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Glyphosate Fact Sheet
Targeting a Plant Enzyme
Although plants and animals differ in many ways, in at least one they are quite similar. They both need to make proteins and they both need to make these proteins from the same twenty amino acids. Amino acids are the basic building blocks of proteins, and proteins make up the basic structure of cells and tissues, and make up all of the metabolic enzymes necessary for life.
Plants can manufacture all twenty amino acids, but animals can only synthesize a subset. The remaining essential amino acids must be supplied in the diet either by ingesting plant material, or other animals. In humans, there are eight essential amino acids, which include isoleucine, leucine, lysine, methionine, phenyalanine, threonine, tryptophan, and valine. By inhibiting one of the enzymes involved in synthesizing some of these essential amino acids in plants, chemical manufacturers have been able to develop specific herbicides that selectively kill plants, without harming animals.
In plants, the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (abbreviated EPSPS) plays a key role in the biochemical pathway that results in the synthesis of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. This enzyme is only present in plants and microorganisms, such as bacteria and fungi, and is not present in animals and humans (Levin & Sprinson 1964; Steinrucken & Amrhein 1980; Franz et al. 1997). In the early 1970s, it was discovered that the simple amino acid analogue, glyphosate, could selectively inhibit the activity of the EPSPS enzyme, thus shutting off aromatic amino acid synthesis. Because these amino acids are needed for protein synthesis, which is required for plant growth and maintenance, the application of glyphosate quickly results in plant death (Kishore & Shah 1988). Monsanto, the company which first produced glyphosate, began commercially marketing this herbicide in 1974 under the trade name Roundup®.
Herbicide Properties
Glyphosate is a broad-spectrum, non-selective, systemic herbicide. It kills all plant types including grasses, perennials and woody plants. When a plant is sprayed with glyphosate, the herbicide is absorbed through the leaves and the soft tissue of the stem. Treated plants are killed in days to weeks.
The high sensitivity of crop plants to glyphosate has limited its use as a pre-crop emergence herbicide in no-till management strategies, and as a herbicide and crop desiccant when applied shortly before crop harvest. With the development of genetically engineered crop plants that are resistant to glyphosate, this herbicide can instead be applied after both crops and weeds have emerged, with little or no damage to the crop.
Potential Toxicity
Pharmacokinetics and metabolism
Absorption of glyphosate from the gastrointestinal tract after oral ingestion in various mammalian species is approximately 30-36% of the dose, and absorption through intact skin is less than 3% of the dose. Glyphosate is essentially not metabolized in animals, and elimination of unchanged glyphosate is rapid, with approximately 80% being excreted via the feces and urine within the first 24 hours after oral administration. There is no evidence of accumulation of glyphosate in the animal body (Williams et al. 2000).
Acute toxicity and irritation studies
The acute toxicity of glyphosate is very low, which can be attributed to the fact that it acts on the shikimate pathway (see above) that is absent from animals. In laboratory studies by the oral and dermal routes of exposure, LD50 values in rats were found to be greater than the limit test dose of 5000 mg/kg body wt (WHO 1994). The acute inhalation toxicity in rats was also low, with LC50 values above the limit concentration of 5 mg/L air (4-hour exposure). Glyphosate is non-irritating to the skin, but can be moderately to severely irritating to the eyes of rabbits. The salts of glyphosate, however, are only slightly to non-irritating to the eyes. Glyphosate has not shown any skin sensitizing effects in guinea pigs (Extoxnet 2001).
Genotoxicity studies
The potential genotoxicity of glyphosate has been examined in a wide range of in vitro and in vivo assays (U.S. EPA. 1993). No genotoxicity was observed in standard, validated assays conducted according to international guidelines by GLP-compliant facilities. These assays include the in vitro Ames assay, E. coli Wp-2 reversion assays, recombination assay with Bacillus subtilis, Chinese Hamster ovary cell gene mutation assay, hepatocyte primary culture/DNA repair assay, in vivo mouse bone marrow micronucleus assay, and rat bone marrow cytogenetics assay.
Long-term toxicity and carcinogenicity studies
Several long-term feeding studies using rats, mice and beagle dogs have been conducted. Few chronic effects occurred and these were limited to the highest doses tested: 20,000 ppm and 30,000 ppm for rats and mice, respectively. No treatment-related effects were observed in the 1-year dog study, even at the highest dose tested of 500 mg/kg/day. No evidence of carcinogenicity was observed in either rats or mice. Regulatory agencies and other scientific organizations have concluded that glyphosate is not carcinogenic or genotoxic (U.S. EPA 1993; WHO 1994; European Commission 2002). In June of 1991, the U.S. EPA (following a thorough review of all toxicology data available) concluded that glyphosate should be classified in Category E ("Evidence of Non-carcinogenicity in Humans"). This classification was based upon the observation of no treatment-related tumors at any dose level with glyphosate tested up to the limit in rats and up to levels higher than the limit dose in mice, and upon the evidence for lack of genotoxicity for glyphosate (U.S. EPA 1992).
Reproductive and developmental toxicity studies
Results from multi-generation reproduction studies in rats did not indicate any adverse effect on the animals' ability to mate, conceive, carry or deliver normal offspring. Based on the findings from developmental toxicity studies in rats and rabbits, it can be concluded that glyphosate does not produce birth defects; developmental toxicity is only seen at maternally toxic doses (Williams et al. 2000).
Toxicity to wildlife
The acute toxicity of glyphosate to terrestrial and aquatic wildlife has been extensively evaluated, with laboratory and field results indicating low acute toxicity and low risk from direct exposure. The scientific literature contains hundreds of articles addressing the effects of glyphosate on non-target organisms (Sullivan & Sullivan 2000). Laboratory studies indicate that glyphosate will not cause adverse effects to earthworms, honeybees, or avian species such as mallard ducks or bobwhite quail under normal use conditions. In 2000, a comprehensive ecotoxicological risk assessment was published for glyphosate (Giesy et al. 2000). The authors concluded that the use of glyphosate does not pose an unreasonable risk of adverse effects to wildlife when used according to label directions.
Glyphosate has low toxicity to non-target aquatic organisms (for example, fish and aquatic invertebrates). While surfactants that might be added to some glyphosate herbicide formulations can have low to moderate toxicity to some aquatic animals, the toxicity and exposure is sufficiently low under normal use conditions that there is no significant risk of adverse effects to aquatic animals under normal use conditions.
Environmental Fate
Persistence in the soil
Glyphosate does not persist in the environment. Glyphosate undergoes microbial degradation over time in soil, sediment and natural waters, under both aerobic and anaerobic conditions (Giesy et al. 2000). The rate of decrease of glyphosate concentration in soil depends on the overall microbial activity (Carlisle & Trevors 1988; Moshier & Penner 1978). The major metabolite formed is aminomethylphosphonic acid (AMPA), which undergoes further microbial degradation. Glyphosate is ultimately metabolized to carbon dioxide, inorganic phosphate, and other naturally occurring compounds. Glyphosate's low volatility means that it is highly unlikely to move offsite as a vapor to damage offsite vegetation.
The herbicidal properties of glyphosate are lost when glyphosate comes into contact with soil or sediment. Glyphosate binds tightly to most types of soil and sediment making it unlikely to be picked up by the roots of off-site vegetation (Giesy et al. 2000). This tight binding results in an extremely low potential for glyphosate to move into groundwater. Glyphosate dissipates from surface water by two primary mechanisms. It quickly partitions from water into sediment, and then is microbially degraded over time in both the water and the sediment. In flowing waters, factors such as tributary dilution and dispersion contribute to the dissipation of glyphosate.
Water quality
Historically, glyphosate has not been included among herbicides that cause concern in water supplies, even though it sometimes has been detected in surface waters. Glyphosate can be removed from water by filtration and chlorination. Therefore, it is highly unlikely that it would be detected in finished drinking water (Speth 1994). When glyphosate has been detected in lakes, ponds and streams, the concentrations have been at levels that will not cause unreasonable adverse effects to human health or the environment.
In the United States, a maximum contaminant level (MCL) of 700 µg/L has been established by the U.S. EPA as a health based upper legal limit for glyphosate in drinking water (U.S. EPA 2000). The California Environmental Protection Agency has established a public health goal (PHG) for glyphosate in drinking water of 1000 µg/L (California EPA 1997). These levels are considered to be protective of human health for potential exposure to glyphosate residues in drinking water.
Glyphosate has rarely been detected in drinking water, and there are no known exceedances of the drinking water standards described above. This is not surprising since glyphosate binds tightly to soil and degrades over time into naturally occurring substances.
The World Health Organization reviewed water quality data for glyphosate (WHO 1997) and stated:
"It was concluded that because of its low toxicity, the health based value derived for glyphosate was orders of magnitude higher than glyphosate concentrations normally found in drinking water. Under usual conditions, therefore, the presence of glyphosate in drinking water does not represent a hazard to human health."
Herbicide Tolerance Strategies
Based on the knowledge of the mode of action of glyphosate, several strategies have emerged for developing plants that are tolerant of exposure to the herbicide. The two successful strategies used to produce glyphosate-tolerant plants are the introduction of a glyphosate-tolerant form of EPSPS and the introduction of an enzyme that inactivates glyphosate, glyphosate oxidoreductase (GOX). Recombinant DNA techniques have been used to express genes that encode glyphosate-tolerant EPSPS enzyme alone or a combination of EPSPS and GOX genes in susceptible plants (Nida et al. 1996; Padgette et al. 1995; Padgette et al. 1996).
Literature Cited
  1. California EPA. (1997). Public health goal for glyphosate in drinking water. Pesticide and Environmental Toxicology Section, Office of Environmental Health Hazard Assessment, California Environmental Protection Agency. Url:
  2. Carlisle, S.M. & Trevors, J.T. (1988). Glyphosate in the Environment. Water, Soil and Air Pollution 39, 409-420. Pesticides in water: Report of The Working Party on the Incidence of Pesticides in Water, Department of the Environment, HMSO, May 1996.
  3. European Commission (2002). Report for the Active Substance Glyphosate, Directive 6511/VI/99, Jan. 21. Url:
  4. EXTOXNET (2001) Glyphosate profile. Url:
  5. Franz, J.E., Mao, M.K. & Sikorski, J.A. (1997). Glyphosate: A Unique Global Herbicide. ACS Monograph No. 189. American Chemical Society. Washington, DC.
  6. Giesy, J.P., Dobson, S. & Solomon, K.R. (2000). Ecotoxicological risk assessment for Roundup herbicide. Reviews of Environmental Contamination and Toxicology 167: 35-120.
  7. Kishore, G. & Shah, D. (1988). Amino acid biosynthesis inhibitors as herbicides. Annu. Rev. Biochem. 57:627-663.
  8. Levin, J.G. & Sprinson, D.B. (1964). The enzymatic formation and isolation of 5-enolpyruvylshikimate-3-phosphate. J. Biol. Chem. 239:1142-1150.
  9. Moshier, L.J., Penner, D. (1978). Factors influencing microbial degradation of 14C-glyphosate to 14CO2 in soil. Weed Science 26(6): 686-91.
  10. Nida, D.L., Kolacz, K.H., Buehler, R.E., Deaton, W.R., Schuler, W.R., Armstrong, T.A., Taylor, M.L., Ebert, C.C. and Rogan, G.J. (1996). Glyphosate-tolerant cotton: Genetic characterization and protein expression. J. Agric. Food Chem. 44(7):1960-1966.
  11. Padgette, S.R., Kolacz, K.H., Delannay, X., Re, D.B., La Vallee, B.J., Tinius, C.N., Rhodes, W.K., Otero, Y.I., Barry, G.F., Eichholtz, D.A., Peschke, V.M., Nida, D.L., Taylor, N.B. and Kishore, G.M. (1995). Development, identification, and characterization of a glyphosate-tolerant soybean line. Crop Science 35(5): 1451-1461.
  12. Padgette, S.R., Re, D.B., Barry, G.F., Eichholtz, D.E., Delannay, X., Fuchs, R.L., Kishore, G.M. and Fraley, R.T. (1996). New weed control opportunities: Development of soybeans with a Roundup Ready gene. In: Duke, S.O. (ed.), Herbicide-resistant crops: Agricultural, environmental, economic, regulatory, and technical aspects. CRC Press Inc., Boca Raton, Florida, and London, England, pp. 53-84.
  13. Speth, T.F. (1994). Glyphosate removal from drinking water. J. Envir. Engr. 119: 1139-1157.
  14. Steinrucken, H.C. & Amrhein, N. (1980). The herbicide glyphosate is a potent inhibitor of 5- enolpyruvyl-shikimate-3-phosphate synthase. Biochem. Biophys. Res. Comm. 94:1207-1212.
  15. Sullivan DS, Sullivan TP (2000). Non-target impacts of the herbicide glyphosate: A compendium of references and abstracts. 5th Edition. Applied Mammal Research Institute, Summerland, British Columbia, Canada.
  16. U.S. EPA (1992). Pesticide tolerance proposed rule. Federal Register 57: 8739-8740.
  17. U.S. EPA (1993) Re-registration Eligibility Decision (RED): Glyphosate. U.S. Environmental Protection Agency. Office of Prevention, Pesticides and Toxic Substances. Washington, D.C.
  18. U.S. EPA (2000). Drinking water standards and health advisories. EPA 822-B-00-001. Office of Water, U.S. Environmental Protection Agency.
  19. WHO (1994). Glyphosate. Environmental Health Criteria No. 159. World Health Organization¸ International Programme of Chemical Safety (IPCS), Geneva.
  20. WHO (1997). Rolling Revisions of WHO Gudielines for Drinking Waster Quality Report of Working Group Meeting on Chemical Substances for the Updating of WHO Guidelines for Drinking Water Quality. World Health Organization, Geneva.
  21. Williams, G.M., Kroes, R. & Munro, I.C. (2000). Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. Regulatory Toxicology and Pharmacology 31: 117-165.
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