Backgrounder
Glyphosate and Standard Toxicology Studies
September 2002
Monsanto Company
Toxicology is the study of the harmful effects of substances on living organisms: humans, plants
and animals. Toxicological testing evaluates the biological response of living organisms to
different routes and durations of exposure to a substance. Modern toxicology contributes to
clinical, legal, occupational and veterinary medicine and plays a key role in the development of
drugs, food additives, home products, cosmetics, industrial chemicals, agrochemicals,
pesticides, etc. Paracelsus, a 16th Century Swiss physician recognized as the "father of
toxicology," is noted for his principle that all substances are poisons if the dose is sufficiently
high 鈥? 鈥渢he dose makes the poison.鈥? He understood that the relationship between dose and
response are inseparable. At very low doses, even notorious toxins such as arsenic will not
cause harm. Conversely, at very high doses, essential substances such as water will harm or
kill.
The story is no different for pesticides; at some dose they are harmful and at some dose they
are harmless.
Pesticides (herbicides, insecticides, rodenticides, fungicides, etc.) cannot be categorized simply
as 鈥渄angerous鈥? just because they are classified as substances that kill pests. Likewise, no
chemical, either natural (made by plants or other organisms) or synthetic (made by man), can
be determined to be completely 鈥渟afe.鈥? The study of toxicology determines what doses are
harmful and what doses would not be expected to pose unreasonable risk. Pesticides are
strictly regulated by governmental agencies around the world. In the United States, the U.S.
Environmental Protection Agency has that responsibility and requires a battery of toxicological
and environmental studies. On average, a pesticide active ingredient must undergo at least 120
tests before it can be registered for use. During the many years that glyphosate and glyphosate
herbicides have been used, hundreds of toxicology studies have been conducted.
All pesticides are evaluated for acute, sub-chronic and chronic effects. Acute toxicological
testing evaluates whether a single high-dose exposure to a substance will produce acute
effects. (An acute effect could be anything from a skin rash to death.) Sub-chronic effects are
related to several days or weeks of continuous exposure to a substance. Chronic effects occur
after a long period (approaching a lifetime) of continuous exposure. Longer-term studies
evaluate whether continual exposure to a substance has the potential to cause adverse effects,
such as cancer, neurotoxicity, birth defects or reproductive problems.
Acute toxicity studies
Acute toxicity studies evaluate the risk from a single exposure to a substance, typically at a high
dose. Acute oral and dermal toxicity studies are frequently designed to express the potency of
a substance in terms of a median lethal dose or LD50. The LD50 is the dose that is lethal to 50
percent of the laboratory animals in the test. The higher the LD50 value, the lower the toxicity.
The dose is calculated as milligrams of the test substance per kilogram of body weight of the
tested animals (mg/kg bw).
Backgrounder: Glyphosate and Standard Toxicology Studies. 2002. Page 1 of 5
Figure 1. Acute Toxicology- Comparative
Glyphosate (active ingredient)
Paraquat
Nicotine Roundup1 (formulated product)
> 5000 mg/kg
Chloroform
1000 2000 3000 4000 5000
Copper
Sulfate
Rat LD50 (oral) mg/kg
Selected from NIOSH Registry of Toxic Effects of Chemical Substances, 1979
Handbook of Pesticide Toxicology, Second Edition 鈥? Agents
1
鈥淩oundup鈥漴efers to the original single active ingredient formulation.
Laboratory studies show that glyphosate has acute rat oral and dermal LD50s of greater than
5,000 mg/kg. The major use of the LD50 study is a comparative one, allowing an investigator to
assess the relative toxicity of one substance with others tested in the same species (Figure 1).
Accepted toxicology standards classify substances with an LD50 greater than 5,000 mg/kg as
鈥減ractically non-toxic.鈥? (Remember, nothing can be considered completely non-toxic, because
as Paracelsus knew, everything is toxic at some dose.)
In addition to acute rat oral and dermal studies, inhalation exposure also is evaluated to
determine a spray concentration that is lethal to 50 percent of the test animals (LC50). The dose
is measured in milligrams of the test substance per liter of water (mg/L). Acute rat inhalation
studies with glyphosate show that a high concentration is required to produce lethality.
The U.S. EPA places pesticides in one of four categories for acute toxicity, based on their LD50
and LC50 values. Category I is considered the most toxic, and category IV the least toxic.
Glyphosate is assigned a Category IV (鈥減ractically non-toxic鈥?) for all three routes of exposure 鈥?
oral, dermal and inhalation. Eye and skin irritation studies also are required to assess the
potential for a substance to cause irritation. Glyphosate is assigned a Category IV for skin
irritation. However because the technical material is an acid it can be moderately to severely
irritating to the eyes. Glyphosate formulations are made not with the acid but with a salt of the
acid. These salt solutions are considered practically non-irritating to the eyes and are assigned
a Category IV. One other acute test is used to evaluate the potential of a pesticide to produce
an allergic skin reaction after repeated skin contact. Glyphosate shows no evidence of causing
a skin reaction.
Not only do the pesticide active ingredients undergo this battery of testing, but so does each
product formulation containing the active ingredient. Most formulated herbicides in which
Backgrounder: Glyphosate and Standard Toxicology Studies. 2002. Page 2 of 5
glyphosate is the active ingredient (e.g. Roundup UltraMAX庐 and Roundup Pro庐) are also in
Category IV for acute oral, dermal and inhalation toxicity.
Subchronic and chronic toxicity studies
The acute toxicity studies determine what dose is lethal to 50 percent of the test animals via a
specific route of exposure, but they do not determine what dose poses no unreasonable risk.
That determination is made by examining effects seen over a range of doses and durations of
time. Sub-chronic studies last for a few weeks to months (~10 percent of the normal life span of
the test animal), and chronic studies can last for a year or more (the expected lifetime of the test
animal). Exposure routes are identical to those of acute testing programs (oral, dermal,
inhalation). In sub-chronic and chronic oral toxicity studies, groups of test animals are given
various daily doses, from zero to thousands of milligrams per kilogram of their body weight. At
the end of a designated exposure period, virtually every organ system and physiological
parameter is examined to determine any differences between exposed and non-exposed test
animals. High doses must elicit sub-lethal effects, middle doses must evoke only minimal
adverse effects and low doses should trigger no toxic effects whatsoever. Generally, three to
five dose levels are tested. The highest tested dose level that produces no observed adverse
effects is referred to as the NOAEL. Different toxicity studies produce different no-effect levels.
The U.S. Environmental Protection Agency (EPA) bases its risk assessment on the lowest
NOAEL recorded in the various studies. See the table below for a summary of NOAELs seen in
various glyphosate toxicity studies submitted to the U.S. EPA.
Glyphosate NOAEL
Toxicity Study (mg/kg/day)1
Rat Subchronic 209
Rat Chronic 409
Rat Reproduction 694
Rabbit Developmental 175
U.S EPA - NOAEL 175
1
Source: EPA, 1993
Between the NOAEL and the highest dose tested, there is usually a range of doses that
produce a range of effects. Some effects can be quite serious, such as tumors or birth defects;
others are minor and would be reversible with cessation of exposure. Through all of these
studies, even very high sub-lethal doses of glyphosate have not produced effects such as
cancer, birth defects, mutagenicity, neurotoxicity or reproductive abnormalities. Other effects,
such as weight loss, elevated enzyme levels, etc. have been detected in those studies, almost
always at very high doses. For example, in the rabbit developmental study, designed to
determine if glyphosate causes adverse effects in pregnant animals and their developing
offspring, no developmental effects were seen even at the highest dose which produced toxicity
to the pregnant animal. The NOAEL for this study was considered to be the 175 mg dose. It
was the lowest NOAEL from various studies.
Backgrounder: Glyphosate and Standard Toxicology Studies. 2002. Page 3 of 5
Reference dose (RfD) includes uncertainty factors to reduce risk
After a NOAEL is determined the U.S. EPA applies uncertainty factors to account for differences
between humans and test animals and individual variability. The agency also considers the
types of effects that were seen at higher doses. Less serious effects normally constitute a lower
margin of exposure. The margin for glyphosate has been set at 100-fold, as opposed to some
other pesticides which have margins of exposure of 1,000 or more because of less favorable
toxicological results. A 100-fold uncertainty factor means that acceptable human exposure
for glyphosate has been established at a level that is 100 times lower than a tested dose
that caused no observable adverse effect in tested animals. For glyphosate, the acceptable
daily dietary exposure, referred to as reference dose (RfD) has been set at 2 mg/kg/day (175
mg/kg/day NOAEL divided by 100 = 1.75 mg/kg/day rounded up to 2 mg/kg/day).
In 1996, Congress unanimously passed landmark pesticide food safety legislation called the
Food Quality Protection Act (FQPA). The FQPA mandated that allowable exposure levels
more closely consider infants and children. The FQPA required the U.S. EPA to apply an
additional 10-fold uncertainty factor to account for exposure to children, who have higher
relative exposure because of their lower body weight. However, EPA was given the option of
applying a lesser uncertainty factor "only if, on the basis of reliable data, such margin will be
safe for infants and children鈥? (FQPA, 1996). The additional uncertainty factor, when applied to
the RfD, yields an exposure level called the chronic Population Adjusted Dose (cPAD).
EPA reviewed the toxicological database for glyphosate, determined that it was complete and
concluded there was no indication of increased sensitivity to glyphosate among infants and
children. Therefore, EPA used an FQPA uncertainty factor of 1, resulting in a cPAD for
glyphosate of 2 mg/kg/day, the same as the RfD.
Calculating human exposure
In order to calculate human exposure to a pesticide, the U.S. EPA considers all possible routes,
including food, water, applicator exposure, or bystander exposure from drift. Conservative
assumptions are made throughout the process. Consider exposure through food, for example.
EPA requires food residue studies for every crop on which a pesticide is to be used. For the
study, the pesticide is applied at the maximum labeled rate. (Most farmers use rates much
lower than the maximum allowed.) Crops are harvested and liquefied, and very sensitive
equipment is used to seek traces of the pesticide. Multiple samples are taken from several test
plots grown in various geographic regions. The sample with the highest amount of residue is
recorded for the crop in question, even if some unusual condition may have been at play. If no
residue is detected in any of the samples, EPA assumes a presence anyway. Based on these
studies, EPA calculates how much residue could be present in crops treated with the pesticide.
It is then assumed that every acre of every crop for which the pesticide is labeled receives an
application of the pesticide (with no allowance for market share). Furthermore, EPA assumes
that people consume every crop every day. (Glyphosate is labeled for use on more than 100
crops, so this is a very conservative assumption.) If adding up the residues from each crop
yields a dose greater than the EPA鈥檚 cPAD, the public is assumed to be at risk and some uses
must be discontinued in order to reduce public exposure.
In September 2000, EPA approved a new crop use for glyphosate. At that time, the agency
concluded that even non-nursing infants, whose food consumption relative to body weight is
higher than adults, were exposed to no more than 3.2 percent of the allowable dose through
food (U.S. EPA 2000).
Backgrounder: Glyphosate and Standard Toxicology Studies. 2002. Page 4 of 5
Wildlife toxicology
In addition to many studies with laboratory animals to assess potential effects from human
exposure, glyphosate has also been studied to determine effects on wildlife. The same
toxicological principles apply 鈥? varying doses are given to representative species of birds, fish,
insects and other invertebrates. The lethal dose or concentration is determined, and effects
seen at lower doses are examined. A no-effect level is also determined. These studies show
that glyphosate has very low toxicity to wildlife and that expected exposure from approved uses
of glyphosate products would pose no unreasonable risk to wildlife.
Related Document:
Backgrounder: Glyphosate and Wildlife. December, 2002.
References
FQPA (Food Quality Protection Act). (1996) Title IV, Section 408 (a)(4)(c).
http://www.fda.gov/opacom/laws/foodqual/fqpa4.htm
U.S. Environmental Protection Agency. (1993) Reregistration Eligibility Decision (RED):
Glyphosate. EAP-738-F-93-011, September 1993, Washington, DC.
http://www.epa.gov/oppsrrd1/REDs/old_reds/glyphosate.pdf
U.S. EPA (2000) Final Rule: Glyphosate; Pesticide Tolerance. Federal Register 65(188):
57957, September 27.
Backgrounder: Glyphosate and Standard Toxicology Studies. 2002. Page 5 of 5
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