Glyphosate (N-(phosphonomethyl)glycine) is a broad-spectrum systemic herbicide and crop desiccant. It is an organophosphorus compound, specifically a phosphonate. It is used to kill weeds, especially annual broadleaf weeds and grasses that compete with crops. It was discovered to be an herbicide by Monsanto chemist John E. Franz in 1970. Monsanto brought it to market in 1974 under the trade name Roundup, and Monsanto's last commercially relevant United States patent expired in 2000.
Farmers quickly adopted glyphosate, especially after Monsanto introduced glyphosate-resistant Roundup Ready crops, enabling farmers to kill weeds without killing their crops. In 2007, glyphosate was the most used herbicide in the United States' agricultural sector and the second-most used in home and garden (2,4-D being the most used), government and industry, and commerce. By 2016 there was a 100-fold increase from the late 1970s in the frequency of application and volume of glyphosate-based herbicides (GBHs) applied, with further increases expected in the future, partly in response to the global emergence and spread of glyphosate-resistant weeds.:1
Glyphosate is absorbed through foliage, and minimally through roots, and transported to growing points. It inhibits a plant enzyme involved in the synthesis of three aromatic amino acids: tyrosine, tryptophan, and phenylalanine. Therefore, it is effective only on actively growing plants and is not effective as a pre-emergence herbicide. An increasing number of crops have been genetically engineered to be tolerant of glyphosate (e.g. Roundup Ready soybean, the first Roundup Ready crop, also created by Monsanto) which allows farmers to use glyphosate as a postemergence herbicide against weeds. The development of glyphosate resistance in weed species is emerging as a costly problem.
While glyphosate and formulations such as Roundup have been approved by regulatory bodies worldwide, concerns about their effects on humans and the environment persist, and have grown as the global usage of glyphosate increases. A number of regulatory and scholarly reviews have evaluated the relative toxicity of glyphosate as an herbicide. The German Federal Institute for Risk Assessment toxicology review in 2013 found that "the available data is contradictory and far from being convincing" with regard to correlations between exposure to glyphosate formulations and risk of various cancers, including non-Hodgkin lymphoma (NHL). A meta-analysis published in 2014 identified an increased risk of NHL in workers exposed to glyphosate formulations.
In March 2015 the World Health Organization's International Agency for Research on Cancer classified glyphosate as "probably carcinogenic in humans" (category 2A) based on epidemiological studies, animal studies, and in vitro studies. In November, 2015, the European Food Safety Authority concluding that "the substance is unlikely to be genotoxic (i.e. damaging to DNA) or to pose a carcinogenic threat to humans," later clarifying that while carcinogenic glyphosate-containing formulations may exist, studies "that look solely at the active substance glyphosate do not show this effect." The WHO and FAO Joint committee on pesticide residues issued a report in 2016 stating the use of glyphosate formulations does not necessarily constitute a health risk, and giving admissible daily intake limits for chronic toxicity. The European Chemicals Agency (ECHA) classified glyphosate as causing serious eye damage and toxic to aquatic life, but did not find evidence implicating it to be a carcinogen, a mutagen, toxic to reproduction, nor toxic to specific organs.
Glyphosate was first synthesized in 1950 by Swiss chemist Henry Martin, who worked for the Swiss company Cilag. The work was never published.:1 Stauffer Chemical patented the agent as a chemical chelator in 1964 as it binds and removes minerals such as calcium, magnesium, manganese, copper, and zinc.
Somewhat later, glyphosate was independently discovered in the United States at Monsanto in 1970. Monsanto chemists had synthesized about 100 derivatives of aminomethylphosphonic acid as potential water-softening agents. Two were found to have weak herbicidal activity, and John E. Franz, a chemist at Monsanto, was asked to try to make analogs with stronger herbicidal activity. Glyphosate was the third analog he made.:1–2 Franz received the National Medal of Technology of the United States in 1987 and the Perkin Medal for Applied Chemistry in 1990 for his discoveries.
Monsanto developed and patented the use of glyphosate to kill weeds in the early 1970s and first brought it to market in 1974, under the Roundup brandname. While its initial patent expired in 1991, Monsanto retained exclusive rights in the United States until its patent on the isopropylamine salt expired in September 2000.
In 2008, United States Department of Agriculture (USDA) Agricultural Research Service (ARS) scientist Stephen O. Duke and Stephen B. Powles—an Australian weed expert—described glyphosate as a "virtually ideal" herbicide. In 2010 Powles stated: "glyphosate is a one in a 100-year discovery that is as important for reliable global food production as penicillin is for battling disease."
Glyphosate is an aminophosphonic analogue of the natural amino acid glycine, and like all amino acids, exists in different ionic states depending on pH. Both the phosphonic acid and carboxylic acid moieties can be ionised and the amine group can be protonated and the substance exists as a series of zwitterions. Glyphosate is soluble in water to 12 g/l at room temperature. The original synthetic approach to glyphosate involved the reaction of phosphorus trichloride with formaldehyde followed by hydrolysis to yield a phosphonate. Glycine is then reacted with this phosphonate to yield glyphosate, and its name is taken as a contraction of the compounds used in this synthesis - viz. glycine and a phosphonate.
Two main approaches are used to synthesize glyphosate industrially. The first is to react iminodiacetic acid with phosphorous acid and hydrochloric acid (sometimes formed in situ by addition of phosphorus trichloride) via a modified Mannich reaction. Oxidation then leads to the desired glyphosate product. Iminodiacetic acid is usually prepared on-site, such as by reaction of chloroacetic acid with ammonia and calcium hydroxide to produce the calcium iminodiacetate salt and then acidification of the product.
The chloroacetic acid approach is less efficient than other iminodiacetic acid approaches, owing to the production of calcium chloride waste and decreased yield. When hydrogen cyanide is readily available as a by-product (say), an alternative approach is to use iminodiacetonitrile, HN(CH2CN)2, and diethanolamine is also a suitable starting material.
The second involves the use of dimethyl phosphite in a one-pot synthesis. Glycine and paraformaldehyde are reacted in a suitable organic solvent (typically triethylamine and methanol) to produce bishydroxymethylglycine, (HOCH2)2NCH2COOH. Dimethyl phosphite is then introduced and work-up with hydrochloric acid cleaves the hydroxymethyl group from the nitrogen atom whilst heating speeds the hydrolysis of both phosphate ester linkages.
This synthetic approach is responsible for a substantial portion of the production of glyphosate in China, with considerable work having gone into recycling the triethylamine and methanol. Progress has also been made in attempting to eliminate the need for triethylamine altogether.
Glyphosate kills plants by interfering with the synthesis of the aromatic amino acids phenylalanine, tyrosine, and tryptophan in the shikimate pathway. It does this by inhibiting the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which catalyzes the reaction of shikimate-3-phosphate (S3P) and phosphoenolpyruvate to form 5-enolpyruvyl-shikimate-3-phosphate (EPSP). Glyphosate is absorbed through foliage and minimally through roots, meaning that it is only effective on actively growing plants and cannot prevent seeds from germinating. After application, glyphosate is readily transported around the plant to growing roots and leaves and this systemic activity is important for its effectiveness. Inhibiting the enzyme causes shikimate to accumulate in plant tissues and diverts energy and resources away from other processes. While growth stops within hours of application, it takes several days for the leaves to begin turning yellow.
EPSP is subsequently dephosphorylated to chorismate, an essential precursor for the amino acids mentioned above. These amino acids are used in protein synthesis and to produce secondary metabolites such as folates, ubiquinones, and naphthoquinone.
X-ray crystallographic studies of glyphosate and EPSPS show that glyphosate functions by occupying the binding site of the phosphoenolpyruvate, mimicking an intermediate state of the ternary enzyme–substrate complex. Glyphosate inhibits the EPSPS enzymes of different species of plants and microbes at different rates.
Glyphosate adsorbs strongly to soil, and residues are expected to generally be immobile in soil. Ground and surface water pollution is limited. Glyphosate is readily degraded by soil microbes to aminomethylphosphonic acid (AMPA, which like glyphosate strongly adsorbs to soil solids and is thus unlikely to leach to groundwater). Though both glyphosate and AMPA are commonly detected in water bodies, a portion of the AMPA detected may actually be the result of degradation of detergents rather than from glyphosate. Glyphosate does have the potential to contaminate surface waters due to its aquatic use patterns and through erosion, as it adsorbs to soil particles suspended in runoff. The mechanism of glyphosate sorption to soil is similar to that of phosphate fertilizers, the presence of which can reduce glyphosate sorption. Phosphate fertilizers are subject to release from sediments into water bodies under anaerobic conditions, and similar release can also occur with glyphosate, though significant impact of glyphosate release from sediments has not been established. Limited leaching can occur after high rainfall after application. If glyphosate reaches surface water, it is not broken down readily by water or sunlight.
The half-life of glyphosate in soil ranges between 2 and 197 days; a typical field half-life of 47 days has been suggested. Soil and climate conditions affect glyphosate's persistence in soil. The median half-life of glyphosate in water varies from a few to 91 days. At a site in Texas, half-life was as little as three days. A site in Iowa had a half-life of 141 days. The glyphosate metabolite AMPA has been found in Swedish forest soils up to two years after a glyphosate application. In this case, the persistence of AMPA was attributed to the soil being frozen for most of the year. Glyphosate adsorption to soil, and later release from soil, varies depending on the kind of soil. Glyphosate is generally less persistent in water than in soil, with 12- to 60-day persistence observed in Canadian ponds, although persistence of over a year has been recorded in the sediments of American ponds. The half-life of glyphosate in water is between 12 days and 10 weeks.
According to the National Pesticide Information Center fact sheet, glyphosate is not included in compounds tested for by the Food and Drug Administration's Pesticide Residue Monitoring Program, nor in the United States Department of Agriculture's Pesticide Data Program. However, a field test showed that lettuce, carrots, and barley contained glyphosate residues up to one year after the soil was treated with 3.71 lb of glyphosate per acre (4.15 kg per hectare). The U.S. has determined the acceptable daily intake of glyphosate at 1.75 milligrams per kilogram of bodyweight per day (mg/kg/bw/day) while the European Union has set it at 0.3.
Glyphosate is effective in killing a wide variety of plants, including grasses and broadleaf and woody plants. By volume, it is one of the most widely used herbicides. In 2007, glyphosate was the most used herbicide in the United States agricultural sector, with 180 to 185 million pounds (82,000 to 84,000 tonnes) applied, the second-most used in home and garden with 5 to 8 million pounds (2,300 to 3,600 tonnes) and government applied 13 to 15 million pounds (5,900 to 6,800 tonnes) in industry and commerce. It is commonly used for agriculture, horticulture, viticulture, and silviculture purposes, as well as garden maintenance (including home use). It has a relatively small effect on some clover species and morning glory.
Glyphosate and related herbicides are often used in invasive species eradication and habitat restoration, especially to enhance native plant establishment in prairie ecosystems. The controlled application is usually combined with a selective herbicide and traditional methods of weed eradication such as mulching to achieve an optimal effect.
In many cities, glyphosate is sprayed along the sidewalks and streets, as well as crevices in between pavement where weeds often grow. However, up to 24% of glyphosate applied to hard surfaces can be run off by water. Glyphosate contamination of surface water is attributed to urban and agricultural use. Glyphosate is used to clear railroad tracks and get rid of unwanted aquatic vegetation. Since 1994, glyphosate has been used in aerial spraying in Colombia in coca eradication programs; Colombia announced in May 2015 that by October, it would cease using glyphosate in these programs due to concerns about human toxicity of the chemical.
In addition to its use as an herbicide, glyphosate is also used for crop desiccation (siccation) to increase harvest yield, and as a result of desiccation, to increase sucrose concentration in sugarcane before harvest. The application of glyphosate just before harvest on grains (like wheat, barley, and oats) kills the food crop so that it dries more quickly and evenly, similar to the use of dessicants. This dry crop does not have to be windrowed (swathed and dried) prior to harvest but can easily be straight cut and harvested. This saves the farmer time and money, which is important in northern regions where the growing season is short. Excess residue levels in beans resulting from incorrect application can render the crop unfit for sale.
Some micro-organisms have a version of 5-enolpyruvoyl-shikimate-3-phosphate synthetase (EPSPS) resistant to glyphosate inhibition. A version of the enzyme that was both resistant to glyphosate and that was still efficient enough to drive adequate plant growth was identified by Monsanto scientists after much trial and error in an Agrobacterium strain called CP4, which was found surviving in a waste-fed column at a glyphosate production facility.:56 This CP4 EPSPS gene was cloned and transfected into soybeans. In 1996, genetically modified soybeans were made commercially available. Current glyphosate-resistant crops include soy, maize (corn), canola, alfalfa, sugar beets, and cotton, with wheat still under development.
Glyphosate is marketed in the United States and worldwide by many agrochemical companies, in different solution strengths and with various adjuvants, under dozens of tradenames. As of 2010, more than 750 glyphosate products were on the market. In 2012, in terms of volume about half of the total global consumption of glyphosate was for conventional crops; Asia Pacific was the largest and fastest growing market. Chinese manufacturers collectively are the world's largest producers of glyphosate and its precursors and account for about 30% of global exports. Key manufacturers include Anhui Huaxing Chemical Industry Company, BASF, Bayer CropScience, Dow AgroSciences, DuPont, Jiangsu Good Harvest-Weien Agrochemical Company, Monsanto, Nantong Jiangshan Agrochemical & Chemicals Co., Nufarm Limited, SinoHarvest, Syngenta, and Zhejiang Xinan Chemical Industrial Group Company.
Glyphosate is an acid molecule, so it is formulated as a salt for packaging and handling. Various salt formulations include isopropylamine, diammonium, monoammonium, or potassium as the counterion. The active ingredient of the Monsanto herbicides is the isopropylamine salt of glyphosate. Another important ingredient in some formulations is the surfactant polyethoxylated tallow amine. Some brands include more than one salt. Some companies report their product as acid equivalent (ae) of glyphosate acid, or some report it as active ingredient (ai) of glyphosate plus the salt, and others report both. To compare performance of different formulations, knowledge of how the products were formulated is needed. Given that different salts have different weights, the acid equivalent is a more accurate method of expressing and comparing concentrations.
Adjuvant loading refers to the amount of adjuvant already added to the glyphosate product. Fully loaded products contain all the necessary adjuvants, including surfactant; some contain no adjuvant system, while other products contain only a limited amount of adjuvant (minimal or partial loading) and additional surfactants must be added to the spray tank before application. As of 2000 (just before Monsanto's patent on glyphosate expired), over 400 commercial adjuvants from over 34 different companies were available for use in commercial agriculture.
Products are supplied most commonly in formulations of 120, 240, 360, 480, and 680 g/l of active ingredient. The most common formulation in agriculture is 360 g/l, either alone or with added cationic surfactants.
For 360 g/l formulations, European regulations allow applications of up to 12 l/ha for control of perennial weeds such as couch grass. More commonly, rates of 3 l/ha are practiced for control of annual weeds between crops.
Glyphosate is the active ingredient in herbicide formulations containing it. However, in addition to glyphosate salts, commercial formulations of glyphosate contain additives such as surfactants which vary in nature and concentration. The surfactants are added to enable the glyphosate to penetrate the cuticle of the plants. Toxicologists have studied such glyphosate-containing formulations and glyphosate alone.
There is limited evidence human cancer risk might increase as a result of exposure to large amounts of glyphosate, but no good evidence of such a risk from typical usage, such as in domestic gardening. A 2014 review article reported a significant association between B-cell lymphoma and glyphosate occupational exposure. In March 2015, the World Health Organization's International Agency for Research on Cancer classified glyphosate as "probably carcinogenic in humans" (category 2A) based on epidemiological studies, animal studies, and in vitro studies. However, in 2016 a joint meeting of the United Nations (FAO) Panel of Experts on Pesticide Residues in Food and the Environment and the World Health Organization Core Assessment Group on Pesticide Residues reported that studies conducted in mammal animal models showed that oral applications of glyphosate at doses as high as 2000 mg/kg was not "associated with genotoxic effects in an overwhelming majority of studies", and that glyphosate was "unlikely to be genotoxic at anticipated dietary exposures". It also reported that glyphosate is unlikely to be carcinogenic in rodents and concluded that glyphosate was "unlikely to pose a carcinogenic risk to humans" from dietary exposure.:p. 2 In September 2016, a systematic review sponsored by Monsanto found no support for a causal relationship between glyphosate exposure and the risk of non-Hodgkins lymphoma or of multiple myeloma.
Amongst mammals, glyphosate is considered to have "low to very low toxicity". The LD50 of glyphosate is 5,000 mg/kg for rats, 10,000 mg/kg in mice and 3,530 mg/kg in goats. The acute dermal LD50 in rabbits is greater than 2,000 mg/kg. Indications of glyphosate toxicity in animals typically appear within 30 to 120 minutes following ingestion of a large enough dose, and include initial excitability and tachycardia, ataxia, depression, and bradycardia, although severe toxicity can develop into collapse and convulsions.
A review of unpublished short-term rabbit-feeding studies reported severe toxicity effects at 150 mg/kg/day and "no observed adverse effect level" doses ranging from 50 to 200 mg/kg/day. Glyphosate can have carcinogenic effects in nonhuman mammals. These include the induction of positive trends in the incidence of renal tubule carcinoma and haemangiosarcoma in male mice, and increased pancreatic islet-cell adenoma in male rats.
In reproductive toxicity studies performed in rats and rabbits, no adverse maternal or offspring effects were seen at doses below 175–293 mg/kg of body weight per day.
Glyphosate-based herbicides may cause life-threatening arrhythmias in mammals. Evidence also shows that such herbicides cause direct electrophysiological changes in the cardiovascular systems of rats and rabbits.
In freshwater invertebrates (species unspecified), glyphosate has a 48-hour LC50 ranging from 55 to 780 ppm. The 96-hour LC50 is 281 ppm for grass shrimp (Palaemonetas vulgaris) and 934 ppm for fiddler crabs (Uca pagilator). These values make glyphosate "slightly toxic to practically non-toxic".
The antimicrobial activity of glyphosate has been described in the microbiology literature since its discovery in 1970 and the description of glyphosate's mechanism of action in 1972. Efficacy was described for numerous bacteria and fungi. Glyphosate can control the growth of apicomplexan parasites, such as Toxoplasma gondii, Plasmodium falciparum (malaria), and Cryptosporidium parvum, and has been considered an antimicrobial agent in mammals. Inhibition can occur with some Rhizobium species important for soybean nitrogen fixation, especially under moisture stress.
When glyphosate comes into contact with the soil, it can be bound to soil particles, thereby slowing its degradation. Glyphosate and its degradation product, aminomethylphosphonic acid are considered to be much more benign toxicologically and environmentally than most of the herbicides replaced by glyphosate. A 2016 meta-analysis concluded that at typical application rates glyphosate had no effect on soil microbial biomass or respiration. A 2016 review noted that contrasting effects of glyphosate on earthworms have been found in different experiments with some species unaffected, but others losing weight or avoiding treated soil. Further research is required to determine the impact of glyphosate on earthworms in complex ecosystems.
Glyphosate-based formulations may contain a number of adjuvants, the identities of which are considered trade secrets. Surfactants are used in herbicide formulations as wetting agents, to maximize coverage and aid penetration of the herbicide(s) through plant leaves. As agricultural spray adjuvants, surfactants may be mixed into commercial formulations, such as Roundup, or they may be purchased separately and mixed on-site (tank mix).
Polyethoxylated tallow amine (POEA) is a surfactant used in the original Roundup formulation and was commonly used in 2015. Different versions of Roundup have included different percentages of POEA. A 1997 US government report said that Roundup is 15% POEA while Roundup Pro is 14.5%. A review of the literature provided to the EPA in 1997 found that POEA was more toxic to fish than glyphosate was. POEA is more toxic to fish and amphibians than glyphosate alone. A 2000 review of the ecotoxicological data on Roundup shows at least 58 studies exist on the effects of Roundup on a range of organisms. This review concluded, "...for terrestrial uses of Roundup minimal acute and chronic risk was predicted for potentially exposed non-target organisms".
Acute toxicity and chronic toxicity are dose-related. Skin exposure to ready-to-use glyphosate formulations can cause irritation, and photocontact dermatitis has been occasionally reported. These effects are probably due to the preservative benzisothiazolin-3-one. Severe skin burns are very rare. Inhalation is a minor route of exposure, but spray mist may cause oral or nasal discomfort, an unpleasant taste in the mouth, or tingling and irritation in the throat. Eye exposure may lead to mild conjunctivitis. Superficial corneal injury is possible if irrigation is delayed or inadequate. Death has been reported after deliberate overdose. Ingestion of Roundup ranging from 85 to 200 ml (of 41% solution) has resulted in death within hours of ingestion, although it has also been ingested in quantities as large as 500 ml with only mild or moderate symptoms. Consumption of over 85 ml of concentrated product are likely to cause serious symptoms in adults including burns due to corrosive effects as well as kidney and liver damage. More severe cases cause "respiratory distress, impaired consciousness, pulmonary edema, infiltration on chest X-ray, shock, arrhythmias, renal failure requiring haemodialysis, metabolic acidosis, and hyperkalaemia" and death is often preceded by bradycardia and ventricular arrhythmias.
A 2000 review concluded that "under present and expected conditions of new use, there is no potential for Roundup herbicide to pose a health risk to humans". A 2002 review by the European Union reached the same conclusion.
A 2012 meta-analysis of all epidemiological studies of exposure to glyphosate formulations found no correlation with any kind of cancer. The 2013 systematic review by the German Institute for Risk Assessment of epidemiological studies of workers who use pesticides, exposed to glyphosate formulations found no significant risk, stating that "the available data are contradictory and far from being convincing".:Volume 1, p64-66 However, a 2014 meta-analysis of the same studies found a correlation between occupational exposure to glyphosate formulations and increased risk of B cell lymphoma, the most common kind of non-Hodgkin lymphoma. Workers exposed to glyphosate were about twice as likely to get B cell lymphoma. A 2015 systematic review of observational studies found no evidence that glyphosate exposure among pregnant mothers caused adverse developmental outcomes in their children. A 2016 systematic review and meta-analysis found limited and weak evidence of an association between glyphosate exposure and risk of non-Hodgkin lymphoma and multiple myeloma, while no association was found between glyphosate and risk of other lymphohematopoietic cancers. The same review noted that the positive associations found may be due to bias and confounding.
Monsanto and other companies produce glyphosate products with alternative surfactants specifically formulated for aquatic use, for example the Monsanto products "Biactive" and "AquaMaster". Glyphosate formulations are much more toxic for amphibians and fish than glyphosate alone. The half-life of POEA (21–42 days) is longer than that for glyphosate (7–14 days) in aquatic environments.
Some researchers have suggested the toxicity effects of pesticides on amphibians may be different from those of other aquatic fauna because of their lifestyle; amphibians may be more susceptible to the toxic effects of pesticides because they often prefer to breed in shallow, lentic, or ephemeral pools. These habitats do not necessarily constitute formal water-bodies and can contain higher concentrations of pesticide compared to larger water-bodies. Studies in a variety of amphibians have shown the toxicity of GBFs containing POEA to amphibian larvae. These effects include interference with gill morphology and mortality from either the loss of osmotic stability or asphyxiation. At sub-lethal concentrations, exposure to POEA or glyphosate/POEA formulations have been associated with delayed development, accelerated development, reduced size at metamorphosis, developmental malformations of the tail, mouth, eye and head, histological indications of intersex and symptoms of oxidative stress. Glyphosate-based formulations can cause oxidative stress in bullfrog tadpoles.
A 2003 study of various formulations of glyphosate found, "[the] risk assessments based on estimated and measured concentrations of glyphosate that would result from its use for the control of undesirable plants in wetlands and over-water situations showed that the risk to aquatic organisms is negligible or small at application rates less than 4 kg/ha and only slightly greater at application rates of 8 kg/ha."
A 2013 meta-analysis reviewed the available data related to potential impacts of glyphosate-based herbicides on amphibians. According to the authors, the use of glyphosate-based pesticides cannot be considered the major cause of amphibian decline, the bulk of which occurred prior to the widespread use of glyphosate or in pristine tropical areas with minimal glyphosate exposure. The authors recommended further study of species- and development-stage chronic toxicity, of environmental glyphosate levels, and ongoing analysis of data relevant to determining what if any role glyphosate might be playing in worldwide amphibian decline, and suggest including amphibians in standardized test batteries.
A correlation was found between an increase in the infection rate of wheat by Fusarium head blight and the application of glyphosate, but "because of the nature of this study, we could not determine if the association between previous GF (glyphosate formulation) use and FHB development was a cause-effect relationship". Other studies have found causal relationships between glyphosate and decreased disease resistance. Exposure to glyphosate has been shown to change the species composition of endophytic bacteria in plant hosts, which is highly variable.
In 2007, the EPA selected glyphosate for further screening through its Endocrine Disruptor Screening Program (EDSP). Selection for this program is based on a compound's prevalence of use and does not imply particular suspicion of endocrine activity. On June 29, 2015 the EPA released Weight of Evidence Conclusion of the EDSP Tier 1 screening for glyphosate, recommending that glyphosate not be considered for Tier 2 testing. The Weight of Evidence conclusion stated "...there was no convincing evidence of potential interaction with the estrogen, androgen or thyroid pathways."
Several studies have not found mutagenic effects, so glyphosate has not been listed in the United States Environmental Protection Agency or the International Agency for Research on Cancer databases. Various other studies suggest glyphosate may be mutagenic. The IARC monograph noted that glyphosate-based formulations can cause DNA strand breaks in various taxa of animals in vitro
This section needs to be updated.(January 2017)
A 2013 systematic review by the German Institute for Risk Assessment (BfR) examined more than 1000 epidemiological studies, animal studies, and in vitro studies. It found that "no classification and labelling for carcinogenicity is warranted" and did not recommend a carcinogen classification of either 1A or 1B.:139, 34–37 It provided the review to EFSA in January 2014 which published it in December 2014. In November 2015, EFSA published its conclusion in the Renewal Assessment Report (RAR), stating it was "unlikely to pose a carcinogenic hazard to humans". The EU will be largely informed by this report when it makes its decision on the use of glyphosate in November 2017.
EFSA's decision and the BfR report were criticized in an open letter published by 96 scientists in November 2015 saying that the BfR report failed to adhere to accepted scientific principles of open and transparent procedures. The BfR report included unpublished data, lacked authorship, omitted references, and did not disclose conflict-of-interest information.
On April 4, 2016, Dr. Vytenis Andriukaitis, European Commissioner for Health and Food Safety, wrote an open letter to the Chair of the Board of the Glyphosate Task at Monsanto Europe asking to publish the full studies provided to the EFSA.
In September 2017, The Guardian reported that sections of the Renewal Assessment Report prepared by the BfR and used by Efsa were copy-pasted from a study done by Monsanto. Some sections of copy contained small changes such as using British spelling rather than American forms but others were copied word for word, including most of the peer-reviewed papers that were used in the report. The Guardian reported that a "Monsanto spokesperson said that Efsa allowed renewal reports to be written this way because of the large volume of toxicological studies submitted."
In a 1993 review, the EPA, considered glyphosate to be noncarcinogenic and relatively low in dermal and oral acute toxicity. The EPA considered a "worst case" dietary risk model of an individual eating a lifetime of food derived entirely from glyphosate-sprayed fields with residues at their maximum levels. This model indicated that no adverse health effects would be expected under such conditions. In 2015, the EPA initiated a review of glyphosate's toxicity and in 2016 reported that glyphosate is likely not carcinogenic.
In March 2015, the International Agency for Research on Cancer published a summary of their forthcoming monograph on glyphosate, and classified glyphosate as "probably carcinogenic in humans" (category 2A) based on epidemiological studies, animal studies, and in vitro studies. It noted that there was "limited evidence" of carcinogenicity in humans for non-Hodgkin lymphoma. The IARC classifies substances for their carcinogenic potential, and "a few positive findings can be enough to declare a hazard, even if there are negative studies, as well." Unlike the BfR, it does not conduct a risk assessment, weighing benefits against risk.
The BfR responded that IARC reviewed only a selection of what they had reviewed earlier, and argued that other studies, including a cohort study called Agricultural Health Study, do not support the classification. The IARC report did not include unpublished industry-funded studies, including one completed by the IARC panel leader, Aaron Blair, who stated that agency policy required that he not consider this study. The agency's international protocol dictates that only published studies be used in classifications of carcinogenicity, since national regulatory agencies including the EPA have allowed agrochemical corporations to conduct their own unpublished research, which may be biased in support of their profit motives. Monsanto called the IARC report biased and said it wanted it to be retracted.
A 2017 review done by personnel from EFSA and BfR argued that the differences between the IARC's and EFSA's conclusions regarding glyphosate and cancer were due to differences in their evaluation of the available evidence. The review concluded that "Two complementary exposure assessments ... suggests that actual exposure levels are below" the reference values identified by the EFSA "and do not represent a public concern." In contrast, a 2016 analysis concluded that in the EFSA's Renewal Assessment Report, "almost no weight is given to studies from the published literature and there is an over-reliance on non-publicly available industry-provided studies using a limited set of assays that define the minimum data necessary for the marketing of a pesticide", arguing that the IARC's evaluation of probably carcinogenic to humans "accurately reflects the results of published scientific literature on glyphosate".
After the California Office of Environmental Health Hazard Assessment (OEHHA) announced, in March 2015, plans to have glyphosate listed as a known carcinogen based on the IARC assessment, Monsanto started a case against OEHHA and its acting director, Lauren Zeise, in 2016, but lost the suit in March 2017.
Glyphosate was listed as "known to the State of California to cause cancer" in 2017.
On March 15, 2017 the European Chemicals Agency (ECHA) announced recommendations proceeding from a risk assessment of glyphosate performed by ECHA's Committee for Risk Assessment (RAC). Their recommendations maintained the current classification of glyphosate as a substance causing serious eye damage and as a substance toxic to aquatic life. However, the RAC did not find evidence implicating glyphosate to be a carcinogen, a mutagen, as toxic to reproduction, nor as toxic to specific organs.
In the 1990s, when the first genetically modified crops-such as glyphosate-resistant corn, canola, soybean and cotton—were introduced, no glyphosate-resistant weeds were known to exist. By 2014, glyphosate-resistant weeds dominated herbicide-resistance research. At that time, 23 glyphosate-resistant species were found in 18 countries.
"Resistance evolves after a weed population has been subjected to intense selection pressure in the form of repeated use of a single herbicide." Weeds resistant to the herbicide have been called 'superweeds'.
According to Ian Heap, a weed specialist, who completed his PhD on resistance to multiple herbicides in annual ryegrass (Lolium rigidum) in 1988 –the first case of an herbicide-resistant weed in Australia–by 2014 the Lolium rigidum was the "world’s worst herbicide-resistant weed with instances in "12 countries, 11 sites of action, 9 cropping regimens" and affecting over 2 million hectares. Annual ryegrass was known to be resistant to herbicides since 1982. By 1996, the first documented case of glyphosate-resistant L. rigidum was reported in Australia in 1996 near Orange, New South Wales. In 2006, farmers associations were reporting 107 biotypes of weeds within 63 weed species with herbicide resistance. In 2009, Canada identified its first resistant weed, giant ragweed, and at that time 15 weed species had been confirmed as resistant to glyphosate. As of 2010, in the United States 7 to 10 million acres (2.8 to 4.0 million hectares) of soil were afflicted by superweeds, or about 5% of the 170 million acres planted with corn, soybeans, and cotton, the crops most affected, in 22 states. In 2012, Charles Benbrook reported that the Weed Science Society of America listed 22 superweeds in the U.S., with over 5.7×106 ha (14×106 acres) infested by GR weeds and that Dow AgroSciences had carried out a survey and reported a figure of around 40×106 ha (100×106 acres). The International Survey of Herbicide Resistant Weeds database lists species that are resistant to glyphosate.
In response to resistant weeds, farmers are hand-weeding, using tractors to turn over soil between crops, and using other herbicides in addition to glyphosate.
In 2004, a glyphosate-resistant variation of Amaranthus palmeri, commonly known as Palmer amaranth, was found in Georgia and confirmed by a 2005 study. In 2005, resistance was also found in North Carolina. Widespread use of Roundup Ready crops led to an unprecedented selection pressure, and glyphosate resistance followed. The weed variation is now widespread in the southeastern United States. Cases have also been reported in Texas and Virginia.
Conyza bonariensis (also known as hairy fleabane and buva) and Conyza canadensis (known as horseweed or marestail), are other weed species that had lately developed glyphosate resistance. A 2008 study on the current situation of glyphosate resistance in South America concluded "resistance evolution followed intense glyphosate use" and the use of glyphosate-resistant soybean crops is a factor encouraging increases in glyphosate use. In the 2015 growing season, glyphosate-resistant marestail proved to be especially problematic to control in Nebraska production fields.
Glyphosate-resistant ryegrass (Lolium) has occurred in most of the Australian agricultural areas and other areas of the world. All cases of evolution of resistance to glyphosate in Australia were characterized by intensive use of the herbicide while no other effective weed control practices were used. Studies indicate the resistant ryegrass does not compete well against nonresistant plants and their numbers decrease when not grown under conditions of glyphosate application.
Use of glyphosate to clear milkweed along roads and fields may have contributed to a decline in monarch butterfly populations in the Midwestern United States. Along with deforestation and adverse weather conditions, the decrease in milkweed contributed to an 81% decline in monarchs. The Natural Resources Defense Council (NRDC) filed a suit in 2015 against the EPA, in which it is argued that the agency ignored warnings about the dangers of glyphosate usage for monarchs.
Glyphosate was first approved for use in the 1970s, and as of 2010 was labelled for use in 130 countries.:2
In June 2015, the French Ecology Minister asked nurseries and garden centers to halt over-the-counter sales of glyphosate in the form of Monsanto's Roundup. This was a nonbinding request and all sales of glyphosate remain legal in France until 2022, when the substance will be banned for home gardening.
A vote on the relicencing of glyphosate in the EU stalled in March 2016. Member states France, Sweden, and the Netherlands objected to the renewal. A vote to reauthorize on a temporary basis failed in June 2016 but at the last-minute the license was extended for 18 months until the end of 2017.
On 27 November 2017, a majority of eighteen EU member states voted in favor of permitting the use of herbicide glyphosate for five more years. A qualified majority of 16 states representing 65% of EU citizens was required. Decisive therefore was the German vote in favor of continued usage. The CSU minister of Agriculture, Christian Schmidt, unexpectedly voted in favor while the German coalition government was internally divided on the issue which usually and normally leads to a German abstention of vote.
In May 2015, Colombia announced that it would stop using glyphosate by October 2015 in the destruction of illegal plantations of coca, the raw ingredient for cocaine. Farmers have complained that the aerial fumigation has destroyed entire fields of coffee and other legal produce.
The New York Times reported that in 1996, "Dennis C. Vacco, the Attorney General of New York, ordered the company Monsanto to pull ads that said Roundup was "safer than table salt" and "practically nontoxic" to mammals, birds and fish. The company withdrew the spots, but also said that the phrase in question was permissible under E.P.A. guidelines."
In 2001, French environmental and consumer rights campaigners brought a case against Monsanto for misleading the public about the environmental impact of its herbicide Roundup, on the basis that glyphosate, Roundup's main component, is classed as "dangerous for the environment" and "toxic for aquatic organisms" by the European Union. Monsanto's advertising for Roundup had presented it as biodegradable and as leaving the soil clean after use. In 2007, Monsanto was convicted of false advertising and was fined 15,000 euros. Monsanto's French distributor Scotts France was also fined 15,000 euros. Both defendants were ordered to pay damages of 5,000 euros to the Brittany Water and Rivers Association and 3,000 euros to the Consommation Logement Cadre de vie, one of the two main general consumer associations in France. Monsanto appealed and the court upheld the verdict; Monsanto appealed again to the French Supreme Court, and in 2009 it also upheld the verdict.
The AAA pathways consist of the shikimate pathway (the prechorismate pathway) and individual postchorismate pathways leading to Trp, Phe, and Tyr.... These pathways are found in bacteria, fungi, plants, and some protists, but are absent in animals. Therefore, AAAs and some of their derivatives (vitamins) are essential nutrients in the human diet, although in animals Tyr can be synthesized from Phe by Phe hydroxylase....The absence of the AAA pathways in animals also makes these pathways attractive targets for antimicrobial agents and herbicides.
'Probable' means that there was enough evidence to say it is more than possible, but not enough evidence to say it is a carcinogen," Aaron Blair, a lead researcher on the IARC's study, said. Blair, a scientist emeritus at the National Cancer Institute, has studied the effects of pesticides for years. "It means you ought to be a little concerned about" glyphosate, he said.
The evidence seems clear that the number of milkweed plants through this region has indeed declined. The cause for the milkweed decline, though, is a little less certain.
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