Content available from Environmental Health
This content is subject to copyright. Terms and conditions apply.
R E V I E W Open Access
Concerns over use of glyphosate-based
herbicides and risks associated with
exposures: a consensus statement
John Peterson Myers
, Michael N. Antoniou
, Bruce Blumberg
, Lynn Carroll
, Theo Colborn
, Lorne G. Everett
, Philip J. Landrigan
, Bruce P. Lanphear
, Robin Mesnage
, Laura N. Vandenberg
Frederick S. vom Saal
, Wade V. Welshons
and Charles M. Benbrook
The broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Since
the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold.
Further increases in the volume applied are likely due to more and higher rates of application in response to the
widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were
developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift
and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs
posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set
high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically
engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed
(soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in
the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health
Organization’s International Agency for Research on Cancer recently concluded that glyphosate is “probably
carcinogenic to humans.”In response to changing GBH use patterns and advances in scientific understanding of
their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the
safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms
of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current
human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage
continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in
agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4)
Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are
rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of
tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We
offer a series of recommendations related to the need for new investments in epidemiological studies,
biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the
effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of
GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National
(Continued on next page)
* Correspondence: firstname.lastname@example.org;email@example.com
Environmental Health Sciences, Charlottesville, VA, and Adjunct Professor,
Carnegie Mellon University, Pittsburg, PA, USA
Benbrook Consulting Services, 90063 Troy Road, Enterprise, OR 97828, USA
Full list of author information is available at the end of the article
© 2016 Myers et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Myers et al. Environmental Health (2016) 15:19
(Continued from previous page)
Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and
Keywords: Glyphosate, Acceptable daily intake (ADI), AMPA, Consensus statement, Endocrine disruptor, Reference
dose (RfD), Risk assessment, Roundup Ready, Toxicology
This Statement of Concern is directed to scientists, phy-
sicians, and regulatory officials around the world. We
highlight changes in the scope and magnitude of risks to
humans and the environment stemming from applica-
tions of glyphosate-based herbicides (GBHs). The objec-
tives of this statement are to: 1) demonstrate the need
for better monitoring of GBH residues in water, food,
and humans; (2) identify limitations or weaknesses in
the way the EPA, the German Federal Institute for Risk
Assessment, and others have previously assessed the po-
tential risks to humans from exposure to GBHs; and (3)
provide recommendations on data needs and ways to
structure future studies addressing potential health risks
arising from GBH exposures.
Our focus is on the unanticipated effects arising from
the worldwide increase in use of GBHs, coupled with
recent discoveries about the toxicity and human
health risks stemming from use of GBHs. Our con-
cern deepened when the World Health Organization’s
International Agency for Research on Cancer (IARC)
re-classified glyphosate as “probably carcinogenic to
humans”(i.e., Group 2A) .
We highlight a number of issues that influence our
concern about GBHs including: 1) increased use of
GBHs over the past decade, including new uses for these
herbicides just prior to harvest that can lead to high
dietary exposures; 2) detection of glyphosate and its me-
tabolites in foods; 3) recent studies that reveal possible
endocrine system-mediated and developmental impacts
of GBH exposures; and 4) additional complications for
farmers, most acutely the emergence and spread of
weeds resistant to glyphosate and the concomitant use
of multiple herbicides in mixtures, both of which in-
crease the risk of human and environmental harm. We
discuss evidence pointing to the need to adjust down-
ward the acceptable daily intake for glyphosate. Our
major concerns are embodied in a series of consensus
points that explicitly address the strength of the support-
ing evidence, and our recommendations focus on re-
search essential in narrowing uncertainty in future GBH
When regulatory agencies conducted their initial as-
sessments of glyphosate toxicity (in the 1970s) and ap-
proved a wide array of agricultural and non-agricultural
uses, only limited and fragmentary data on GBH toxicity
and risks were available. Testing done by contract la-
boratories were commissioned by the registrant and sub-
mitted to regulatory agencies. Results indicated minimal
mammalian toxicity. A large review published in 2000,
written by consultants associated with the registrant and
drawing on unpublished industry reports, agreed with and
reinforced that conclusion . However, their review did
not address some statistical differences reported between
test and control groups that could be interpreted more
cautiously, and surely warrant further assessment [3, 4].
In killing weeds and indeed almost all growing
plants, the primary mode of glyphosate herbicidal ac-
tivity is the inhibition of a key plant enzyme, namely
5-enolpyruvylshikimate-3-phosphate synthase (EPSPS).
This enzyme is part of the shikimic acid pathway and
is essential for the synthesis of aromatic amino acids
that govern multiple, essential metabolic processes in
plants, fungi, and some bacteria. Since this EPSPS-
driven pathway does not exist in vertebrate cells, some
scientists and most regulators assumed that glyphosate
would pose minimal risks to mammals. However, sev-
eral studies, some described below, now show that
GBHs can adversely affect mammalian biology via
Glyphosate use is increasing significantly
The United States has the world’s most complete, pub-
licly accessible dataset on GBH use trends over the past
40 years. Usage trends have been analyzed by EPA in a
series of pesticide sales and use reports spanning 1982–
2007 [5, 6], U.S. Geological Survey scientists [7, 8], the
USDA’s National Agricultural Statistics Service (NASS)
, and academic and industry analysts [10–12].
Briefly, glyphosate was registered in 1974 in the U.S.
Initially, this broad-spectrum, contact herbicide was
sprayed by farmers and ranchers primarily to kill weeds
before the planting of fields, and for weed control in
pastures and non-crop areas. In 1987 between 6 and 8
million pounds (~2.72–3.62 million kilograms) were ap-
plied by U.S. farmers and ranchers . In 1996, the first
year genetically engineered (GE), glyphosate-tolerant
crops were planted commercially in the U.S., glyphosate
accounted for just 3.8% of the total volume of herbicide
active ingredients applied in agriculture .
By 2007, the EPA reports agricultural use of glyphosate
in the range of 180–185 million pounds (~81.6–83.9
Myers et al. Environmental Health (2016) 15:19 Page 2 of 13
million kilograms) . The USGS team projects that gly-
phosate accounted for 53.5% of total agricultural herbi-
cide use in 2009 . In the 20-year timespan covered by
EPA sales and usage reports (1987–2007), glyphosate
use rose faster and more substantially than any other
pesticide. Usage in the range of 81.6–83.9 million kilo-
grams, which occurred in 2007, was more than double
the next most heavily sprayed pesticide (atrazine, 73–78
million pounds; ~33.1–35.4 million kilograms). For over
a decade, GBHs have been, by far, the most heavily ap-
plied pesticides in the U.S.
By 2014, annual farm-sector glyphosate usage increased
to approximately 240 million pounds (~108.8 million kilo-
grams), based on average annual crop use reported by the
NASS [9, 12]. Available use data published by the USDA,
USGS, and EPA show that a surprisingly large share
(approximately two-thirds) of the total volume of GBH ap-
plied since 1974 has been sprayed in just the last decade.
Glyphosate residues are found in foods
GBHs are widely used on a range of crops including
maize, soy grain, canola, wheat, barley, and edible beans,
among others . GBH application to these crops can
result in residues of glyphosate and its primary metabol-
ite AMPA in crops at harvest , as well as in proc-
essed foods. For example, the UK-Food Standard Agency
residue testing conducted in October 2012 found gly-
phosate residues at or above 0.2 mg/kg in 27 out of 109
samples of bread . Testing by the US Department of
Agriculture in 2011 revealed residues of glyphosate in
90.3% of 300 soybean samples, and AMPA in 95.7% of
samples at concentrations of 1.9 ppm and 2.3 ppm re-
spectively . Other laboratories have reported much
higher levels in soybeans in recent years (e.g., [15, 16]).
Late season, harvest aid use of GBHs is an important
new contributor to the increase in residue frequency and
levels in some grain-based food products. This is par-
ticularly true in humid, temperate-climate countries
such as the UK. Such applications are made within one
to two weeks of harvest to accelerate crop drying, thus
permitting harvest operations to begin sooner (a so-called
“green burndown”use ). Such late season applications
typically result in much higher residue levels in the final
harvested product compared to crops subjected to typical
application rates at earlier stages in the crop growth cycle.
Pre-plant applications of GBHs, as well as post-harvest or
fallow period applications, rarely result in detectable resi-
dues in grain, oilseeds, or forage crops.
Data from humans and laboratory animals indicate
hazards associated with exposure
Classical toxicity studies assess high doses and examine
‘validated’endpoints –those that have been shown to be
replicated easily in many laboratories . Although
these endpoints are known to represent adverse out-
comes, they typically do not correlate with human dis-
eases, and are not considered comprehensive for all
toxicological endpoints [19, 20]. Regulatory long-term
(2 year) toxicity studies in rodents revealed adverse ef-
fects of glyphosate on the liver and kidney (reviewed in
[3, 4]). These studies, however, typically do not address
a wide range of potential adverse effects triggered by
disruption in endocrine-system mediated developmen-
tal or metabolic processes [3, 21–24]. Studies examin-
ing low doses of GBHs, in the range of what are now
generally considered ‘safe’for humans, show that these
compounds can induce hepatorenal damage [25–28].
Concerns about the carcinogenic properties of GBHs
have increased after the World Health Organization’s
International Agency for Research on Cancer (IARC)
re-classified glyphosate as “probably carcinogenic to
humans”. This decision was based on a small num-
ber of epidemiological studies following occupational
exposures, rodent studies showing associations between
glyphosate and renal tubule carcinoma, haemangiosar-
coma, pancreatic islet cell adenoma, and/or skin tu-
mors, and strong, diverse mechanistic data.
Human epidemiological [23, 29–31] and domesticated
animal studies [32, 33] suggest associations between expo-
sures to GBHs and adverse health outcomes. For example,
congenital malformations have been reported in young
pigs fed GBH residues-contaminated soybeans . This
suggests that GBHs may be at least a contributing factor
to similar birth defects observed in human populations
living in and near farming regions with substantial land
area planted to GBH-tolerant GE crop cultivars [23, 34].
Collectively, studies from laboratory animals, human
populations, and domesticated animals suggest that current
levels of exposure to GBHs can induce adverse health out-
comes. Many of these effects would likely not be detected
in experiments adhering to traditional toxicology test
guidelines promulgated by pesticide-regulatory authorities.
Further complications: resistance and mixtures
Genetically engineered crops with tolerance to glypho-
sate are widely grown, and their use has led to increased
application of GBHs [10, 35]. This increased use has
contributed to widespread growth of glyphosate-resistant
weeds [36, 37]. To combat the proliferation of glyphosate-
resistant weeds, GE plant varieties have been approved for
commercial use that are resistant to multiple herbi-
cides, including several older compounds that are pos-
sibly more toxic and environmentally disruptive than
GBHs (for example, 2,4-D and dicamba).
While farmers have struggled for 30 years with the
steady increase in the number of weeds resistant to one
or more herbicides, the geographic scope and severity of
the weed control challenges posed, worldwide, by the
Myers et al. Environmental Health (2016) 15:19 Page 3 of 13
emergence and spread of glyphosate-resistant weeds is
unprecedented . Moreover, the consequences trig-
gered by the spread of glyphosate-resistant weeds, in
contrast to the emergence in the past of other herbicide-
resistant weeds, are unparalleled, and include the need
for major changes in tillage and cropping patterns, and
large increases in farmer costs and the diversity and vol-
ume of herbicides applied [10, 36, 38, 39].
In addition to resistance, concerns have been raised
about the toxicity of herbicide mixtures, because current
data suggest that chemicals in combination can have ef-
fects that are not predicted from tests of single com-
pounds [40, 41]. GBHs themselves are chemical mixtures;
in addition to the inclusion of glyphosate (the active in-
gredient), these herbicides include adjuvants such as
surfactants, which can make GBH-product formula-
tions more toxic than glyphosate alone [42–44]. In light
of the increased numbers, levels and extent of herbicide
use elicited by weed resistance, it is reasonable to pre-
of biological pathways affected, the number and dur-
ation of high-exposure periods, and the magnitude of
potential risks facing non-target organisms, including
humans. Such impacts could be limited, or even largely
prevented, if there are substantial changes in weed-
management systems and regulatory policy, including
enforceable limits on herbicide-use patterns known to
cause relatively high and potentially unsafe residue
levels in food, water, and the air.
Setting an acceptable intake level of GBHs
Different countries have established a range of “accept-
able”daily intake levels of glyphosate-herbicide expo-
sures for humans, generally referred to in the U.S. as the
chronic Reference Dose (cRfD), or in the E.U. as the
Acceptable Daily Intake (ADI).
The current U.S. Environmental Protection Agency
(EPA) cRfD is 1.75 mg of glyphosate per kilogram body
weight per day (mg/kg/day). In contrast, the current E.U.
ADI is more than 5-fold lower at 0.3 mg/kg/day, a level
adopted in 2002. The data upon which these exposure
thresholds are based were supplied by manufacturers dur-
ing the registration process, are considered proprietary,
and are typically not available for independent review.
The German Federal Institute for Risk Assessment is the
lead regulatory authority currently conducting an E.U.-wide
reassessment of GBHs. Their renewal assessment report
calls for an increase of the E.U. ADI from 0.3 mg/kg/day to
0.5 mg/kg/day . However, from an analysis of their as-
sessment, it is difficult to understand the basis on which the
German regulators are making this recommendation, since
they still rely on the same proprietary, industry-supplied
dataset that led to setting a lower ADI (0.3 mg/kg/day) in
2002. In contrast, an international team of independent
scientists concluded that the current E.U. ADI is probably
at least three-fold too high, based on a transparent, fully
documented review of the same dataset 
In December 2009, the U.S. EPA’s re-registration review
of glyphosate identified a number of issues of ongoing con-
cern, as well as GBH data gaps . In particular, it noted
that data relating to the effects of GBHs on the immune
and neurological systems were limited and announced that
future registrants would be required to conduct both
neurotoxicity and immunotoxicity studies. The U.S. EPA’s
updated risk assessment and final re-registration decision
on GBHs is scheduled to be completed in 2015–2016.
As noted above, most GBH use has occurred in the
last 10 years, while most studies considered by regula-
tory agencies for the assessment of GBHs focused just
on the active ingredient, and were conducted in the
1970s through mid-1980s. Since the late 1980s, only a
few studies relevant to identifying and quantifying hu-
man health risks have been submitted to the U.S. EPA
and incorporated in the agency’s GBH human-health
.We believe that the ability to establish
appropriate GBH exposure and use levels should be en-
hanced and grounded in “up-to-date science”to support
refined and accurate assessments of GBH health risks
and to assure that regulators understand both the likely
and possible consequences of the decisions they make.
Table 1 lists a few of the known environmental risks
arising from use of GBHs.
Table 1 Environmental Risks
This overview of possible adverse effects associated with rising GBH use is focused on mammalian health risks. There are also many environmental
and soil-ecosystem problems associated with heavy and repeated uses of GBHs affecting other organisms (for example, fish, butterflies, earth-
worms, beneficial soil microorganisms) .
These problems arise from the large volumes of GBHs applied across vast areas in many farming areas (for example, 80% or more of the harvested
cropland in many counties in the U.S., and provinces or political jurisdictions in other countries, are sprayed with GBHs).
Glyphosate binds strongly to some soils, but not others. After repeated applications, it can accumulate and become a long-term source of soil and
groundwater contamination . The main pathways of GBH degradation are known and the principal breakdown products (AMPA, formaldehyde)
could be toxic to a variety of non-target organisms. Continued long-term use of GBHs could pose a threat to soil health and fertility [47,49], with
possible adverse effects on crop productivity.
Low levels (50 ppb) of glyphosate have been shown to have significant negative effects on the aquatic invertebrate Daphnia magna . When
measured against the U.S. EPA’s Maximum Contaminant Level of 700 ppb, or the Canadian short-term (27,000 ppb) and the long-term (800 ppb)
freshwater aquatic standards , one quickly sees how the regulatory eco-toxicological risk levels set for glyphosate are orders of magnitude too high.
Myers et al. Environmental Health (2016) 15:19 Page 4 of 13
With respect to glyphosate-based herbicides, we are cer-
tain of the following:
GBH Use, exposure, presence
1. GBHs are currently the most heavily applied
herbicides in the world.
Trends in the volume and intensity of GBH uses
have been rising sharply since the mid-1990s, in step
with global adoption of genetically engineered,
glyphosate-tolerant crops [10,52,53]. Use of GBHs
is likely to continue increasing if Roundup Ready
glyphosate-tolerant maize, soybeans, cotton, canola,
alfalfa and sugar beet are approved for planting in
regions not now dominated by such cultivars.
2. GBHs contaminate drinking water via rainwater,
surface runoff and leaching into groundwater,
thereby adding drinking water, bathing, and
washing water as possible routine exposure
3. The half-life of glyphosate in water and soil is
longer than previously recognized. In field studies,
the half-life of glyphosate in soil ranged between
a few days to several months, or even a year,
depending on soil composition . Studies have
shown that soil sorption and degradation of
glyphosate exhibit great variation depending on
soil physical, chemical, and biological properties.
The risk of long-term, incremental buildup of
glyphosate contamination in soil, surface water,
and groundwater is therefore driven by highly
site-specific factors, and as a result, is difficult to
predict and costly to monitor.
4. Residues of glyphosate and its principle
metabolite AMPA are present in nearly all
soybeans harvested from fields planted with
Roundup Ready soybeans [13,16]. The intensity
of glyphosate use has trended upward on most
GE Roundup Ready crops. In addition,
applications are now being made later in the crop
cycle on GE crops. In addition, wheat, barley and
other grain, and some vegetable crops are
sprayed very late in the crop season to accelerate
crop death, drying, and harvest operations. For
these reasons, average residue levels on and in
some harvested grains, oilseeds, and certain other
crops are substantially higher than they were a
decade ago and, as a result, human dietary
exposures are rising.
5. The emergence and spread of glyphosate-resistant
herbicides, including older herbicides posing
documented environmental and public health
risks and/or newer, more costly herbicides to
avoid crop yield losses and slow the spread of
these weeds . This is particularly problematic
in grain and row-crop fields planted for several
years with Roundup Ready GE crops. In the U.S.,
contending with resistant weeds has already increased
total herbicide use per acre by approximately 70
% in soybeans, and 50 % in the case of cotton
compared to herbicide rates on these crops in
the mid-1990s when GE varieties were first
We estimate with confidence that:
1. Glyphosate provokes oxidative damage in rat liver
and kidneys by disrupting mitochondrial metabolism
[57–59] at exposure levels currently considered safe
and acceptable by regulatory agencies [4,25,26].
Therefore, the ADI governing exposures to GBHs is
overestimated. Adverse effects impacting other
endpoints are less certain, but still worrisome and
indicative of the need for more in-depth research
(see following sections).
2. Residues from GBHs may pose higher risks to
the kidneys and liver. Metabolic studies in a
variety of laboratory and farm animal species
show that levels of glyphosate and AMPA in
kidney and liver tissues are 10- to 100-fold (or
more) higher than the levels found in fat, muscle
(meat) and most other tissues
frequency of serious, chronic kidney disease have
been observed among male agricultural workers in
some regions in which there is a combination of
heavy GBH use and ‘hard’water [60,61]. These
possible adverse effects of GBH exposure on kidney
and liver warrant a focused, international research
3. There are profound gaps in estimates of worldwide
human GBH exposure. Glyphosate and AMPA are
not monitored in the human population in the
United States, despite the 100-fold increase in use of
GBHs over recent decades. In circumstances where
there is substantial uncertainty in a pesticide’sdietary
risk, the EPA is presumptively required by the U.S.
Food Quality Protection Act (FQPA) of 1996 to
impose an added safety factor of up to 10-fold in
the setting of glyphosate’s cRfD. Such uncertainty
can arise from gaps in the scope and quality of a
pesticide’s toxicology dataset, or uncertainty in
exposure assessments. Considering the uncertainties
regarding both GBH safety and exposure, the
EPA should impose a 10-fold safety factor on
glyphosate, which would reduce the EPA chronic
Myers et al. Environmental Health (2016) 15:19 Page 5 of 13
Population Adjusted Dose (cPAD) to 0.175 mg/kg
bw/day. [Note: the U.S. EPA adopted the new
term cPAD to designate a chronic Reference
Dose for a pesticide that had been lowered by
the Agency as a result of the application of an
added, FQPA-mandated safety factor. Virtually all
FQPA safety factors have reduced chronic
Reference Doses by 3-fold or 10-fold].
4. Nevertheless, imposing a 10-fold decrease in
glyphosate’s chronic Reference Dose, as seemingly
called for in current U.S. law, should only be
viewed as an interim step in the reassessment of
glyphosate toxicity and risk, and re-adjustment of
glyphosate uses and tolerances in food. Consider-
able work on glyphosate and GBH toxicity, mech-
anisms of action, and exposure levels must be
completed before the U.S. EPA can credibly con-
clude that GBH uses and exposures are consistent
with the FQPA’s basic safety standard, namely that
there is a “reasonable certainty of no harm”from
ongoing, chronic exposures to GBHs across the
Current models and data from the biological sciences
1. Glyphosate and GBHs disrupt endocrine-signaling
systems in vitro, including multiple steroid
hormones, which play vital roles in the biology of
vertebrates [21,22,24,62]. Rat maternal exposure to
a sublethal dose of a GBH resulted in male offspring
reproductive development impairment . As an
endocrine-disrupting chemical (EDC), GBH/glyphosate
can alter the functioning of hormonal systems
and gene expression patterns at various dosage
levels. Such effects will sometimes occur at low,
and likely environmentally-relevant exposures.
Contemporary endocrine science has
demonstrated that dose–response relationships
will sometimes deviate from a linear increase in
the frequency and severity of impacts expected as
dose levels rise [19,63].
2. The timing, nature, and severity of endocrine system
impacts will vary depending on the levels and timing
of GBH exposures, the tissues exposed, the age and
health status of exposed organisms, and other biotic
or abiotic stressors impacting the developmental
stage and/or physiology of the exposed organism.
Exposures can trigger a cascade of biological effects
that may culminate many years later in chronic
degenerative diseases or other health problems.
Exposures leading to serious complications later in
life might occur over just a few days to a month in
short-lived animals, and over a few days to several
months in humans.
3. The study used by the EPA to establish the current
glyphosate cRfD used gavage as a system of
delivery, as recommended by OECD guidelines for
prenatal developmental toxicity studies, which in all
likelihood underestimates both exposure and
toxicity . This conclusion is derived from two
considerations: (i) gavage bypasses sublingual
exposure, and thus overestimates the portion of the
chemical subjected to first pass metabolism in the
liver, and (ii) gavage stresses the experimental
subjects inducing endocrine effects that can lead to
artefacts including, crucially, a reduction in the
difference between control and experimental
4. The incidence of non-Hodgkin’s Lymphoma (NHL)
has nearly doubled in the U.S. between 1975 and
2006 . GBHs are implicated in heightened risk of
developing NHL among human populations exposed
to glyphosate occupationally, or by virtue of
residence in an area routinely treated with herbicides
. A causal link between GBH exposures and
NHL may exist, but has not been rigorously studied
in human populations.
5. Uncertainty persists over the doses required to cause
most of the above endocrine-system-mediated
effects. Some published data indicate that doses
well within the range of current human exposure
may be sufficient [22,25], whereas other studies
demonstrating distinct, adverse impacts have explored
high doses and exposures that are unlikely to reflect
any real world levels of ingestion. Additional in vivo
studies are needed at environmentally relevant doses
to distinguish the combination of factors likely to give
rise to endocrine-system-driven morbidity and
mortality. Nevertheless, the epidemiological data
described above provides evidence of heightened
cancer risk in human populations at levels of
exposure actually experienced in human
6. Glyphosate is a chelating agent with potential to
sequester essential micronutrient metals such as
zinc, cobalt and manganese [67,68]. This property
of GBHs can alter the availability of these
micronutrients for crops, people, wildlife, pets, and
livestock. These micronutrient metals are enzymatic
cofactors, so their loss has the potential to
contribute to a number of deleterious effects,
especially on kidney and liver function .
Existing data suggest, but do not empirically confirm, a
wide range of adverse outcomes:
Myers et al. Environmental Health (2016) 15:19 Page 6 of 13
1. Multiple studies on GBHs have reported effects
indicative of endocrine disruption [21–24]. Based on
knowledge from studies of other endocrine
disruptors, the developing fetus, infants, and
children are most at risk. Effects following GBH
exposure may not be immediately apparent, because
some adverse conditions caused by early-life exposure
only manifest in later stages of development and/or in
adulthood. These include both acute diseases and
chronic health problems. In addition, proving links
between chronic disease and exposures to GBHs is
made more difficult by the fact that people are
routinely exposed to complex mixtures of
glyphosate and other toxic chemicals.
2. The action of glyphosate as an antibiotic may
alter the gastrointestinal microbiome in
vertebrates [33,70–72], which could favor the
proliferation of pathogenic microbes in humans,
farm animals, pets and other exposed vertebrates.
3. Increased incidence of severe birth defects in
Argentina and Paraguay in areas where GE Roundup
Ready crops are widely grown may be linked to the
ability of GBHs to increase retinoic acid activity
during fetal development 
contaminated soybean feeds used in the pork
industry have also been associated with elevated
rates of gastrointestinal-health problems and birth
defects in young pigs . Related impacts have
been observed in poultry .
4. Some developmental studies in rats undertaken at
relatively high levels of exposure suggest possible
GBH-induced neurotoxicity through multiple
mechanisms . Replication of these studies using
doses relevant to human exposures should be a
high priority. Further work on GBH-induced
neurotoxicity should be conducted to test whether
glyphosate can act as a disruptor of neurotransmitter
function given its similarity in structure to glycine and
5. GBHs may interfere with normal sexual
development and reproduction in vertebrates.
Experiments with zebrafish with dosing of GBH in
the upper range of environmentally-relevant
contamination levels, show morphological damage
to ovaries .
6. A recent report demonstrates that environmentally
relevant concentrations of commercially available
GBHs alter the susceptibility of bacteria to six
classes of antibiotics (for example, either raise or
lower the minimum concentration needed to inhibit
growth) . Furthermore, GBHs can also induce
multiple antibiotic-resistance phenotypes in potential
human pathogens (E. coli and Salmonella enterica
serovar typhimurium). Such phenotypes could both
undermine antibiotic therapy and significantly
increase the possibility of mutations conferring
more permanent resistance traits. Since GBHs and
antibiotics are widely used on farms, farm animals
may be exposed to both, with a concomitant
decrease in antibiotic effectiveness and increase in
the diversity of newly resistant bacterial phenotypes
that might find their way into the human population.
Risk assessors have not previously considered the
finding that herbicides might have sublethal adverse
effects on bacteria, but this should be considered in
future risk assessments.
Uncertainties in current assessments persist because:
1. A steadily growing portion of global GBH use is
applied in conjunction with multiple other
herbicides, insecticides, and fungicides. Herbicide
and other pesticide active ingredient safety levels are
calculated for each active ingredient separately,
despite the fact that tank mixes including two to
five, or even more active ingredients account for a
significant portion of the volume of pesticides
applied. Regulators do not require further testing of
such mixtures, nor do they conduct any additional
risk assessments designed to quantify possible
additive or synergistic impacts among all herbicides
applied, let alone the combination of all herbicides,
insecticides, fungicides, and other pesticides applied
on any given field.
2. The full list of chemicals in most commercial GBHs
is protected as “confidential business information,”
despite the universally accepted relevance of such
information to scientists hoping to conduct an
accurate risk assessment of these herbicide
formulations. The distinction in regulatory review
and decision processes between ‘active’and ‘inert’
ingredients has no toxicological justification, given
increasing evidence that several so-called ‘inert’
adjuvants are toxic in their own right .
Moreover, in the case of GBHs, the adjuvants and
surfactants, which include ethoxylated
tallowamines, alkylpolyglycosides or petroleum
distillates in most commonly used commercial
formulations, alters both the environmental fate
and residue levels of glyphosate and AMPA in
harvested foodstuffs and animal feeds. They do so
by enhancing the adhesion of glyphosate to plant
surfaces, as well as facilitating the translocation of
applied glyphosate from the surface of weed leaves
into sub-surface plant tissues, where it exerts its
herbicidal function and where rainfall can no
longer dissipate the glyphosate.
Myers et al. Environmental Health (2016) 15:19 Page 7 of 13
3. The vast majority of GBH-toxicology studies used
for regulatory assessments lack a sufficient range of
dose levels to adequately assess adverse impacts that
might be initiated by low, environmentally-relevant
. Most toxicology studies examine only a
high dose between the LD50 (the dose required to kill
50 % of treated animals) and the maximum tolerated
dose (a dose that has high toxicity but does not kill),
and then typically two lower doses (allowing for the
identification of the Lowest Observed Adverse Effect
Level [LOAEL] and the No Observed Adverse Effect
Level [NOAEL]). Environmentally relevant doses are
rarely examined . A further complication arises
specifically for endocrine disrupting chemicals: there
are theoretical and empirical findings concluding that
one cannot assume any no-impact exposure threshold
for endocrine processes that are already underway
because of endogenous hormones .
4. Residues of GBHs in plants are often present in
conjunction with: (a) residues of systemic seed
treatments, especially neonicotinoid insecticides (for
example, clothianidin and thiamethoxam) and their
adjuvants (such as organosilicone surfactants), (b)
residues of systemic insecticides and fungicides
applied during the season, and (c) Bt endotoxins in
the case of GE, insect-protected Bt cultivars. Such
mixtures and combinations are never tested, and
thus it is unknown how GBHs might interact with
these other agents.
5. Large-scale and sophisticated biomonitoring studies
of the levels of glyphosate, its metabolites, and other
components of GBH mixtures in people have not
been conducted anywhere in the world.
Biomonitoring studies should include measurement
of glyphosate residues, metabolites, and adjuvants in
blood and urine to obtain meaningful insights into
internal contamination levels and the
pharmacokinetics of GBHs within vertebrates
6. Adequate surveys of GBH contamination in food
products have not as yet been conducted on a
large scale, even in the U.S. The first and only
in-depth USDA testing of glyphosate and AMPA
residues in food targeted soybeans, and occurred
once in 2011 . Of the three hundred samples
tested, 90.3 % contained glyphosate at a mean
level of 1.9 ppm, while 95.7 % contained AMPA
at 2.3 ppm. In contrast, the next highest residue
reported by USDA in soybeans was malathion,
Thus, the mean levels of glyphosate and AMPA
in soybeans were 73-fold and 83-fold higher than
malathion, respectively. Residues in animal
products, sugar beet, pre-harvest treated wheat,
corn silage, and alfalfa hay and sprouts are
unknown, but likely much higher, given the series of
recent requests by Monsanto to increase tolerance
levels in a range of foods and animal feeds .
7. There is no thorough, up-to-date government
survey of glyphosate and AMPA residues in U.S.
grown Roundup Ready GE soybeans, nor
manufactured foods that contain soy-based
ingredients. However, changes in the rate of GBH
applications on many other crops, and/or the
timing of applications, have clearly increased
residue levels in some circumstances. In particular,
GBH uses late in the growing season as a
pre-harvest desiccant have become more common.
Such applications speed up the drying of crops in
the field, so that harvest operations can be
completed before bad weather sets in. Such
harvest-aid uses are popular, especially in wet years,
on wheat, canola, and other grain farms in some
humid, temperate climates, such as in the UK and
northern-tier states in the US. While pre-harvest
uses have only modestly increased the total volume
of GBHs applied, they have significantly increased
the frequency and levels of residues in harvested
grains, and have required GBH registrants to seek
significant increases in tolerance levels. These
residues are also contributing to dietary exposures
via a number of grain-based products, as clearly
evident in data from the U.K. Food Standard
Agency’s residue testing program .
8. Glyphosate residues are generally uncontrolled for
in the standard rations fed to animals in
laboratory studies. GBH residues can often be
found in common laboratory animal chows used
in feeding studies, thus potentially confounding
the results of GBH toxicity tests . Out of 262
pesticide residues analyzed in 13 commonly used
rodent laboratory diets, glyphosate was the most
frequently found pesticide, with concentrations
reaching 370 ppb . Therefore, GBH residues
should be accounted for in animal chows used in
controls for GBH studies.
9. The limited data currently available on glyphosate
pharmacokinetics in vertebrates are insufficient to
predict transport and fate of glyphosate in
different mammalian tissues, organs and fluids in
the body, and to determine whether or where
bioaccumulation occurs, although animal
metabolism studies point strongly to the kidney
and the liver.
The following recommendations are offered to further
improve our predictive capability regarding glyphosate
Myers et al. Environmental Health (2016) 15:19 Page 8 of 13
1. Scientists independent of the registrants should
conduct regulatory tests of GBHs that include
glyphosate alone, as well as GBH-product
formulations. [Note: in the latest glyphosate
regulatory assessment process by the German
Federal Institute for Risk Assessment, the
description and assessment of studies was provided
by the Glyphosate Task Force, a group of 25
agrochemical companies that combined resources to
jointly apply for renewal of registrations for this
herbicide within Europe. By way of contrast, in
order to avoid conflicts of interests, the Glyphosate
Task Force was restricted to a role of observer to the
evaluation of data by independent scientists at the
recent WHO IARC evaluation of glyphosate’s
2. Epidemiological studies are needed to improve
knowledge at the interface of GBH uses, exposures,
and human-health outcomes.
3. Biomonitoring studies examining reference
populations like the U.S. CDC’s NHANES program
should examine human fluids for glyphosate and its
4. More comprehensive toxicity experiments are
needed including those using “two hit”study
designs, which examine early life exposures to GBHs
followed by later-life exposures to chemical or other
5. Because GBHs are potential endocrine disruptors,
future studies should incorporate testing principles
6. Future studies of laboratory animals should use
designs that examine the full lifespan of the
experimental animal, use multiple species and
strains, examine appropriate numbers of animals,
and carefully avoid contaminating GBH and other
pesticides within control feeds and drinking water.
7. GBHs should be prioritized by the U.S. National
Toxicology Program for safety investigations,
including tests of glyphosate and common
1. The margin of safety between typical glyphosate and
AMPA exposure levels and the maximum allowed
human exposures has narrowed substantially in the
last decade. The margin may well have disappeared
for heavily exposed segments of the population in
some countries, especially where glyphosate and
AMPA are present in drinking water. In addition,
farmworkers and rural residents may incur relatively
high dermal absorption and/or exposures via drinking
water. We conclude that existing toxicological data
and risk assessments are not sufficient to infer that
GBHs, as currently used, are safe.
2. GBH-product formulations are more potent, or
toxic, than glyphosate alone to a wide array of
non-target organisms including mammals [42,43],
aquatic insects, and fish . As a result, risk
assessments of GBHs that are based on studies
quantifying the impacts of glyphosate alone
underestimate both toxicity and exposure, and thus
risk. This all-too-common shortcoming has
repeatedly led regulators to set inappropriately high
exposure thresholds (cRfDs, ADIs).
3. The toxicological data supporting current GBH
regulatory risk assessments are out-of-date and
insufficient to judge the impacts of contemporary
glyphosate and AMPA exposure levels on the
developing mammalian fetus, the liver and kidneys,
and reproductive outcomes in humans and a variety
of other animals [3,25].
4. Most toxicological studies using advanced, modern
tools and experimental designs within molecular
genetics, reproductive, developmental,
endocrinological, immunological and other
disciplines have been undertaken in academic and
research institute laboratories, and results have been
published in peer-reviewed journals. Regulators have
not incorporated, formally or indirectly, such
research into their risk assessments. Rather, they rely
on unpublished, non-peer reviewed data generated
by the registrants. They have largely ignored
published research because it often uses standards
and procedures to assess quality that are different
from those codified in regulatory agency data
requirements, which largely focus on avoiding fraud
. Additionally, endocrine-disruption study
protocols have not been codified by regulators
5. While the German Federal Institute for Risk
Assessment, rapporteur for the European Food
Safety Authority’s current reassessment of
glyphosate, claimed to have examined more than
900 scientific studies published in peer-reviewed
journals, most of the studies were deemed of limited
value, and hence had little influence on the outcome
of their assessment. Studies were classified of ‘limited
value’based on degree of adherence to traditional,
toxicology protocols and ‘validated’endpoints, rather
than scientific rigor and relevance in understanding
the mechanisms leading to adverse health outcomes.
Had the German Institute used scientific quality and
relevance in identifying useful studies, instead of
relying on similarity to outdated methodologies and/
or controversial evaluation criteria  (such as the
Klimisch score), we are nearly certain that they would
Myers et al. Environmental Health (2016) 15:19 Page 9 of 13
have concluded that published studies collectively
provide strong evidence in support of at least a
three-fold reduction in the glyphosate E.U. ADI
and consequently a 15-fold reduction in the U.S.
GBH use has increased approximately 100-fold since the
first decade of its use in the 1970s. It is now the world’s
most heavily applied herbicide. Major increases in its use
resulted from widespread adoption of Roundup Ready
crops that were genetically engineered to be tolerant to
glyphosate. Applications of GBHs have also expanded in
aquatic, estuarine, rangeland, and forest habitats.
Initial risk assessments of glyphosate assumed a lim-
ited hazard to vertebrates because its stated herbicidal
mechanism of action targeted a plant enzyme not
present in vertebrates. In addition, because GBHs kill
nearly all actively growing plants, farmers had to apply
GBHs early in the year, before crop germination or
post-harvest, and so it seemed unlikely that there
would be residues in harvested crops and the food sup-
ply. However, these assumptions ignored the possibility
that glyphosate and its metabolites might act via other
pathways, including those present in vertebrates, as
well as the profound consequences of major increases
in the area treated and volume applied, coupled with
changes in how and when GBHs are used by farmers
(e.g., on GE, herbicide-tolerant crops, and as a pre-
harvest desiccant to accelerate harvest).
Evidence has accumulated over the past two decades,
especially, that several vertebrate pathways are likely
targets of action, including hepatorenal damage, effects
on nutrient balance through glyphosate chelating action
and endocrine disruption. Other early assumptions
about glyphosate, for example that it is not persistent
in the environment, have also been called into question,
depending upon soil type. In addition, the prediction
that glyphosate would never be present widely in sur-
face water, rainfall, or groundwater has also been shown
to be inaccurate.
Existing data, while not systematic, indicate GBHs and
metabolites are widely present in the global soybean sys-
tem and that human exposures to GBHs are clearly ris-
ing. Tolerable daily intakes for glyphosate in the U.S.
and Germany are based upon outdated science.
Taken together, these conclusions all indicate that a
fresh and independent examination of GBH toxicity
should be undertaken, and that this re-examination be
accompanied by systematic efforts by relevant agencies
to monitor GBH levels in people and in the food supply,
none of which are occurring today. The U.S. National
Toxicology Program should prioritize a thorough toxico-
logical assessment of the multiple pathways now
identified as potentially vulnerable to GBHs. The urgency
of such work was reinforced in March 2015 when the
IARC concluded glyphosate is a probable human
We are aware of current limits on, and demands for,
public funding for research. In the absence of govern-
ment funds to support essential GBH research, we rec-
ommend that a system be put in place through which
manufacturers of GBHs provide funds to the appropriate
regulatory body as part of routine registration actions
and fees. Such funds should then be transferred to ap-
propriate government research institutes, or to an
agency experienced in the award of competitive grants.
In either case, funds would be made available to inde-
pendent scientists to conduct the appropriate long-term
(minimum 2 years) safety studies in recognized animal
model systems. A thorough and modern assessment of
GBH toxicity will encompass potential endocrine disrup-
tion, impacts on the gut microbiome, carcinogenicity,
and multigenerational effects looking at reproductive
capability and frequency of birth defects.
The E.U. ADI was calculated based on observed kid-
ney (hepatorenal) effects in rat chronic toxicity studies.
The “No Observable Adverse Effect Level”(NOAEL)
was 31 mg/kg/day, and the “Lowest Observable Adverse
Effect Level”(LOAEL) occurred at a dose of 60 mg/kg/
day (determined then to be the LOAEL). A standard
100-fold safety factor was applied in converting the E.U.-
set NOAEL to the ADI of 0.3 mg/kg/day. The new ADI
recommended by the German regulators of 0.5 mg/kg/
day is based on teratogenic effects in rabbits. The
NOAEL was considered to be 50 mg/kg/day. Independ-
ent scientists argue that the 2002 determination was not
based on the most sensitive species or dataset, as is re-
quired by regulatory authorities. See ref 14. Antoniou M,
Habib MEM, Howard CV, Jennings RC, Leifert C,
Nodari RO, Robinson CJ, Fagan J: Teratogenic effects of
glyphosate-based herbicides: divergence of regulatory de-
cisions from scientific evidence. J Environ Anal Toxicol
The EPA issued an updated registration review of
GBHs in 1993. Studies dating from the early 1970s
through mid-1980s dominated the reference list accom-
panying the chapter setting forth the EPA’s estimate of
GBH human health risks.
Table B.7.3-8 in the document “Renewal Assessment
Report, Glyphosate Residue Data”(Vol. 3, Annex B.7,
Dec. 18, 2013, RMS: Germany, Co-RMS-Slovakia) pro-
vides an overview of the levels of glyphosate and AMPA
measured in the meat, milk, and eggs from several live-
stock species, as well as in the fat, meat, kidney, and
livers of the animals. In most cases the levels reported in
Myers et al. Environmental Health (2016) 15:19 Page 10 of 13
liver and kidney exceed those in other tissues by several-
fold, and the levels in kidney exceed those in liver by 3-
fold to over 10-fold.
Retinoic acid signaling plays a key role in guiding em-
bryonic development, affecting the expression of mul-
tiple genes in a variety of cell types. Altered retinoic acid
activity causes birth defects (see 58. Duester G: Retinoic
acid synthesis and signaling during early organogenesis.
Cell 2008, 134(6):921-931.
Glutamate is a common vertebrate neurotransmitter
released by neurons into the synapse, and is important
for learning and memory (for a review, see 59. Mel-
drum BS: Glutamate as a neurotransmitter in the brain:
review of physiology and pathology. J Nutr 2000, 130(4S
Suppl):1007s-1015s. Glyphosate’s structural similarity to
glutamate creates the potential for interfering with this
key signaling process.
“Environmentally relevant”exposures to GBHs are
those that fall within the documented exposure levels
arising from the way GBHs are typically used.
Pharmacokinetic studies project and monitor the
levels of a chemical absorbed by an organism (via inges-
tion, inhalation, dermal absorption, or some other route
of exposure), how the chemical is distributed throughout
the body to specific tissues (measuring the concentra-
tions in different organs and in the blood), how the
chemical is metabolized (including which metabolites
are produced, and whether the presence of these metab-
olites and their relative abundance is dependent on route
of exposure), and finally, how a compound is excreted
(e.g., in feces or urine). Pharmacokinetic studies provide
a valuable link between estimates of exposure, toxicity
studies, and estimates of human risk.
The process of establishing testing protocols for
endocrine-mediated impacts has been underway in the
U.S. since 1997, in response to a mandate in the 1996
Food Quality Protection Act to consider such effects in
assuring a “reasonable certainty of no harm”for preg-
nant women, infants, and children. Seventeen years later,
the EPA remains years away from codifying a new bat-
tery of tests capable of identifying the risk of low-dose,
endocrine-disruption driven effects.
2,4-D: 2,4-Dichlorophenoxyacetic acid; ADI: Acceptable daily intake;
AMPA: Aminomethylphosphonic acid; Bt: Bacillus thuringiensis;
cPAD: Chronic Population Adjusted Dose; cRfD: Chronic reference dose;
EPSPS: 5-enolpyruvylshikimate-3-phosphate synthase; EU: European Union;
FQPA: US food quality protection act of 1996; GBHs: Glyphosate-based
herbicides; IARC: International Agency for Research on Cancer;
LOAEL: Lowest Observed Adverse Effect Level; NOAEL: No Observed Adverse
Effect Level; US EPA: United States Environmental Protection Agency.
John Peterson Myers received support from the Broad Reach Fund, the
Marisla Foundation and the Wallace Genetic Foundation for this work.
Michael Antoniou received support from the Sustainable Food Alliance,
Breast Cancer UK, The Sheepdrove Trust (UK) and the Safe Food Institute
(Australia). He is also serving as an expert witness on behalf of the State of
Vermont (U.S.A.) in a case involving the labeling of food products containing
ingredients from GE organisms.
Bruce Blumberg is a named inventor on several patents related to nuclear
receptor function and testing (US 5,861,274; 6,200,802; 6,815,168; 6,274,321;
6,391,847; 6,756,491; 6,809,178; 6,984,773), some of which generate royalty
income. He has received grant support from the U.S. National Institutes of
Health, National Science Foundation, American Heart Association, State of
California, and the Swedish Environmental Agency FORMAS. He receives
occasional research gifts from Advancing Green Chemistry and occasional
travel awards from professional societies in the US and elsewhere. None of
these constitutes an actual, or perceived conflict of interest.
Contributions by Lynn Carroll and Theo Colborn were supported entirely by
grants to TEDX from the Winslow Foundation and the Wallace Genetic
Lorne Everett declares no conflicts of interest. He is principle of Lorne Everett
Michael Hansen declares no conflicts of interest.
Philip Landrigan declares no conflicts of interest.
Bruce Lanphear served as an expert witness in California for the plaintiffs in a
public nuisance case of childhood lead poisoning, a Proposition 65 case on
behalf of the California Attorney General’s Office, a case involving lead-
contaminated water in a new housing development in Maryland, and Canadian
tribunal on trade dispute about using lead-free galvanized wire in stucco
lathing but he received no personal compensation for these services. He is
currently representing the government of Peru as an expert witness in a
suit involving Doe Run vs Peru, but he is receiving no personal compensation.
Dr. Lanphear has served as a paid consultant on a US Environmental Protection
Agency research study, NIH research awards and the California Department of
Toxic Substance Control. Dr. Lanphear has received federal research awards
from the National Institute of Environmental Health, the US Environmental
Protection Agency, the Centers for Disease Control and the US Department
of Housing and Urban Development. He is also the recipient of federal research
awards from the Canada Institutes of Health Research and Health Canada.
Robin Mesnage declares no conflicts of interest. He has received no
independent funding but has been employed by others with funding from
the Lea Nature, Malongo, JMG, Charles Léopold Mayer for the Progress of
Humankind, Nature Vivante and the Denis Guichard Foundations, from the
Institute Bio Forschung Austria, Breast Cancer UK, the Sustainable Food
Alliance and the Committee for Independent Research and Information on
Frederic S. vom Saal declares no conflicts of interest.
Laura Vandenberg declares no conflicts of interest.
Wade V. Welshons declares no conflicts of interest. He is supported by the
University of Missouri VMFC0018 on estrogen and xenoestrogen action and
by the Jenifer Altman Foundation on potential endocrine disrupting activity
Charles Benbrook declares no conflicts of interest. He received support for
work on this paper in a grant to Washington State University from the Ceres
Trust. He is the principle of Benbrook Consulting Services. He is currently a
member of the U.S. Department of Agriculture AC 21 Agricultural
Biotechnology Advisory Committee. He has served as an expert witness in
cases involving herbicide drift and damage, and the labeling of food
products containing genetically engineered ingredients.
JPM recruited team members and chaired over 30 conference calls of the
authors between August 2014 and May 2015. All authors contributed to the
writing and editing, with JPM and CMB playing the lead roles. CMB added
detailed information about changes in GBH use over time. All authors read
and approved the final manuscript.
The Broad Reach Fund supported the writing and editing effort.
Environmental Health Sciences, Charlottesville, VA, and Adjunct Professor,
Carnegie Mellon University, Pittsburg, PA, USA.
Department of Medical and
Molecular Genetics, Faculty of Life Sciences and Medicine, King’s College
London, London, UK.
Department of Developmental and Cell Biology,
University of California, Irvine, CA, USA.
The Endocrine Disruption Exchange,
Myers et al. Environmental Health (2016) 15:19 Page 11 of 13
Paonia, CO, USA.
L. Everett & Associates, Santa Barbara, CA, USA.
Consumers Union, Yonkers, NY, USA.
Department of Preventive Medicine,
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Child & Family
Research Institute, BC Children’s Hospital, University of British Columbia,
Vancouver, BC, Canada.
Department of Environmental Health Sciences,
School of Public Health and Health Sciences, University of Massachusetts –
Amherst, Amherst, MA, USA.
Division of Biological Sciences, University of
Missouri, Columbia, MO, USA.
Department of Biomedical Sciences,
University of Missouri-Columbia, Columbia, MO, USA.
Services, 90063 Troy Road, Enterprise, OR 97828, USA.
Sciences, 421 Park St, Charlottesville, VA 22902, USA.
Received: 8 June 2015 Accepted: 6 February 2016
1. Guyton KZ, Loomis D, Grosse Y, El Ghissassi F, Benbrahim-Tallaa L, Guha N,
Scoccianti C, Mattock H, Straif K, International Agency for Research on
Cancer Monograph Working Group ILF. Carcinogenicity of
tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet
2. Williams GM, Kroes R, Munro IC. Safety evaluation and risk assessment of
the herbicide Roundup and its active ingredient, glyphosate, for humans.
Regul Toxicol Pharmacol. 2000;31(2 Pt 1):117–65.
3. Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, Nodari RO, et al.
Teratogenic effects of glyphosate-based herbicides: divergence of regulatory
decisions from scientific evidence. J Environ Anal Toxicol. 2012;S4:006.
4. Mesnage R, Defarge N, Spiroux de Vendomois J, Seralini GE. Potential toxic
effects of glyphosate and its commercial formulations below regulatory
limits. Food Chem Toxicol. 2015;84:133–53.
5. Aspelin A, Grube AH. Pesticide Industry Sales and Usage: 1996 and 1997
Market Estimates, Office of Pesticide Programs, U.S. Environmental
Protection Agency, Washington, D.C.; 1999. http://1.usa.gov/20qXcOb.
Accessed 03 February 2016.
6. Grube A DD, Kiely T, Wu L. Pesticides Industry Sales and Usage, 2006 and
2007 Market Estimates, United States Environmental Protection Agency, EPA
733-R-11-001, 34 p. 2011. http://1.usa.gov/1VN2QDo. Accessed 03 February
7. Coupe RH, Capel PD: Trends in pesticide use on soybean, corn and cotton
since the introduction of major genetically modified crops in the United
States. Pest Manag Sci 2015.
8. Thelin GP, Stone WW. Estimation of annual agricultural pesticide use for
counties of the conterminous United States, 1992–2009: U.S. Geological
Survey Scientific Investigations Report 2013–5009, 54 p. http://on.doi.gov/
1TEeEJD. Accessed 03 February 2016.
9. Service. USDoANAS: Agricultural Chemical Usage - Field Crops and
do?documentID=1001. Accessed 03 February 2016.(multiple years).
10. Benbrook C. Impacts of genetically engineered crops on pesticide use in
the U.S. –the first sixteen years. Environ Sci Eur. 2012;24:24.
11. Barfoot P, Brookes G. Key global environmental impacts of genetically
modified (GM) crop use 1996–2012. GM Crops & Food. 2014;5(2):149–60.
12. Benbrook C. Trends in the use of glyphosate herbicide in the U.S. and
globally. Environmental Sciences Europe. 2015;28(3). http://dx.doi.org/10.
1186/s12302-016-0070-0. Accessed 03 February 2016.
13. Agricultural Marketing Service. Pesticide data program annual summary,
program year 2011. In: Appendix C Distribution of Residues in Soybean by
Pesticide. Washington, D.C: U.S. Department of Agriculture; 2013.
14. (PRiF) UDECoPRiF: Monitoring program. http://www.food.gov.uk/business-
industry/farmingfood/pesticides. Accessed 03 February 2016. (Multiple
15. Test Biotech. High levels of residues from spraying with glyphosate found in
soybeans in Argentina. 2013. http://www.testbiotech.org/node/926.
Accessed 03 February 2016
16. Bohn T, Cuhra M, Traavik T, Sanden M, Fagan J, Primicerio R. Compositional
differences in soybeans on the market: glyphosate accumulates in Roundup
Ready GM soybeans. Food Chem. 2014;153:207–15.
17. Moechnig M, Deneke D. Harvest aid weed control in small grain. In. Edited
by South Dakota Cooperative Extension Service. 2009. https://www.sdstate.
Control-in-Small-Grain-2009.pdf. Accessed 03 February 2016.
18. Myers JP, Zoeller RT, Vom Saal FS. A clash of old and new scientific
concepts in toxicity, with important implications for public health. Environ
Health Perspect. 2009;117(11):1652–5.
19. Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, et al.
Endocrine-disrupting chemicals and public health protection: a statement of
principles from the Endocrine Society. Endocrinology. 2012;153(9):4097–110.
20. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Lee DH, et al.
Regulatory decisions on endocrine disrupting chemicals should be based
on the principles of endocrinology. Reprod Toxicol. 2013;38C:1–15.
21. Romano MA, Romano RM, Santos LD, Wisniewski P, Campos DA, de Souza
PB, et al. Glyphosate impairs male offspring reproductive development by
disrupting gonadotropin expression. Arch Toxicol. 2012;86(4):663–73.
22. Thongprakaisang S, Thiantanawat A, Rangkadilok N, Suriyo T, Satayavivad J.
Glyphosate induces human breast cancer cells growth via estrogen
receptors. Food Chem Toxicol. 2013;59C:129–36.
23. Paganelli A, Gnazzo V, Acosta H, Lopez SL, Carrasco AE. Glyphosate-based
herbicides produce teratogenic effects on vertebrates by impairing retinoic
acid signaling. Chem Res Toxicol. 2010;23(10):1586–95.
24. Gasnier C, Dumont C, Benachour N, Clair E, Chagnon MC, Seralini GE.
Glyphosate-based herbicides are toxic and endocrine disruptors in human
cell lines. Toxicology. 2009;262(3):184–91.
25. Seralini GE, Clair E, Mesnage R, Gress S, Defarge N, Malatesta M, et al.
Republished study: long-term toxicity of a Roundup herbicide and a Roundup-
tolerant genetically modified maize. Environ Sci Europe. 2014;26:14.
26. Benedetti AL, Vituri Cde L, Trentin AG, Domingues MA, Alvarez-Silva M. The
effects of sub-chronic exposure of Wistar rats to the herbicide Glyphosate-
Biocarb. Toxicol Lett. 2004;153(2):227–32.
27. Larsen K, Najle R, Lifschitz A, Mate ML, Lanusse C, Virkel GL. Effects of
Sublethal Exposure to a Glyphosate-Based Herbicide Formulation on
Metabolic Activities of Different Xenobiotic-Metabolizing Enzymes in Rats.
Int J Toxicol 2014.
28. Mesnage R, Arno M, Costanzo M, Malatesta M, Seralini GE, Antoniou MN.
Transcriptome profile analysis reflects rat liver and kidney damage following
chronic ultra-low dose Roundup exposure. Environ Health. 2015;14:70.
29. De Roos AJ, Zahm SH, Cantor KP, Weisenburger DD, Holmes FF, Burmeister
LF, et al. Integrative assessment of multiple pesticides as risk factors for non-
Hodgkin’s lymphoma among men. Occup Environ Med. 2003;60(9):E11.
30. Eriksson M, Hardell L, Carlberg M, Akerman M. Pesticide exposure as risk
factor for non-Hodgkin lymphoma including histopathological subgroup
analysis. Int J Cancer. 2008;123(7):1657–63.
31. McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, et
al. Non-Hodgkin’s lymphoma and specific pesticide exposures in men:
cross-Canada study of pesticides and health. Cancer Epidemiol Biomarkers
32. Kruger M, Schrodl W, Pedersen I, Shehata AA. Detection of glyphosate in
malformed piglets. J Environ Anal Toxicol. 2014;4:5.
33. Shehata AA, Schrodl W, Aldin AA, Hafez HM, Kruger M. The effect of
glyphosate on potential pathogens and beneficial members of poultry
microbiota in vitro. Curr Microbiol. 2013;66(4):350–8.
34. Laborde A, Tomasina F, Bianchi F, Brune MN, Buka I, Comba Pet al.
Children’s Health in Latin America: The Influence of Environmental
Exposures. Environ Health Perspect 2014.
35. Powles S. Global herbicide resistance challenge. Pest Manag Sci. 2014;70:1305.
36. Cerdeira AL, Gazziero DL, Duke SO, Matallo MB. Agricultural impacts of
glyphosate-resistant soybean cultivation in South America. J Agric Food
37. Heap I. Global perspective of herbicide-resistant weeds. Pest Manag Sci.
38. Mortensen DA, Egan JF, Maxwell BD, Ryan MR, Smith RG. Navigating a critical
juncture for sustainable weed management. Bioscience. 2012;62(1):75–84.
39. Duke SO. Perspectives on transgenic, herbicide-resistant crops in the United
States almost 20 years after introduction. Pest Manag Sci. 2015;71(5):652–7.
40. Rajapakse N, Silva E, Kortenkamp A. Combining xenoestrogens at levels
below individual no-observed-effect concentrations dramatically enhances
steroid hormone activity. Environ Health Perspect. 2002;110:917–21.
41. Silva E, Rajapakse N, Kortenkamp A. Something from “nothing”- eight weak
estrogenic chemicals combined at concentrations below NOECs produce
significant mixture effects. Environ Sci Technol. 2002;36:1751–6.
42. Mesnage R, Bernay B, Seralini GE. Ethoxylated adjuvants of glyphosate-
based herbicides are active principles of human cell toxicity. Toxicology.
Myers et al. Environmental Health (2016) 15:19 Page 12 of 13
43. Tsui MT, Chu LM. Aquatic toxicity of glyphosate-based formulations:
comparison between different organisms and the effects of environmental
factors. Chemosphere. 2003;52(7):1189–97.
44. Folmar LC, Sanders HO, Julin AM. Toxicity of the herbicide glyphosphate
and several of its formulations to fish and aquatic invertebrates. Arch
Environ Contam Toxicol. 1979;8(3):269–78.
45. European Food Safety Authority E. Renewal Assessment Report: Glyphosate.
In: Rapporteur member state G. 2013. p. 01.
46. EPA U. Glyphosate Summary Document Registration Review: Initial Docket.
2009. p. Case Number 0178.
47. Zaller JG, Heigl F, Ruess L, Grabmaier A. Glyphosate herbicide affects
belowground interactions between earthworms and symbiotic mycorrhizal
fungi in a model ecosystem. Scientific reports. 2014;4:5634.
48. Battaglin WA, Meyer MT, Kuivila KM, Dietze JE. Glyphosate and its
degradation product AMPA occur frequently and widely in U.S. soils, surface
water, groundwater, and precipitation. JAWRA Journal of the American
Water Resources Association. 2014;50(2):275–90.
49. Gaupp-Berghausen M, Hofer M, Rewald B, Zaller JG. Glyphosate-based
herbicides reduce the activity and reproduction of earthworms and lead to
increased soil nutrient concentrations. Scientific reports. 2015;5:12886.
50. Cuhra M, Traavik T, Bohn T. Clone- and age-dependent toxicity of a
glyphosate commercial formulation and its active ingredient in Daphnia
magna. Ecotoxicology. 2013;22(2):251–62.
51. Canadian Council of Ministers of the Environment. Scientific Criteria
Document for the Development of the Canadian Water Quality Guidelines
for the Protection of Aquatic Life: Glyphosate. In: Canadian Environmental
Quality Guidelines. Gatineau, QC: Canadian Council of Ministers of the
52. National Research Council. Impact of Genetically Engineered Crops on Farm
Sustainability in the United States. Washington, DC: The National Academies
53. National Agricultural Statistics Service. NASS releases 2012 chemical use
data for soybeans and wheat. In: Agricultural Statistics Board. 2013.
54. Majewski MS, Coupe RH, Foreman WT, Capel PD. Pesticides in Mississippi air
and rain: a comparison between 1995 and 2007. Environ Toxicol Chem.
55. Coupe RH, Kalkhoff SJ, Capel PD, Gregoire C. Fate and transport of
glyphosate and aminomethylphosphonic acid in surface waters of
agricultural basins. Pest Manag Sci. 2012;68(1):16–30.
56. Szekacs A, Darvas B. Forty years with Glyphosate. In: Herbicides - Properties,
Synthesis and Control of Weeds. Edited by Nagib Hasaneen M, vol.
Available from: http://www.intechopen.com/books/herbicides-properties-
synthesis-and-control-of-weeds/forty-years-with-glyphosate. : InTech, doi: 10.
5772/32491; 2012. Accessed 14 January 2016.
57. Peixoto F. Comparative effects of the Roundup and glyphosate on
mitochondrial oxidative phosphorylation. Chemosphere. 2005;61(8):1115–22.
58. Olorunsogo OO. Modification of the transport of protons and Ca2+ ions
across mitochondrial coupling membrane by N-(phosphonomethyl)glycine.
59. Olorunsogo OO, Bababunmi EA, Bassir O. Effect of glyphosate on rat liver
mitochondria in vivo. Bull Environ Contam Toxicol. 1979;22(3):357–64.
60. Jayasumana C, Gunatilake S, Senanayake P. Glyphosate, hard water and
nephrotoxic metals: are they the culprits behind the epidemic of chronic
kidney disease of unknown etiology in Sri Lanka? Int J Environ Res Public
61. Jayasumana C, Paranagama P, Agampodi S, Wijewardane C, Gunatilake S,
Siribaddana S. Drinking well water and occupational exposure to Herbicides
is associated with chronic kidney disease, in Padavi-Sripura. Sri Lanka
Environ Health. 2015;14(1):6.
62. Walsh LP, McCormick C, Martin C, Stocco DM. Roundup inhibits
steroidogenesis by disrupting steroidogenic acute regulatory (StAR) protein
expression. Environ Health Perspect. 2000;108(8):769–76.
63. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs Jr DR, Lee DH, et al.
Hormones and endocrine-disrupting chemicals: low-dose effects and
nonmonotonic dose responses. Endocr Rev. 2012;33(3):378–455.
64. Vandenberg LN, Welshons WV, Vom Saal FS, Toutain PL, Myers JP. Should
oral gavage be abandoned in toxicity testing of endocrine disruptors?
Environ Health. 2014;13(1):46.
65. SEER Stat Fact Sheets: Non-Hodgkin Lymphoma [http://seer.cancer.gov/
statfacts/html/nhl.html]. Accessed 14 January 2016.
66. Schinasi L, Leon ME. Non-Hodgkin lymphoma and occupational exposure
to agricultural pesticide chemical groups and active ingredients: a
systematic review and meta-analysis. Int J Environ Res Public Health. 2014;
67. Toy ADF, Uhing EH. Aminomethylenephosphinic acids, salts thereof, and
process for their production. In: 3160632 UPN: Stauffer Chemical Co. 1964.
68. Johal GS, Huber DM. Glyphosate effects on diseases in plants. Eur J
69. Kruger M, Schrodl W, Neuhaus J, Shehata AA. Field investigations of
glyphosate in urine of Danish dairy cows. J Environ Anal Toxicol. 2013;3:186.
70. Kruger M, Shehata AA, Schrodl W, Rodloff A. Glyphosate suppresses the
antagonistic effect of Enterococcus spp. on Clostridium botulinum.
71. Abraham W. Glyphosate formulations and their use for the inhibition of 5-
enolpyruvylshikimate-3-phosphate synthase. In: US Patent. 2010.
72. Ackermann W, Coenen M, Schrodl W, Shehata AA, Kruger M. The Influence
of Glyphosate on the Microbiota and Production of Botulinum Neurotoxin
During Ruminal Fermentation. Curr Microbiol 2014.
73. Cattani D, De Liz Oliveira Cavalli VL, Heinz Rieg CE, Domingues JT, Dal-Cim
T, Tasca CI, et al. Mechanisms underlying the neurotoxicity induced by
glyphosate-based herbicide in immature rat hippocampus: involvement of
glutamate excitotoxicity. Toxicology. 2014;320:34–45.
74. Armiliato N, Ammar D, Nezzi L, Straliotto M, Muller YM, Nazari EM. Changes
in ultrastructure and expression of steroidogenic factor-1 in ovaries of
zebrafish Danio rerio exposed to glyphosate. J Toxicol Environ Health A.
75. Kurenbach B, Marjoshi D, Amabile-Cuevas CF, Ferguson GC, Godsoe W,
Gibson P, et al. Sublethal exposure to commercial formulations of the
herbicides dicamba, 2,4-dichlorophenoxyacetic acid, and glyphosate cause
changes in antibiotic susceptibility in escherichia coli and salmonella
enterica serovar typhimurium. mBio. 2015;6:2.
76. Sheehan DM. No-threshold dose–response curves for nongenotoxic
chemicals: findings and application for risk assessment. Environ Res. 2006;
77. Mesnage R, Defarge N, Spiroux De Vendomois J, Seralini GE. Letter to the
Editor regarding “Delaney et al., 2014”: uncontrolled GMOs and their
associated pesticides make the conclusions unreliable. Food Chem Toxicol.
78. Mesnage R, Defarge N, Rocque LM, Spiroux de Vendomois J, Seralini GE.
Laboratory rodent diets contain toxic levels of environmental contaminants:
implications for regulatory tests. PLoS ONE 2015: 10.1371/journal.pone.
79. Myers JP, vom Saal FS, Akingbemi BT, Arizono K, Belcher S, Colborn T, et al.
Why public health agencies cannot depend upon ‘Good Laboratory
Practices’as a criterion for selecting data: the case of bisphenol-A. Environ
Health Perspect. 2009;117(3):309–15.
80. Zoeller RT, Vandenberg LN. Assessing dose–response relationships for
endocrine disrupting chemicals (EDCs): a focus on non-monotonicity.
Environ Health. 2015;14:42.
• We accept pre-submission inquiries
• Our selector tool helps you to ﬁnd the most relevant journal
• We provide round the clock customer support
• Convenient online submission
• Thorough peer review
• Inclusion in PubMed and all major indexing services
• Maximum visibility for your research
Submit your manuscript at
Submit your next manuscript to BioMed Central
and we will help you at every step:
Myers et al. Environmental Health (2016) 15:19 Page 13 of 13
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
Content uploaded by Charles Benbrook
All content in this area was uploaded by Charles Benbrook on Jan 20, 2019
Content may be subject to copyright.