Glyphosate’s mode of action is to inhibit an enzyme involved in the synthesis of the amino acids tyrosine, tryptophan and phenylalanine. It is absorbed through foliage and translocated to growing points. Because of this mode of action, it is only effective on actively growing plants; it is not effective as a pre-emergence herbicide.

Some crops have been genetically engineered to be resistant to it (i.e. Roundup Ready). Such crops allow farmers to use glyphosate as a post-emergence herbicide against both broadleaf and cereal weeds. Soy was the first Roundup Ready crop.

Chemistry

Glyphosate is an aminophosphonic analogue of the natural amino acid glycine and the name is a contraction of glycine, phospho-, and -ate. The molecule has several dissociable hydrogens, especially the first hydrogen of the phosphate group. The molecule tends to exist as a zwitterion where a phosphonic hydrogen dissociates and joins the amine group. Glyphosate is soluble in water to 12g/L at room temperature.

Glyphosate was first discovered to have herbicidal activity in 1970 by John E. Franz, while working for Monsanto.^[4] Franz received the National Medal of Technology in 1987,^[5] and the Perkin Medal for Applied Chemistry^[6] in 1990 for his discoveries.

Formulas and tradenames

Although the Roundup trademark is registered with the US Patent Office and still extant, the patent has expired. Glyphosate is marketed in the US and worldwide in different solution strengths under many tradenames^[7]: Roundup, Buccaneer, Razor Pro (41%), Genesis Extra II (41% w/ Surfactant), Roundup Pro Concentrate (50.2 %), Rodeo (51.2%), Aquaneat (53.8%), and Aquamaster (53.5%)^[8]. These products may contain other ingredients, causing them to have different effects. For example, Roundup was found to have different effects to glyphosate alone.^[9] Roundup is a water-based solution containing glyphosate, a surfactant, and other substances. Other formulations contain additional active ingredients to improve the speed of action. In the UK, Weedol Rootkill Plus, which contains glyphosate and pyraflufen-ethyl, and Resolva 24H^[10] which contains glyphosate and diquat, are available.

Biochemistry

Glyphosate kills plants by interfering with the synthesis of the amino acids phenylalanine, tyrosine and tryptophan. 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 (ESP). ESP is subsequently dephosphorylated to chorismate, an essential precursor in plants for the aromatic amino acids: phenylalanine, tyrosine and tryptophan.^[11][12] These amino acids are used as building blocks in peptides, 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 phosphoenol pyruvate, mimicking an intermediate state of the ternary enzyme substrates complex.^[13] The shikimate pathway is not present in animals, which instead obtain aromatic amino acids from their diet. Glyphosate has also been shown to inhibit other plant enzymes^[14][15], and also has been found to affect animal enzymes.^[16]

Use

Roundup used as an alternative to mowing in an apple orchard in Ciardes, Italy

Glyphosate is effective in killing a wide variety of plants, including grasses, broadleaf, and woody plants.^[17] It has a relatively small effect on some clover species^[18]. By volume, it is one of the most widely used herbicides.^[19] It is commonly used for agriculture, horticulture, and silviculture purposes, as well as garden maintenance (including home use).^[19]

Glyphosate is supplied in several formulations for different uses:

• Ammonium salt.
• Isopropyl amine salt.
• Glyphosate acid - standalone, as ammonium salt or as isopropyl salt.
• Potassium salt

Products are supplied most commonly in formulations of 120, 240, 360, 480 and 680g active ingredient per litre. The most common formulation in agriculture is 360g, either alone or with added cationic surfactants.

For 360g formulations, European regulations allow applications of up to 12 litres per hectare for control of perennial weeds such as couch grass. More commonly, rates of 3 litres per hectare are practiced for control of annual weeds between crops^[20].

Genetically modified crops

In 1996, genetically modified soybeans were made commercially available.^[21] Current Roundup Ready crops include soy, maize (corn), sorghum, canola, alfalfa, and cotton, with wheat still under development. These cultivars greatly improved conventional farmers’ ability to control weeds, since glyphosate could be sprayed on fields without damaging the crop. As of 2005, 87% of U.S. soybean fields were planted with glyphosate-resistant varieties.^[22][23]

While the use of Roundup Ready crops may have increased the usage of herbicides measured in pounds applied per acre^[24], its use has changed the herbicide use profile away from atrazine, metribuzin, and alachlor. This has the benefit of reducing the dangers of herbicide runoff into drinking water.^[25][26]

In 1999, a review of Roundup Ready soybean crops found that, compared to the top conventional varieties, they had a 6.7% lower yield ^[24]. This so called “yield drag” follows the same pattern observed when other traits are introduced into soybeans by conventional breeding ^[27] and can not be attributed to the Roundup Ready trait or the GM nature of the crop since Monsanto have recently released Roundup Ready 2 soybeans, which are claimed to yield 7-11% higher than RR version 1 ^[28]. There have been no reports of “yield drag” with the other Roundup Ready crops maize, sorghum or canola.

Development

Some micro-organisms have a version of 5-enolpyruvoyl-shikimate-3-phosphate synthetase (EPSPS) that is resistant to glyphosate inhibition. The version used in genetically modified crops was isolated from Agrobacterium strain CP4 (CP4 EPSPS) that was resistant to glyphosate.^[29][30] This CP4 EPSPS gene was cloned and transfected into soybeans. The CP4 EPSPS gene was engineered for plant expression by fusing the 5′ end of the gene to a chloroplast transit peptide derived from the petunia EPSPS. This transit peptide was used because it had shown previously an ability to deliver bacterial EPSPS to the chloroplasts of other plants. The plasmid used to move the gene into soybeans was PV-GMGTO4. It contained three bacterial genes, two PC4 EPSPS genes, and a gene encoding beta-glucuronidase (GUS) from Escherichia coli as a marker. The DNA was injected into the soybeans using the particle acceleration method. Soybean cultivar A54O3 was used for the transformation. The expression of the GUS gene was used as the initial evidence of transformation. GUS expression was detected by a staining method in which the GUS enzyme converts a substrate into a blue precipitate. Those plants that showed GUS expression were then taken and sprayed with glyphosate, and their tolerance was tested over many generations.

Other uses

Herbicides sprayed over a coca field in Colombia

Glyphosate is one of a number of herbicides used by the United States government to spray Colombian coca fields through Plan Colombia. Its health effects, effects on legal crops, and effectiveness in fighting the war on drugs have been widely disputed.^[31] There are reports that widespread application of glyphosate in attempts to destroy coca crops in South America have resulted in the development of glyphosate-resistant strains of coca known as Boliviana negra, which have been selectively bred to be both “Roundup Ready” and larger and higher yielding than the original strains of the plant.^[32] However, there are no reports of glyphosate-resistant coca in the peer-reviewed literature. In addition, since spraying of herbicides is not permitted in Colombian national parks, this has encouraged coca growers to move into park areas, cutting down the natural vegetation, and establishing coca plantations within park lands.

Toxicity

Glyphosate is rated least dangerous in comparison to other herbicides and pesticides, such as those from the organochlorine family.^[33] Roundup has a United States Environmental Protection Agency‎ (EPA) Toxicity Class of III for oral and inhalation exposure.^[34] It has been rated as class I (Severe) for eye irritation.

A recent study, on the other hand, has shown that Roundup formulations and metabolic products cause the death of human embryonic, placental, and umbilical cells in vitro even at low concentrations. The effects are not proportional to Glyphosate concentrations but dependent on the nature of the adjuvants used in the formulation.^[35]

Humans

Glyphosate has a United States Environmental Protection Agency‎ Toxicity Class of III in 1993,^[34] . It has been rated as class I (Severe) for eye irritation. Glyphosate is being evaluated for effects to unborn fetuses and their development. It is currently on the USEPA Endocrine Disrupter Screening list, published in 2007.^[36][37]

Outside its intended use, glyphosate can be lethal. For example, with intentional poisonings there is approximately a 10% mortality for those ingesting glyphosate, compared to 70% for those ingesting paraquat.^[38]

Laboratory toxicology studies suggest that other ingredients combined with glyphosate may have greater toxicity than glyphosate alone. For example, a study comparing glyphosate and Roundup found that Roundup had a greater effect on aromatase than glyphosate alone.^[9]

Statistics from the California Environmental Protection Agency’s Pesticide Illness Surveillance Program indicate that glyphosate-related incidents are one of the highest reported of all pesticides.^[39][40] However, incident count does not take into account the number of people exposed and the severity of symptoms associated with each incident.^[40] For example, if hospitalization were used as a measure of the severity of pesticide related incidents, then glyphosate would be considered relatively safe, since, over a 13 year period in California, none of the 515 pesticide-related hospitalizations recorded were attributed to glyphosate.^[40]

Greenpeace states that the acute human toxicity of glyphosate is very low, but note that, as mentioned above, other added chemicals (particularly surfactants, e.g. polyoxy-ethyleneamine, POEA), can be more toxic than glyphosate itself.^[17] Over-application, or application directly to the soil may impact earthworms.

A review of the toxicological data on Roundup shows that there are at least 58 studies of the effects of Roundup itself on a range of organisms.^[41] This review concluded that “for terrestrial uses of Roundup minimal acute and chronic risk was predicted for potentially exposed non-target organisms”. It also concluded that there were some risks to aquatic organisms exposed to Roundup in shallow water. More recent research suggests glyphosate induces a variety of functional abnormalities in fetuses and pregnant rats.^[42] Also in recent mammalian research, glyphosate has been found to interfere with an enzyme involved testosterone production in mouse cell culture^[43] and to interfere with an estrogen biosynthesis enzyme in cultures of human placental cells.^[44]

There is a reasonable correlation between the amount of Roundup ingested and the likelihood of serious systemic sequelae or death. Ingestion of >85 mL of the concentrated formulation is likely to cause significant toxicity in adults. Gastrointestinal corrosive effects, with mouth, throat and epigastric pain and dysphagia are common. Renal and hepatic impairment are also frequent, and usually reflect reduced organ perfusion. Respiratory distress, impaired consciousness, pulmonary oedema, infiltration on chest x-ray, shock, arrythmias, renal failure requiring haemodialysis, metabolic acidosis and hyperkalaemia may supervene in severe cases. Bradycardia and ventricular arrhythmias are often present pre-terminally. Dermal exposure to ready-to-use glyphosate formulations can cause irritation, and photo-contact dermatitis has been reported occasionally; these effects are probably due to the preservative Proxel (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, tingling and throat irritation. Eye exposure may lead to mild conjunctivitis, and superficial corneal injury is possible if irrigation is delayed or inadequate.^[45]

Other species

The direct toxicity of pure glyphosate to mammals and birds is low.^{[46][unreliable source?]} The acute oral toxicity of Roundup is > 5,000 mg/kg in the rat.^[47] It showed no toxic effects when fed to animals for 2 years, and only produced rare cases of reproductive effects when fed in extremely large doses to rodents and dogs. It has not demonstrated any increase in cancer rates in animal studies and is poorly absorbed in the digestive tract. Glyphosate has no significant potential to accumulate in animal tissue.^[48][49]

An in vitro study indicates that glyphosate formulations could harm earthworms^[50] and beneficial insects.^[51] However, the reported effect of glyphosate on earthworms has been criticized.^[41] The results conflict with results from field studies where no effects were noted for the number of nematodes, mites, or springtails after treatment with Roundup at 2 kilograms active ingredient per hectare.^[52] Glyphosate can negatively affect nitrogen-fixing bacteria,^[53] and increase the susceptibility of plants to disease.^[54] A 2005 study concluded that certain amphibians may be at risk from glyphosate use.^[55]

Certain surfactants used in some glyphosate formulations have higher toxicity to fish and invertebrates, resulting in some formulations of glyphosate not being registered for use in aquatic applications.^[56] Monsanto produces glyphosate products with alternative surfactants that are specifically formulated for aquatic use, for example “Biactive” and “AquaMaster”.^[57] According to Monsanto, “Conservation groups have chosen glyphosate formulations because of their effectiveness against most weeds as glyphosate has very low toxicity to wildlife”.^[58] Glyphosate is used with five different salts, but commercial formulations of it contain surfactants, which vary in nature and concentration. As a result, human poisoning with this herbicide is not with the active ingredient alone, but with complex and variable mixtures.^[45]

Glyphosate’s effect on soil life may be limited, because when glyphosate comes into contact with the soil, it rapidly binds to soil particles and is inactivated.^[59][60] Unbound glyphosate is degraded by bacteria. Low activity because of binding to soil particles suggests that glyphosate’s effects on soil flora are limited. Low glyphosate concentrations can be found in many creeks and rivers in U.S. and Europe.^{[citation needed]}

The United States Environmental Protection Agency,^[59] the EC Health and Consumer Protection Directorate, and the UN World Health Organization have all concluded that pure glyphosate is not carcinogenic. Opponents of glyphosate claim that Roundup has been found to cause genetic damage, citing Peluso et al.^[61] The authors concluded that the damage was “not related to the active ingredient, but to another component of the herbicide mixture“.

Mammal research indicates oral intake of 1% glyphosate induces changes in liver enzyme activities in pregnant rats and their fetuses.^[62]

Aquatic effects

Fish and aquatic invertebrates are more sensitive to Roundup than terrestrial organisms.^[41] Glyphosate is generally less persistent in water than in soil, with 12 to 60 day persistence observed in Canadian pond water, yet persistence of over a year have been observed in the sediments of ponds in Michigan and Oregon.^[34]
The EU classifies Roundup as R51/53 Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.^[63]

Roundup is not registered for aquatic uses^[64] and studies of its effects on amphibians indicate it is toxic to them.^[65] Other glyphosate formulations that are registered for aquatic use have been found to have negligible adverse effects on sensitive amphibians.^[66]

Endocrine disruptor debate

In vitro studies have shown glyphosate affects progesterone production in mammalian cells^[67] and can increase the mortality of placental cells.^[9] Whether these studies classify glyphosate as an endocrine disruptor is debated.

Some^[who?] feel that in vitro studies are insufficient, and are waiting to see if animal studies show a change in endocrine activity, since a change in a single cell line may or may not impact an entire organism. Additionally, current in vitro studies expose cell lines to concentrations orders of magnitude greater than would be found in expected exposures, and through pathways that would not be typically experienced in real organisms.

Others^[who?] feel that in vitro studies, particularly ones identifying not only an effect, but a chemical pathway, are sufficient evidence to classify glyphosate as an endocrine disruptor, on the basis that even small changes in endocrine activity can have lasting effects on an entire organism that may be difficult to detect through whole organism studies alone. Further research on the endocrine effects of glyphosate is ongoing, including through the EPA endocrine screening program on 73 chemicals, published in 2007.

Environmental degradation

When glyphosate comes into contact with the soil, it can be rapidly bound to soil particles and be inactivated.^[34] Unbound glyphosate can be degraded by bacteria.^[68] However, glyphosate has been shown to increase the infection rate of wheat by fusarium head blight in fields that have been treated with glyphosate.^[69]

In soils, half-lives vary from as little as 3 days at a site in Texas to 141 days at a site in Iowa.^[70] In addition, the glyphosate metabolite aminomethylphosphonic acid has been shown to persist up to 2 years in Swedish forest soils.^[71] Glyphosate adsorption varies depending on the kind of soil.^[72]

Resistance in weeds and microorganisms

The first documented cases of weed resistance to glyphosate were found in Australia, involving rigid ryegrass near Orange, New South Wales.^[73] Some farmers in the United States have expressed concern that weeds are now developing with glyphosate resistance, with 13 states now reporting resistance, and this poses a problem to many farmers, including cotton farmers, that are now heavily dependent on glyphosate to control weeds.^[74][75] Farmers associations are now reporting 103 biotypes of weeds within 63 weed species with herbicide resistance^[74][75]. This problem is likely to be exacerbated by the use of roundup-ready crops ^[76].

Legal cases

False advertising

In 1996 Monsanto was accused of false and misleading advertising of glyphosate products, prompting a law suit by the New York State attorney general.^[77]

On Fri Jan 20, 2007, Monsanto was convicted of false advertising of Roundup for presenting Roundup as biodegradable and claiming that it left the soil clean after use. Environmental and consumer rights campaigners brought the case in 2001 on the basis that glyphosate, Roundup’s main ingredient, is classed as “dangerous for the environment” and “toxic for aquatic organisms” by the European Union. Monsanto France planned to appeal the verdict at the time.^[78]

Scientific fraud

On two occasions the United States Environmental Protection Agency has caught scientists deliberately falsifying test results at research laboratories hired by Monsanto to study glyphosate.^[79][80][81] In the first incident involving Industrial Biotest Laboratories, an EPA reviewer stated after finding “routine falsification of data” that it was “hard to believe the scientific integrity of the studies when they said they took specimens of the uterus from male rabbits”.^[82][83][84] In the second incident of falsifying test results in 1991, the owner of the lab (Craven Labs), and three employees were indicted on 20 felony counts, the owner was sentenced to 5 years in prison and fined 50,000 dollars, the lab was fined 15.5 million dollars and ordered to pay 3.7 million in restitution.^[85][86] Craven laboratories performed studies for 262 pesticide companies, including Monsanto.

Monsanto has stated that the studies have been repeated, and Roundup’s EPA certification does not now use any studies from Craven Labs or IBT. Monsanto also claims that the Craven Labs investigation was started by the EPA after a pesticide industry task force discovered irregularities.^[87]

Monsanto developed and patented the glyphosate molecule in the 1970s, and marketed Roundup from 1973. It retained exclusive rights in the US until its US patent expired in September, 2000, and maintained a predominant marketshare in countries where the patent expired earlier.

The main active ingredient of roundup is the isopropylamine salt of glyphosate. Another important ingredient of Roundup is the surfactant POEA (polyethoxylated tallow amine), which is known for its toxicity in wildlife.^[6] It increases herbicide penetration in plant^[7] and animal^[8] cells.

Monsanto also produces seeds which grow into plants genetically engineered to be tolerant to glyphosate, which are known as Roundup Ready crops. The genes contained in these seeds are patented. Such crops allow farmers to use glyphosate as a post-emergence herbicide against most broadleaf and cereal weeds. Soy was the first Roundup Ready crop, and was produced at Monsanto’s Agracetus Campus located in Middleton, Wisconsin.

Regulation

Roundup commercial formulations were never submitted to test by the United States Environmental Protection Agency‎ (EPA); its main active ingredient, glyphosate, received EPA Toxicity Class of III for oral and inhalation exposure.^[9]

Beyond the glyphosate salts content, commercial formulations of Roundup contain surfactants, which vary in nature and concentration. As a result, human poisoning with this herbicide is not with the main active ingredient alone, but with complex and variable mixtures.^[10]

Human and mammalian health effects

Toxicity

By 2000, a review published in a Monsanto sponsored journal,^[11] conducted by Ian C. Munro (a member of the Cantox scientific and regulatory consulting firm whose role is defined as to “protect client interests while helping our clients achieve milestones and bring products to market”^[12]) concluded that “under present and expected conditions of new use, there is no potential for Roundup herbicide to pose a health risk to humans”.^[13] Monsanto uses that study as the main source to support Roundup safety for humans.^[14]

A 2008 scientific study has shown that Roundup formulations and metabolic products cause the death of human embryonic, placental, and umbilical cells in vitro, even at low concentrations. The effects were not proportional to the main active ingredient concentrations (glyphosate), but dependent on the nature of the adjuvants used in the Roundup formulation.^[15]

Deliberate ingestion of Roundup in quantities ranging from 85-200 ml has resulted in death within hours of ingestion, although it has also been ingested in quantities as large as 500ml with only mild or moderate symptoms following ingestion.^[16] There is a reasonable correlation between the amount of Roundup ingested and the likelihood of serious systemic sequelae or death. Ingestion of >85 mL of the concentrated formulation is likely to cause significant toxicity in adults. Gastrointestinal corrosive effects, with mouth, throat and epigastric pain and dysphagia are common. Renal and hepatic impairment are also frequent and usually reflect reduced organ perfusion. Respiratory distress, impaired consciousness, pulmonary oedema, infiltration on chest x-ray, shock, arrythmias, renal failure requiring haemodialysis, metabolic acidosis and hyperkalaemia may supervene in severe cases. Bradycardia and ventricular arrhythmias are often present pre-terminally. Dermal exposure to ready-to-use glyphosate formulations can cause irritation, and photo-contact dermatitis has been reported occasionally; these effects are probably due to the preservative Proxel (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, tingling and throat irritation. Eye exposure may lead to mild conjunctivitis, and superficial corneal injury is possible if irrigation is delayed or inadequate.^[10]

Endocrine disruptor

A 2000 in vitro study on mouse MA-10 cells concluded that Roundup inhibited progesterone production by disrupting StAR protein expression.^[17]

A 2005 in vitro study on human placental JEG3 cells concluded that the glyphosate disruption of aromatase is facilitated by adjuvants of the Roundup formulation.^[18]

A 2009 in vitro experiment with glyphosate formulations on human liver HepG2 cells has observed endocrine disruption at sub-agricultural doses, where a Roundup formulation showed to be the most active formulation. The effects were more dependent on the formulation than on the glyphosate concentration.^[19]

A 2009 study on rats has found that Roundup is a potent endocrine disruptor causing disturbances in the reproductive development when the exposure was performed during the puberty period.^[20]

Genetic damage

A 1998 study on mice concluded that Roundup is able to cause genetic damage. The authors concluded that the damage was “not related to the active ingredient, but to another component of the herbicide mixture“.^[21]

A 2005 study raised concerns over the effects of Roundup in transcription.^[22]

A 2009 study on mice has found that a single intraperitoneal injection of Roundup in concentration of 25 mg/kg caused chromosomal aberrations and induction of micronuclei.^[23]

A 2009 in vitro experiment with glyphosate formulations on human liver cells has observed DNA damages at sub-agricultural doses, where a Roundup formulation showed to be the most active formulation. The effects were more dependent on the formulation than on the glyphosate concentration.^[19]

Ecologic effects

A 2000 review of the toxicological data on Roundup concluded that “for terrestrial uses of Roundup minimal acute and chronic risk was predicted for potentially exposed nontarget organisms”. It also concluded that there were some risks to aquatic organisms exposed to Roundup in shallow water.^[24]

Toxicity

A 2009 study has concluded that while physiological pH decreases glyphosate uptake in animal cells Roundup formulation contains surfactants that increases membrane permeability allowing cellular uptake at physiological pH.^[8]

Aquatic effects

Fish and aquatic invertebrates are more sensitive to Roundup than terrestrial organisms.^[24] Glyphosate is generally less persistent in water than in soil, with 12 to 60 day persistence observed in Canadian pond water, yet persistence of over a year have been observed in the sediments of ponds in Michigan and Oregon.^[9]
The EU classifies Roundup as R51/53 Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment.^[25]

Although Roundup is not registered for aquatic uses^[26] and studies of its effects on amphibians indicate it is toxic to them,^[27] scientists have found that it may wind up in small wetlands where tadpoles live, due to inadvertent spraying during its application. A recent study found that even at concentrations one-third of the maximum concentrations expected in nature, Roundup still killed up to 71 percent of tadpoles raised in outdoor tanks.^[28]

Environmental degradation and effects

When glyphosate comes into contact with the soil, it can be rapidly bound to soil particles and be inactivated.^[9] Unbound glyphosate can be degraded by bacteria.^[29] Glyphosphate has been shown to increase the infection rate of wheat by fusarium head blight in fields that have been treated with glyphosphate.^[30] A 2009 study using a RoundUp formulation has concluded that absorption into plants delays subsequent soil-degradation, and can increase glyphosate persistence in soil from two to six times.^[31]

In soils, half lives vary from as little as 3 days at a site in Texas, to as much as 141 days at a site in Iowa^[32]. In addition, the glyphosate metabolite aminomethylphosphonic acid was shown to persist up to 2 years in Swedish forest soils.^[33].

A recent study concluded that certain amphibians may be at risk from glyphosate use.^[34] One study has shown an effect on growth and survival of earthworms.^[35] The results of this study are in conflict with other data, and have been criticized on methodological grounds.^[24] In other studies, nitrogen fixing bacteria have been impaired, and also crop plant susceptibility to disease has been increased.^{[30][36][37][38][39][40][41]}

False advertising and scientific fraud

False advertising

In 1996, Monsanto was accused of false and misleading advertising of glyphosate products, prompting a law suit by the New York State attorney general.^[42] Monsanto had made claims that its spray-on glyphosate based herbicides, including Roundup, were safer than table salt and “practically non-toxic” to mammals, birds, and fish.^[43]

Environmental and consumer rights campaigners brought a case in France in 2001 for presenting Roundup as biodegradable and claiming that it left the soil clean after use; glyphosate, Roundup’s main ingredient, is classed by the European Union as “dangerous for the environment” and “toxic for aquatic organisms”. In January 2007, Monsanto was convicted of false advertising.^[44] The result was confirmed in 2009.^[45]

Scientific fraud

On two occasions, the United States Environmental Protection Agency has caught scientists deliberately falsifying test results at research laboratories hired by Monsanto to study glyphosate.^[46][47][48] In the first incident involving Industrial Biotest Laboratories, an EPA reviewer stated after finding “routine falsification of data” that it was “hard to believe the scientific integrity of the studies when they said they took specimens of the uterus from male rabbits”.^[49][50][51] In the second incident of falsifying test results in 1991, the owner of the lab (Craven Labs), and three employees were indicted on 20 felony counts, the owner was sentenced to 5 years in prison and fined 50,000 dollars, the lab was fined 15.5 million dollars and ordered to pay 3.7 million dollars in restitution.^[32][52][53] Craven laboratories performed studies for 262 pesticide companies including Monsanto.

Monsanto has stated that the studies have been repeated, and that Roundup’s EPA certification does not now use any studies from Craven Labs or IBT. Monsanto also said that the Craven Labs investigation was started by the EPA after a pesticide industry task force discovered irregularities.^[54]

Difference between regulatory registered and commercialized formulations

In November 2009, a French environment group (MDRGF) accused Monsanto of using chemicals in Roundup formulations not informed the country’s regulatory bodies, and demanded the removal of those products from the market.^[55][56]

Herbicide selection

Resistance evolves after a weed population has been subjected to intense selection pressure in the form of repeated use of a single herbicide.^[57] These weeds resistant to the herbicide have been called “Superweeds”.^[58][59]

The first documented cases of weed resistance to glyphosate were found in Australia, involving rigid ryegrass near Orange, New South Wales.^[60] Some farmers in the United States have expressed concern that weeds are now developing with glyphosate resistance, with 13 states now reporting resistance, and this poses a problem to many farmers, including cotton farmers, that are now heavily dependent on glyphosate to control weeds.^[61][62] Farmers associations are now reporting 103 biotypes of weeds within 63 weed species with herbicide resistance^[61][62]. This problem is likely to be exacerbated by the use of Roundup Ready crops ^[63]. Fifteen weed species have been confirmed as resistant to glyphosate.^[57]

Palmer amaranth

In 2004, a glyphosate-resistant variation of palmer amaranth, commonly known as pigweed, was found in Georgia and confirmed by a 2005 study.^[64] In 2005 resistance was also found in North Carolina.^[65] Glyphosate resistance followed the widespread use of Roundup Ready crops, which lead to an unprecedented selection pressure to glyphosate.^[65] The weed variation is now widespread in southeast US.^[66] Cases are also reported in Texas^[66] and Virginia^[67].

Conyza biotypes

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.^{[68][69] [70]}A 2008 study on the current situation of glyphosate resistance in South America concluded that “resistance evolution followed intense glyphosate use” and the utilization of glyphosate-resistant soybean crops is a factor encouraging increase in glyphosate use.^[71]

Ryegrass

Glyphosate resistant ryegrass (Lolium) has occurred in most of the Australian agricultural area 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 that resistant ryegrass does not compete well against non-resistant plants and their numbers decrease when not grown under conditions of glyphosate application.^[72]

Johnsongrass

Glyphosate resistant Johnson grass (Sorghum halepense) has occurred in Roundup Ready soybean culture in Argentina.^[73]

Genetically modified crops

In 1996, genetically modified Roundup Ready soybeans resistant to Roundup became commercially available, followed by Roundup Ready corn in 1998.^[74] Roundup Ready soybeans patent is due to expire in 2014.^[75] Current Roundup Ready crops include soy, maize (corn), canola^[76], sugar beet^[77] and cotton, with wheat^[78] and alfalfa^[79] still under development. As of 2005, 87% of U.S. soybean fields were planted with glyphosate resistant varieties.^[80][81] While the use of Roundup Ready crops may have increased the usage of herbicides measured in pounds applied per acre,^[82] the use of Roundup Ready crops has changed the herbicide use profile away from atrazine, metribuzin, and alachlor^{[citation needed]} which are more likely to be present in run off water.^[83]

Genetic engineering

Some microorganisms have a version of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS: EC 2.5.1.19, 3-phosphoshikimate 1-carboxyvinyltransferase; 5-enolpyruvylshikimate-3-phosphate synthetase; phosphoenolpyruvate:3-phosphoshikimate 5-O-(1-carboxyvinyl)-transferase) that is resistant to glyphosate inhibition. The version used in genetically modified crops was isolated from Agrobacterium strain CP4 (CP4 EPSPS) that was resistant to glyphosate.^[84][85] The CP4 EPSPS gene was cloned and inserted into soybeans. The CP4 EPSPS gene was engineered for plant expression by fusing the 5′ end of the gene to a chloroplast transit peptide derived from the petunia EPSPS. This transit peptide was used because it had shown previously an ability to deliver bacterial EPSPS to the chloroplasts of other plants. The plasmid used to move the gene into soybeans was PV-GMGTO4. It contained three bacterial genes, two CP4 EPSPS genes, and a gene encoding beta-glucuronidase (GUS) from Escherichia coli as a marker. The DNA was injected into the soybeans using the particle acceleration method. Soybean cultivar A54O3 was used for the transformation. The expression of the GUS gene was used as the initial evidence of transformation. GUS expression was detected by a staining method in which the GUS enzyme converts a substrate into a blue precipitate. Those plants that showed GUS expression were then taken and sprayed with glyphosate and their tolerance was tested over many generations.

Productivity claims

In 1999, a review of Roundup Ready soybean crops found that, compared to the top conventional varieties, they had a 6.7% lower yield^[82]. This so called “yield drag” follows the same pattern observed when other traits are introduced into soybeans by conventional breeding.^[86] Monsanto claims later patented varieties yield 7-11% higher than their poorly performing initial varieties, closer to those of conventional farming, although the company refrains from citing actual yields ^[87]. Monsanto’s 2006 application to USDA states that RR2 (mon89788) yields 1.6 bu less than A3244, the conventional variety that the trait is inserted into.^[88]

Tradenames

The Roundup trademark is registered with the US Patent Office and still extant. However, glyphosate is no longer under patent, so similar products use it as an active ingredient.^[89]

Other uses

Glyphosate is one of a number of herbicides used by the United States government to spray Colombian coca fields through Plan Colombia. There are reports that widespread application of glyphosate in attempts to destroy coca crops in South America have resulted in the development of glyphosate-resistant strains of coca known as Boliviana negra, which have been selectively bred to be both “Roundup Ready” and larger and higher yielding than the original strains of the plant. [11]^[90] However, there are no reports of glyphosate-resistant coca in the peer-reviewed literature.^[91] In addition, since spraying of herbicides is not permitted in Colombian national parks, this has encouraged coca growers to move into park areas, cutting down the natural vegetation, and establishing coca plantations within park lands.

Cosmetic purposes

In many cities, Roundup is sprayed along the sidewalks and streets, as well as crevices in between pavement where weeds often grow. However, up to 24% of the glyphosate from a Roundup formulation applied to hard surfaces can be run off by water.^[92] Glyphosate contamination of surface water is highly attributed to urban use.^[93]

In many Canadian cities Roundup use for cosmetic purposes is either banned or restricted.^[94][95]

What is glyphosate?
Glyphosate was first reported as a herbicide in 1971. Three related products are now manufactured under the name glyphosate: glyphosate-isopropylammonium and glyphosate-sesquisodium patented by Monsanto, and glyphosate-trimesium patented by ICI (now Zeneca). In pure chemical terms glyphosate is an organophosphate in that it contains carbon and phosphorous. However, it does not affect the nervous system in the same way as organophosphate insecticides, and is not a cholinesterase inhibitor.
    Glyphosate is a broad spectrum, non-selective systemic herbicide. It is effective in killing all plant types including grasses, perennials and woody plants. As a herbicide glyphosate works by being absorbed into the plant mainly though its leaves but also through soft stalk tissue. It is then transported throughout the plant where it acts on various enzyme systems inhibiting amino acid metabolism in what is known as the shikimic acid pathway. This pathway exists in higher plants and microorganisms but not in animals. Plants treated with glyphosate slowly die over a period of days or weeks, and because the chemical is transported throughout the plant, no part survives.

Usage
Glyphosate is sold around the world and is formulated into dozens of products by many pesticide companies. Glyphosate product sales are currently worth approximately US$1,200 million annually and represent about 60% of global non-selective herbicides sales(2). The total world herbicide market was worth about US$14,285 million in 1995(3).
    In UK arable agriculture, glyphosate was the 12th most extensively used pesticide active ingredient; the 5th most extensively used herbicide by weight with 251 tonnes being used; and 38th most widely applied herbicide, being applied over 334,529 ha annually in 1994(4). In the US nearly 8,500 tonnes was being used on 5-8 million hectares annually in the years leading up to 1991(5).

Acute toxicity
The acute toxicity of glyphosate itself is very low. According to the World Health Organisation, the oral LD50 in the rat of pure glyphosate is 4,230 mg/kg, or 5,600 mg/kg according to Monsanto(6). The low acute toxicity of glyphosate can be attributed to its biochemical mode of action on a metabolic pathway in plants (called the shikimic acid pathway) which does not exist in animals(7). However, glyphosate can also disrupt functions of enzymes in animals. In rats it was found to decrease the activity of some detoxification enzymes when injected into the abdomen(8). In general, controlled toxicity tests report adverse symptoms from exposure to glyphosate only at extremely high doses, ie several grammes per kg body weight.
    While glyphosate itself may be relatively harmless, some of the products with which it is formulated have a rather less benign reputation. Marketed formulations of glyphosate generally contain a surfactant. The purpose of this is to prevent the chemical from forming into droplets and rolling off leaves which are sprayed. Some of these surfactants are serious irritants, toxic to fish, and can themselves contain contaminants which are carcinogenic to humans.
    The most widely used type of surfactants in glyphosate formulations are known as ethylated amines. POEA (polyoxy-ethyleneamine) has been frequently mentioned as a surfactant, but in fact it refers to a group of ethylated amine products used in glyphosate formulations. Members of this group of surfactants are significantly more toxic than glyphosate. They are serious irritants of eyes, the respiratory tract and skin, and have been found to contain dioxane (not dioxin) contaminants which are suspected of being carcinogenic. Accordingly, the UN FAO has set standards of 1ppm for levels of the contaminant 1,4 dioxane which may be present in POEA surfactants.
    Monsanto states that all surfactants used in its glyphosate formulations fall well within the FAO standard. However, being aware of the irritant and toxic potential of the surfactants in general, the company has now developed new surfactants which have none of these toxic effects. Products containing the new formulants are sold in the UK and elsewhere and are recognised by approval authorities as being non-irritant(9). Currently in the UK, all garden products contain the new surfactant, and most local authorities are using it. However, the new formulations are more expensive and as long as there is demand for the cheaper, old formulations they will continue to be sold. Currently these are available in UK agriculture and horticulture and for professional amenity use(10).
    In the UK, a local authority was prosecuted after a child was accidentally sprayed with a glyphosate formulation and suffered allergic reactions. Recently there have also been claims from residents of St. Just in Cornwall that they have suffered severe reactions following application of glyphosate for weed control(11).
    In the UK, glyphosate is the most frequent cause of complaints and poisoning incidents recorded by the Health and Safety Executive’s Pesticides Incidents Appraisal Panel (PIAP). Between 1990 and 1995, 33 complaints were received and 34 poisonings recorded including a single death by suicide in 1990(12,13). In California, glyphosate is one of the most commonly reported causes of illness or injury to workers from pesticides. The most common complaints are eye and skin irritation(14). The US authorities have recommended a no re-entry period of 12 hours where glyphosate is used in agricultural or industrial situations. No such recommendation exists in the UK.

Chronic toxicity
Some literature suggests that glyphosate can cause some chronic health effects and birth defects in certain test animals when administered at high doses over prolonged periods(15). Chronic feeding studies have shown reduced weight gain, blood and pancreatic effects, but no evidence of carcinogenicity to humans. A US EPA report says: “Effects on pregnant mothers and foetuses included diarrhoea, decreased weight gain, nasal discharge and death of mothers and kidney and digestive disorders in rat pups”(16).
    It is extremely unlikely that human users or members of the public would be exposed to doses as high as those used in the trials, but extrapolating toxicity data from rats, mice and rabbits on which trials are run, to humans can be inaccurate and misleading.

Glyphosate in the environment
Glyphosate is inactivated when it comes into contact with soil since it is adsorbed onto soil particles. This mechanism is not fully understood, but in part glyphosate binds to soil in the same way as inorganic phosphates(17). Un-bound glyphosate is rapidly degraded by microbial activity to carbon dioxide, and bound glyphosate is degraded more slowly, sometimes remaining un-degraded but inactive in soil for years(18). Glyphosate has been found to inhibit anaerobic nitrogen fixation in soil(19 ,20).
    Because of its adsorption to soil, glyphosate is not easily leached and is unlikely to contaminate ground water. However, glyphosate is used in water for the control of aquatic weeds, and it can be carried with eroded soil into surface waters where natural breakdown processes are much slower. On rare occasions glyphosate has been detected in water, but generally it is not looked for because it is extremely difficult to isolate and is not considered to be of major concern as a water contaminant(21).
    The Forestry Commission believes that glyphosate and other herbicides commonly affect hedgerow trees causing die-back. In the US it has been suggested that herbicides, including glyphosate reduce winter hardiness in trees and their resistance to fungal disease(22). It has been suggested that damage to maple trees increases during the second year following treatment with glyphosate, and that clover planted 120 days following treatment showed reduced nitrogen fixation and growth. This implies that glyphosate which is bound to soil particles can remain active and may be released from soil and taken up by plants(23). The US-EPA has also stated that many endangered plants may be at risk from glyphosate use(24).
    There may also be cause for concern where glyphosate is used extensively in programmes to eradicate drug producing plants such as coca, opium poppies and marijuana. Glyphosate is sprayed indiscriminately over vast areas and will inevitably kill non-target vegetation some of which may be endangered.
    The toxicity of glyphosate to mammals and birds is generally relatively low. However, its broad spectrum of herbicidal activity has led to the destruction of habitats and food sources for some birds and amphibians leading to population reductions(25). The Houston toad is an extreme case in that it is now an endangered species due to destruction of its habitat by glyphosate(26).
    Fish and aquatic invertebrates are more sensitive to glyphosate and its formulations. Its toxicity is increased with higher water temperatures and pH. Some soil invertebrates including springtails, mites and isopods are also adversely affected by glyphosate. Of nine herbicides tested for their toxicity to soil microorganisms, glyphosate was found to be the second most toxic to a range of bacteria, fungi, actinomycetes and yeasts(27).
    However, while glyphosate alone has low toxicity, the formulation of glyphosate with the surfactant polyoxyethylene amine (POEA), which is widely used, is significantly more toxic.
    In Australia most formulations of glyphosate have been banned from use in or near water because of their toxic effects on tadpoles and to a lesser extent on adult frogs. There is also concern about non-lethal effects of the herbicide on frogs. New non-irritant formulations such as Roundup Biactive are excluded from the ban(28 ,29). 

Resistance
Crops with genetically engineered resistance to glyphosate are being developed so that weeds can be controlled in fields where the crops are growing without harming the crop plants themselves. This strategy will make farmers more dependent on particular pesticidal products and will probably lead to increased use. There is also concern that the genes which display glyphosate resistance may be transferred to non-crop species including weeds.
    Recent reports in professional journals indicate that resistance to glyphosate has developed in annual ryegrass in Australia(30,31).  Anecdotal evidence from users in the UK suggests that similar signs of resistance in annual ryegrass and knotgrass have existed for some time.

Conclusion
Glyphosate can be an effective tool in weed control programmes and is relatively less harmful than many of the products which compete with it in the market place. There is nevertheless evidence of toxic effects on humans as well as environmental toxicity, indirect environmental damage and resistance in some target weed species.
    Since glyphosate is being marketed as a safe and environmentally friendly product and its use is so extensive, there is a danger that damage to non-target plants including endangered species will increase. Habitat damage and destruction will occur more frequently and more instances of weed resistance will appear. Cultivation of glyphosate resistant crops will potentially exacerbate these problems.
    So while glyphosate provides a welcome move away from chemicals which are highly toxic to humans and other non target organisms, and from chemicals which cause direct and lasting damage to the environment, it may be introducing more subtle indirect forms of damage of which users need to be aware.