difference between these and glyphosate. The same order of cellular toxicity seen in average cell area has been indicated under quantitative cell visualization. The results indicate that toxicity of the formulated herbicide is caused by the formulating agent, but in some parameters toxicological synergy occurs between POEA and glyphosate.
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    • "These include effects on the disturbances of sex hormones and severe dysfunctions in liver and kidneys. Moreover, our study represents the only study on Roundup that includes blood analyses of treated animals (and from very low environmental levels, 0.1 ppb), since regulatory agencies only have chronic data with glyphosate used alone (Mortureux, 2013), which is highly less toxic than Roundup (Mesnage et al., 2013; Richard et al., 2005). Such analyses have never been conducted on the complete herbicide formulation for regulatory purposes. "

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    • "The tolerances established by the U.S. Environmental Protection Agency under 40 CFR Part 180 for commodities such as grains or livestock are " expressed in terms of glyphosate, including its metabolites and degradates " (U.S. Environmental Protection Agency, 1993, 2011). Some studies indicate that commercial glyphosate formulations can be more toxic than pure glyphosate due to the toxicity and (or) action of the surfactants and other adjuvants used (Giesy et al., 2000; Edginton et al., 2004; Bringolf et al., 2007; Mesnage et al., 2012; Moore et al., 2012). Surfactants such as polyethoxylated tallowamine (POEA) are added to some commercial glyphosate formulations to enhance its efficacy. "
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    ABSTRACT: Glyphosate use in the United States increased from less than 5,000 to more than 80,000 metric tons/yr between 1987 and 2007. Glyphosate is popular due to its ease of use on soybean, cotton, and corn crops that are genetically modified to tolerate it, utility in no-till farming practices, utility in urban areas, and the perception that it has low toxicity and little mobility in the environment. This compilation is the largest and most comprehensive assessment of the environmental occurrence of glyphosate and aminomethylphosphonic acid (AMPA) in the United States conducted to date, summarizing the results of 3,732 water and sediment and 1,018 quality assurance samples collected between 2001 and 2010 from 38 states. Results indicate that glyphosate and AMPA are usually detected together, mobile, and occur widely in the environment. Glyphosate was detected without AMPA in only 2.3% of samples, whereas AMPA was detected without glyphosate in 17.9% of samples. Glyphosate and AMPA were detected frequently in soils and sediment, ditches and drains, precipitation, rivers, and streams; and less frequently in lakes, ponds, and wetlands; soil water; and groundwater. Concentrations of glyphosate were below the levels of concern for humans or wildlife; however, pesticides are often detected in mixtures. Ecosystem effects of chronic low-level exposures to pesticide mixtures are uncertain. The environmental health risk of low-level detections of glyphosate, AMPA, and associated adjuvants and mixtures remain to be determined.
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