Glyphosate Part 1: Toxicology

Caroline Cox. Journal of Pesticide Reform, Volume 15, Number 3, Fall 1995. Northwest Coalition for Alternatives to Pesticides, Eugene, OR.

Introduction

Glyphosate is a broad-spectrum herbicide widely used to kill unwanted plants both in agriculture and in nonagricultural landscapes. Estimated use in the U.S. is between 19 and 26 million pounds per year.

Most glyphosate-containing products are either made or used with a surfactant, chemicals that help glyphosate to penetrate plant cells.

Glyphosate-containing products are acutely toxic to animals, including humans. Symptoms include eye and skin irritation, cardiac depression, gastrointestinal pain, vomiting, and accumulation of excess fluid in the lungs. The surfactant used in a common glyphosate product (Roundup) is more acutely toxic than glyphosate itself; the combination of the two is
yet more toxic.

In animal studies, feeding of glyphosate for three months caused reduced weight gain, diarrhea, and salivary gland lesions. Lifetime feeding of glyphosate caused excess growth and death of liver cells, cataracts and lens degeneration, and increases in the frequency of thyroid, pancreas, and liver tumors.

Glyphosate-containing products have caused genetic damage in human blood cells, fruit flies, and onion cells.

Glyphosate causes reduced sperm counts in male rats, a lengthened estrous cycle in female rats, and an increase in fetal loss together with a decrease in birth weights in their offspring.

It is striking that laboratory studies have identified adverse effects of glyphosate or glyphosate containing products in all standard categories of toxicological testing.

Two serious cases of fraud have occurred in laboratories conducting toxicology and residue testing for glyphosate and glyphosate-containing products.

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Advertised as herbicides that can "eradicate weeds and unwanted grasses effectively with a high level of environmental safety,"¹ glyphosate-based herbicides can seem like a silver bullet to those dealing with unwanted vegetation. However, an independent, accurate evaluation of their health and environmental hazards can draw conclusions very different than those presented by these advertisements.

The following summary of glyphosate's hazards is intended to serve that purpose. It will appear in two parts: Part 1 discusses the toxicology of glyphosate, its metabolites, and the other ingredients of glyphosate products and Part 2 will discuss human exposure to glyphosate and its ecological effects.

Glyphosate, N-(phosphonomethyl) glycine (Figure 1), is a post-emergent, systemic, and non-selective herbicide used to kill broad-leaved, grass, and sedge species.² It has been registered as a broad spectrum herbicide in the U.S. since 1974 and is used to control weeds in a wide variety of agricultural, lawn and garden, aquatic, and forestry situations.³

Most glyphosate herbicides contain the isopropylamine salt of glyphosate. A related chemical, the sodium salt of glyphosate, acts as a growth regulator in sugar cane and peanuts and is marketed for that purpose. The monoammonium salt of glyphosate is also marketed as an herbicide and growth regulator.⁴

Glyphosate products are manufactured by Monsanto Company worldwide. The herbicide is marketed under a variety of trade names: Roundup (including Roundup D-Pak, Roundup Lawn and Garden Concentrate, and Roundup Ready-to-Use) and Rodeo are the most common U.S. trade names.² The sodium salt is sold as Quotamaster. The monoammonium salt is sold as Deploy Dry.² Other brand names used for the isopropylamine salt are Accord,5 Vision, Ranger, and Sting.²

As an herbicidal compound, glyphosate is unusual in that essentially no structurally related compounds show any herbicidal activity.⁶

Use

Glyphosate is the eighth most commonly used herbicide in U.S. agriculture and the second most commonly used herbicide in nonagricultural situations. Estimated annual use according to the U.S. Environmental Protection Agency (EPA) is between 15 and 20 million pounds in agriculture and between 4 and 6 million pounds elsewhere.⁷The largest agricultural uses are in the production of soybeans, hay and pasture, corn, and oranges.4

About 25 million applications per year are made in U.S. households; most of these are made on lawns or outdoor areas where a total vegetation kill is wanted.⁸

In California, where pesticide use reporting is more comprehensive than in other states, about 3.4 million pounds were used in 1992; about 25 percent of this was used along rights-of-way, while 15 percent was used on almonds and 10 percent was used on grapes.⁹

Mode of Action

The mode of action of glyphosate is "not known at this time,"⁴ according to EPA. However, "herbicidal action probably arises from the inhibition of the biosynthesis of aromatic amino acids."¹⁰These amino acids (phenylalanine, tyrosine, and tryptophan) are used in the synthesis of proteins and are the essential for growth and survival of most plants. One particular enzyme important in aromatic amino acid synthesis, called 5-enolpyruvylshikimate-3-phosphate synthase, is inhibited by glyphosate.¹⁰ Glyphosate also "may inhibit or repress"⁴ two other enzymes, chlorismate mutase and prephrenate hydratase, involved in other steps of the synthesis of the same amino acids. These enzymes are all part of what is called the shikimic acid pathway, present in higher plants and microorganisms but not in animals.¹¹

Two of the three aromatic amino acids (tryptophan and phenylalanine) are essential amino acids in the human diet because humans, like all higher animals, lack the shikimic acid pathway, cannot synthesize these amino acids, and rely on their foods to provide these compounds. Tyrosine is synthesized in animals through another pathway.¹²

Glyphosate can affect enzymes not connected with the shikimic acid pathway. In sugar cane, it reduces the activity of one of the enzymes involved in sugar metabolism, acid invertase. This reduction appears to be mediated by auxins, plant hormones.¹³

Glyphosate also affects enzyme systems found in animals and humans. In rats, injection into the abdomen decreases the activity of two detoxification enzymes, cytochrome P-450 and a monooxygenase, and decreases the intestinal activity of the enzyme aryl hydrocarbon hydroxylase (another detoxification enzyme).¹⁴

"Inert" Ingredients in Glyphosate-containing Products

Virtually every pesticide product contains ingredients other than what is called the "active" ingredient(s), those designed to provide killing action. Their purpose is to make the product easier to use or more efficient. These ingredients are called "inert," although they are often not biologically, chemically, or toxicologically inert. In general, they are not identified on the label of the pesticide product.

In the case of glyphosate products, many "inerts" have been identified. Roundup contains a polyethoxylated tallowamine surfactant (usually abbreviated POEA), related organic acids of glyphosate, isopropylamine, and water. Both Rodeo and Accord contain glyphosate and water.¹⁵ (However, label instructions usually require adding a surfactant during use.15) See "Toxicology of 'Inert' Ingredients of Glyphosate-containing Products," p. 17, for basic information about these "inert" ingredients.

Many of the toxicology studies that will be summarized in this factsheet have been conducted using glyphosate, the active ingredient, alone. Some have been conducted with commercial products containing glyphosate and "inert" ingredients. When toxicology testing is not done with the product as it is actually used, it is impossible to accurately assess its hazards.

We will discuss both types of studies, and will identify insofar as is possible exactly what material was used to conduct each study.

Acute Toxicity to Laboratory Animals

Glyphosate's acute oral median lethal dose (the dose that causes death in 50 percent of a population of test animals; LD50) in rats is greater than 4,320 milligrams per kilogram (mg/kg) of body weight. This places the herbicide in Toxicity Category III (Caution).⁴ Its acute dermal toxicity (dermal LD50) in rabbits is greater than 2,000 mg/kg of body weight, also Toxicity Category III.⁴

If animals are given glyphosate in other ways, it is much more acutely toxic. When given intraperitoneally (the dose applied by injection into the abdomen), glyphosate is between 10 and 20 times more toxic to rats (with an LD50 between 192-467 mg/kg)^2,16 than it is when given orally. Intraperitoneal injection also caused fever, cessation of breathing, and convulsions.¹⁷ While this kind of exposure is not one that would be encountered under conditions of normal use, these studies indicate the kinds of effects glyphosate can potentially cause in mammals.

Commercial glyphosate-containing products are more acutely toxic than glyphosate alone. Two recent (1990 and 1991) studies compared the amount of Roundup required to cause death in rats with the amount of either glyphosate alone or POEA alone that would cause death. The studies found that in combination, the amount of glyphosate and POEA required to kill was about 1/3 of a lethal dose of either compound separately. The Roundup formulation tested was also more toxic than POEA alone.^18,19

As with glyphosate alone, glyphosate-containing products are more toxic when administered other ways than orally. Inhalation of Roundup by rats caused "signs of toxicity in all test groups,"²⁰ even at the lowest concentration tested. These signs included a dark nasal discharge, gasping, congested eyes, reduced activity, hair standing erect,²¹ and body weight loss following exposure.²⁰ Lungs were red or blood-congested.²¹ The dose required to cause lung damage and mortality following pulmonary administration of Roundup Lawn and Garden Concentrate or Roundup-Ready-to-Use (the glyphosate product is directly forced into the trachea, the tube carrying air into the lungs) was only 1/10 the dose causing damage through oral administration.¹⁸

Effects on the Circulatory System: When dogs were given intravenous injections of glyphosate, POEA, or Roundup so that blood concentrations were approximately those found in humans who ingested glyphosate, a variety of circulatory effects were found. Glyphosate increased the ability of the heart muscle to contract. POEA reduced the output of the heart and the pressure in the arteries. Together (Roundup), the result was cardiac depression.²²

Eye Irritation: Glyphosate is classified as a mild eye irritant by EPA, with effects lasting up to seven days⁴ although more serious effects were found by the World Health Organization. In two of the four studies they reviewed, glyphosate was "strongly irritating"² to rabbits' eyes and a third test found it "irritating."² In tests of glyphosate-containing products, all eight products tested were irritating to rabbit eyes, and four of the products were "strongly" or "extremely" irritating.²

Skin Irritation: Glyphosate is classified as a slightly irritating to skin. Roundup is a "moderate skin irritant" and causes redness and swelling on both intact and abraded rabbit skin. Recovery can take more than two weeks.²⁰

Acute Toxicity to Humans

The acute toxicity of glyphosate products to humans was first widely publicized by physicians in Japan who studied 56 cases of Roundup poisoning. Most of the cases were suicides or attempted suicides; nine cases were fatal. Symptoms of acute poisoning in humans included gastrointestinal pain, vomiting, excess fluid in the lungs, pneumonia, clouding of consciousness, and destruction of red blood cells.²³ They calculated that the mean amount ingested in the fatal cases was slightly more than 200 milliliters (about 3/4 of a cup). They believed that POEA was the cause of Roundup's toxicity.²³ More recent reviews of glyphosate poisoning incidents have found similar symptoms, as well as lung congestion or dysfunction,^24-26, erosion of the gastrointestinal tract,^24,26 abnormal electrocardiograms,26 massive gastrointestinal fluid loss,²⁷low blood pressure,^23,26 and kidney damage or failure.^24,25,27

Smaller amounts of Roundup also cause adverse effects. In general these include the skin or eye irritation documented in animal studies, as well as some of the symptoms seen in humans following ingestion. For example, rubbing of Roundup in an eye caused swelling of the eye and lid, rapid heartbeat, palpitations, and elevated blood pressure. Wiping the face with a hand that had contacted leaky Roundup spray equipment caused a swollen face and tingling of the skin. Accidental drenching with Roundup (horticultural strength) caused recurrent eczema of the hands and feet lasting two months.²⁵

Different symptoms have been observed when a different type of exposure has occurred. In Great Britain, a study compared the effects of breathing dust from a flax milling operation that used flax treated with Roundup with the effects of dust from untreated flax. Treated flax dust caused a decrease in lung function and an increase in throat irritation, coughing, and breathlessness.²⁸

Subchronic Toxicity

Experiments in which glyphosate was fed to laboratory animals for 13 weeks showed a variety of effects. In experiments conducted by the National Toxicology Program (NTP), microscopic salivary gland lesions were found in all doses tested in rats (200 - 3400 mg/kg per day) and in all but the lowest dose tested in mice (1,000-12,000 mg/kg per day). Both the parotid and submandibular salivary glands were affected in rats; in mice the lesions were confined to the parotid gland. Based on further experiments, NTP concluded the lesions were mediated by the adrenal hormone adrenalin.²⁹

The NTP study also found evidence of effects on the liver: increases in bile acids as well as two liver enzymes were found in both males and females. Other effects found in this study were reduced weight gain in male and female rats and mice; diarrhea in male and female rats; and changes in the relative weights of kidney, liver and thymus in male rats and mice.²⁹

Other subchronic laboratory tests found decreased weight gains (using doses of 2500 mg/kg per day)30 along with an increase in the weights of brain, hearts, kidney, and livers in mice.² In rats, blood levels of potassium and phosphorus increased at all doses tested (60-1600 mg/kg/day) in both sexes. There was also an increase in pancreatic lesions in males.⁴

As in acute toxicity tests, glyphosate-containing products are more toxic than glyphosate alone in subchronic tests. In a 7 day study with calves, 790 mg/kg of Roundup caused labored breathing, pneumonia, and death of 1/3 of the animals tested. At lower doses decreased food intake and diarrhea were observed.²

Chronic Toxicity

Glyphosate is also toxic in long-term studies. The following effects were found in lifetime glyphosate feeding studies using mice: decreased body weight, excessive growth of particular liver cells, death of the same liver cells, and chronic inflammation of the kidney. Effects were significant only in males and at the highest dose tested (about 4800 mg/kg of body weight per day). In females, excessive growth of some kidney cells occurred.³¹ At a lower dose (814 mg/kg of body weight per day) excessive cell division in the urinary bladder occurred.²

Lifetime feeding studies with rats found the following effects: decreased body weight in females; an increased incidence of cataracts and lens degeneration in males; and increased liver weight in males. These effects were significant at the highest dose tested (900-1200 mg/kg of body weight per day).⁴ At a lower dose (400 mg/kg of body weight per day) inflammation of the stomach's mucous membrane occurred in both sexes.²

Carcinogenicity

The potential of glyphosate to cause cancer has been a controversial subject since the first lifetime feeding studies were analyzed in the early 1980s. The first study (1979-1981) found an increase in testicular interstitial tumors in male rats at the highest dose tested (30 mg/kg of body weight per day).³² as well as an increase in the frequency of a thyroid cancer in females.³³ The second study (completed in 1983) found dose-related increases in the frequency of a rare kidney tumor in male mice.³⁴ The most recent study (1988-1990) found an increase in the number of pancreas and liver tumors in male rats together with an increase of the same thyroid cancer found in the 1983 study in females.³⁵

All of these increases in tumor incidence are "not considered compound-related"³⁵ according to EPA. In each case, different reasons are given for this conclusion. For the testicular tumors, EPA accepted the interpretation of an industry pathologist who said that the incidence in treated groups (12 percent) was similar to those observed in other control (not glyphosate-fed) rat feeding studies (4.5 percent).³⁶ For the thyroid cancer, EPA stated that it was not possible to consistently distinguish between cancers and tumors of this type, so that the incidences of the two should be considered together. The combined data are not statistically significant.³³For the kidney tumors, the registrants reexamined slides of kidney tissue, finding an additional tumor in untreated mice so that statistical significance was lost. This was despite a memo from EPA's pathologist stating that the lesion in question was not really a tumor.³⁴For the pancreatic tumors, EPA stated that there was no dose-related trend and no progression to malignancy. For the liver tumors and the thyroid tumors, EPA stated that pairwise comparisons between treated and untreated animals were not statistically significant and there was no progression to malignancy.³⁵

EPA concluded that glyphosate should be classified as Group E, "evidence of non-carcinogenicity for humans."³⁵ They added that this classification "is based on the available evidence at the time of evaluation and should not be interpreted as a definitive conclusion that the agent will not be a carcinogen under any circumstances."³⁵ From a public health perspective, the results of the laboratory tests leave many questions unanswered. An EPA statistician wrote in a memo concerning one of the carcinogenicity studies, "Viewpoint is a key issue. Our viewpoint is one of protecting the public health when we see suspicious data."³⁶ Unfortunately, EPA has not taken that conservative viewpoint in its assessment of glyphosate's cancer-causing potential.

There are no studies available to NCAP evaluating the carcinogenicity of Roundup or other glyphosate-containing products. Without such tests, the carcinogenicity of glyphosate-containing products is unknown.

Mutagenicity

Laboratory studies of a variety of organisms have shown that glyphosate-containing products cause genetic damage:

* In fruit flies, Roundup and Pondmaster (an aquatic herbicide consisting of glyphosate and a trade secret surfactant)³⁷ both increased the frequency of sex-linked, recessive lethal mutations. (These are mutations that are usually visible only in males because two damaged genes are required in order to be expressed in females.) In this study, the frequency of lethal mutations was between 3 and 6 times higher in fruit flies that had been exposed to glyphosate products during their larval development than in unexposed flies.³⁸

* A laboratory study of human lymphocytes (one type of white blood cell) showed an increase in the frequency of sister chromatid exchanges following exposure to high doses of Roundup.³⁹ (Sister chromatid exchanges are exchanges of genetic material during cell division between members of a chromosome pair. They result from point mutations.)

* In Salmonella bacteria, Roundup was weakly mutagenic at high concentrations. In onion root cells, Roundup caused an increase in chromosome aberrations.⁴⁰

Glyphosate alone has rarely caused genetic damage in laboratory tests. None of the mutagenicity studies required for registration of glyphosate have shown it to be mutagenic. Tests included studies of mutations in hamster ovary cells, bacteria, and mouse bone marrow cells.⁴ Glyphosate was also not mutagenic in other studies of rats, mice,² and onion cells⁴⁰ but caused chromosome stickiness and fragmentation in water hyacinth root cells.⁴¹

Reproductive Effects

Laboratory studies have demonstrated a number of effects of glyphosate on reproduction, including effects on mothers, fathers, and offspring.

In rat feeding studies, glyphosate reduced sperm counts (at the two highest doses tested) and lengthened the estrous cycle, how often a female comes into heat (at the highest dose tested).²⁹Other effects on mother rats in laboratory tests include soft stools, diarrhea, breathing rattles, red nasal discharge, reduced activity, growth retardation, decreased body weights, and increased mortality.² Effects on offspring included an increase in fetal loss, a decrease in the number of embryos successfully implanted into the uterus, a decrease in the number of viable fetuses, a slight decrease in litter size, a decrease in fetal and pup weights, and an increase in problems with breast bone formation.² Effects were observed at the highest doses tested (1500 and 3500 mg/kg of body weight per day).²

In a study of rabbits using doses that were lower than those used in the rat studies above, glyphosate caused diarrhea, nasal discharge, and death in mothers.² The only effect on offspring was a decrease in fetal weight in all treated groups.⁴²

A study in which glyphosate was fed to rats for three generations after which the offspring were examined for birth defects found kidney damage at a relatively low dose (30 mg/kg of body weight). However, a second study (only two generations long) did not find similar effects, and EPA called the damage in the first study "spurious."⁴From a public health perspective, however, a new three generation study is crucial.

Toxicology of Glyphosate's Major Metabolite

In general, studies of the breakdown of glyphosate find only one metabolite, minomethylphosphonic acid (AMPA).² (See Figure 5.) Although AMPA has low acute toxicity (its LD50 is 8,300 mg/kg of body weight in rats)²⁰ and is only slightly irritating to eyes,⁴³ it causes a variety of toxicological problems. In subchronic tests on rats, AMPA caused decreased weight gain in males; an increase in the acidity of urine in both males and females; an increase in the activity of an enzyme, lactic dehydrogenase, in both sexes; a decrease in liver weights in males at all doses tested; and excessive cell division in the lining of the urinary bladder and in part of the kidney in both sexes.²⁰ AMPA is much more persistent than glyphosate; studies in eight states found that the half-life in soil (the time required for half of the original concentration of a compound to break down or dissipate) were between 119 and 958 days.²

Quality of Toxicology Testing

Tests done on glyphosate to meet registration requirements have been associated with fraudulent practices.

Laboratory fraud first made headlines in 1983 when EPA publicly announced that a 1976 audit had discovered "serious deficiencies and improprieties" in toxicology studies conducted by Industrial Biotest Laboratories (IBT).⁴⁴ Problems included "countless deaths of rats and mice that were not reported," "fabricated data tables," and "routine falsification of data."⁴⁴

IBT was one of the largest laboratories performing tests in support of pesticide registrations.⁴⁴ About 30 tests on glyphosate and glyphosate-containing products were performed by IBT, including 11 of the 19 chronic toxicology studies.⁴⁵A compelling example of the poor quality of IBT data comes from an EPA toxicologist who wrote, "It is also somewhat difficult not to doubt the scientific integrity of a study when the IBT stated that it took specimens from the uteri (of
male rabbits) for histopathological examination."⁴⁶ (Emphasis added.)

In 1991, laboratory fraud returned to the headlines when EPA alleged that Craven Laboratories, a company that performed contract studies for 262 pesticide companies including Monsanto, had falsified test results.⁴⁷ "Tricks" employed by Craven Labs included "falsifying laboratory notebook entries" and "manually manipulating scientific equipment to produce false reports."⁴⁸ Roundup residue studies on plums, potatoes, grapes, and sugar beets were among the tests in question.⁴⁹

The following year, the owner/president of Craven Laboratories and three employees were indicted on 20 felony counts. A number of other employees agreed to plead guilty on a number of related charges.⁵⁰ The owner was sentenced to five years in prison and fined $50,000; Craven Labs was fined 15.5 million dollars, and ordered to pay 3.7 million dollars in restitution.⁴⁸

Although the tests of glyphosate identified as fraudulent have been replaced, these practices cast shadows on the entire pesticide registration process.

References

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to W. Dykstra, Toxicology Branch. Washington, D.C. (December 4.)

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feeding study; and some remarks on false positives. Memo from Herbert Lacayo to Reto Engler (both Office of Pesticide Programs, Health Effects Division). Washington, D.C. (February 26.)

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48. U.S. EPA. Communications, Education, And Public Affairs. 1994. Press advisory. Craven Laboratories, owner, and 14 employees sentenced for falsifying pesticide tests. Washington, D.C. (March 4.)

49. U.S. EPA. Communications and Public Affairs. 1991. Press advisory. EPA lists crops associated with pesticides for which residue and environmental fate studies were allegedly
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50. U.S. Dept. of Justice. United States Attorney. Western District of Texas. 1992. Texas laboratory, its president, 3 employees indicted on 20 felony counts in connection with
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Glyphosate, Part 1: Toxicology.

Caroline Cox. Journal of Pesticide Reform, Volume 15, Number 3, Fall 1995. Northwest Coalition for Alternatives to Pesticides, Eugene, OR.