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Teratogenic Effects of Glyphosate-Based Herbicides: Divergence of Regulatory Decisions from Scientific Evidence

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Abstract

The publication of a study in 2010, showing that a glyphosate herbicide formulation and glyphosate alone caused malformations in the embryos of Xenopus laevis and chickens through disruption of the retinoic acid signalling pathway, caused scientific and regulatory controversy. Debate centred on the effects of the production and consumption of genetically modified Roundup Ready® soy, which is engineered to tolerate applications of glyphosate herbicide. The study, along with others indicating teratogenic and reproductive effects from glyphosate herbicide exposure, was rebutted by the German Federal Office for Consumer Protection and Food Safety, BVL, as well as in industry-sponsored papers. These rebuttals relied partly on unpublished industry-sponsored studies commissioned for regulatory purposes, which, it was claimed, showed that glyphosate is not a teratogen or reproductive toxin. However, examination of the German authorities’ draft assessment report on the industry studies, which underlies glyphosate’s EU authorisation, revealed further evidence of glyphosate’s teratogenicity. Many of the malformations found were of the type defined in the scientific literature as associated with retinoic acid teratogenesis. Nevertheless, the German and EU authorities minimized these findings in their assessment and set a potentially unsafe acceptable daily intake (ADI) level for glyphosate. This paper reviews the evidence on the teratogenicity and reproductive toxicity of glyphosate herbicides and concludes that a new and transparent risk assessment needs to be conducted. The new risk assessment must take into account all the data on the toxicity of glyphosate and its commercial formulations, including data generated by independent scientists and published in the peer-reviewed scientific literature, as well as the industry-sponsored studies.
Research Article Open Access
Open Access
Review Article
Environmental & Analytical
Toxicology
Antoniou et al., J Environ Anal Toxicol 2012, S:4
http://dx.doi.org/10.4172/2161-0525.S4-006
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
*Corresponding authors: Claire Robinson, Research director, Earth Open Source,
London, UK, E-mail: claire.robinson@earthopensource.org
John Fagan, Director, Earth Open Source, E-mail: jfagan64@gmail.com
Received June 01, 2012; Accepted June 21, 2012; Published June 23, 2012
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al.
(2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence of
Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006.
doi:10.4172/2161-0525.S4-006
Copyright: © 2012 Antoniou M, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Teratogenic Effects of Glyphosate-Based Herbicides: Divergence of
Regulatory Decisions from Scientific Evidence
M Antoniou1, MEM Habib2, CV Howard3, RC Jennings4, C Leifert5, RO Nodari6, CJ Robinson7* and J Fagan8*
1Head, Gene Expression and Therapy Group, Department of Medical and Molecular Genetics, King’s College London School of Medicine, UK
2Professor of entomology, former director, Institute of Biology, UNICAMP, and former provost of extension and community affairs, UNICAMP, São Paulo, Brazil
3Professor, Centre for Molecular Biosciences, University of Ulster, Northern Ireland
4Afliated research scholar, Department of History and Philosophy of Science, University of Cambridge, UK
5Research development professor for ecological agriculture at the University of Newcastle, UK. Interests: director and trustee of the Stockbridge Technology Centre Ltd
(STC), UK
6Professor, Center for Agricultural Sciences (department of plant science), Federal University of Santa Catarina, Brazil
7Research director, Earth Open Source, London, UK. Interests: editor, GM Watch, UK
8Director, Earth Open Source. Interests: employed at a GMO testing and certication company
Keywords: Glyphosate; Roundup; Teratogenicity; Teratogenic
eects; Malformations; Risk assessment; Reproductive toxicity
Introduction
An investigation (Paganelli et al.) of the toxicity of a commercial
Roundup® herbicide formulation and its active ingredient glyphosate
found that these substances caused severe malformations in embryos
of the South African clawed frog Xenopus laevis and chickens.
In frogs, dilutions of 1/5000 of the formulation (equivalent to
430 μM of glyphosate) were sucient to induce malformations,
including shortening of the anterior−posterior axis, microcephaly,
microphthalmia, cyclopia, and craniofacial malformations at tadpole
stages. Embryos injected with pure glyphosate showed similar
phenotypes, suggesting that glyphosate itself, rather than a surfactant
or other adjuvant present in the formulation, was responsible for these
developmental abnormalities. Roundup® produced similar eects
in chicken embryos, which showed a loss of rhombomere domains,
reduction of the optic vesicles, and microcephaly.
rough the use of reporter gene assays and phenotypic rescue
via administration of an antagonist, the authors conrmed that the
mechanism by which glyphosate and Roundup caused the observed
teratogenic eects in Xenopus embryos was via disruption of the
retinoic acid signalling pathway. is resulted in dysregulation of
the shh, slug and otx2 regulatory genes, which are crucial to the
development of the central nervous system [1]. e study, while not
a classical toxicological study, is relevant to human risk assessment
because the retinoic acid signalling pathway is a central signalling
pathway in embryonic development that operates in virtually all
vertebrates, whether amphibians, birds, or mammals.
Other Studies Showing Malformations from Glyphosate
and Roundup Exposure
Paganelli et al.’s study was one among several to nd malformations
from glyphosate and Roundup exposure. Jayawardena et al. (2010)
found nearly 60% malformations in tadpoles of the tree frog Polypedates
cruciger treated with an environmentally relevant concentration of 1
ppm Roundup. Eects included kyphosis, scoliosis, and edema [2].
Relyea (2012) found that environmentally relevant concentrations of
Roundup induced relatively deeper tails similar to the adaptive changes
caused by the presence of a predator in the tadpoles of the wood frog
(Rana sylvatica or Lithobates sylvaticus) and leopard frog (R. pipiens
or L. pipiens) [3]. A study on tadpoles of Scinax nasicus (Lajmanovich
et al., 2005) found that exposure to glyphosate herbicide caused
craniofacial and mouth deformities, eye abnormalities and bent, curved
tails, as well as mortality. Malformations and mortality increased with
dose and time of exposure. A 2-day exposure to 3.07 mg/l glyphosate
Abstract
The publication of a study in 2010, showing that a glyphosate herbicide formulation and glyphosate alone caused malformations in
the embryos of Xenopus laevis and chickens through disruption of the retinoic acid signalling pathway, caused scientic and regulatory
controversy. Debate centred on the effects of the production and consumption of genetically modied Roundup Ready® soy, which is
engineered to tolerate applications of glyphosate herbicide. The study, along with others indicating teratogenic and reproductive effects
from glyphosate herbicide exposure, was rebutted by the German Federal Ofce for Consumer Protection and Food Safety, BVL, as well
as in industry-sponsored papers. These rebuttals relied partly on unpublished industry-sponsored studies commissioned for regulatory
purposes, which, it was claimed, showed that glyphosate is not a teratogen or reproductive toxin.
However, examination of the German authorities’ draft assessment report on the industry studies, which underlies glyphosate’s EU
authorisation, revealed further evidence of glyphosate’s teratogenicity. Many of the malformations found were of the type dened in the
scientic literature as associated with retinoic acid teratogenesis. Nevertheless, the German and EU authorities minimized these ndings
in their assessment and set a potentially unsafe acceptable daily intake (ADI) level for glyphosate. This paper reviews the evidence
on the teratogenicity and reproductive toxicity of glyphosate herbicides and concludes that a new and transparent risk assessment
needs to be conducted. The new risk assessment must take into account all the data on the toxicity of glyphosate and its commercial
formulations, including data generated by independent scientists and published in the peer-reviewed scientic literature, as well as the
industry-sponsored studies.
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 2 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
herbicide caused only 10% mortality but caused malformations in 55%
of the test animals [4].
Malformations have also been found in mammals treated with
glyphosate herbicides. A toxicological study by Dallegrave et al. (2003)
found that the ospring of pregnant rats dosed with 500, 750 and
1000mg/kg Roundup on days 6–15 aer fertilisation had increased
skeletal abnormalities, including at doses that were not maternally
toxic. Malformations consisted of the absence of bones or parts of
bones, shortened and bent bones, asymmetry, fusions, and cles.
e percentage of altered foetuses increased with dose. e authors
concluded that the formulated product was more toxic than the
technical glyphosate evaluated by the World Health Organisation [5]
and tested in the industry-sponsored teratogenicity studies described
in Germany’s 1998 dra assessment report on glyphosate.
Scientic and Political Controversy in Europe
In Europe, the publication in 2010 of the study by Paganelli et al.
[1] coincided with rising concern over the 40 million tons of soy that
are imported each year, mostly to feed livestock. Much of this soy is
the genetically modied (GM) Roundup Ready® variety [6], which is
engineered to tolerate applications of glyphosate herbicide. Scientic
and political debate had continued for many years over the public
health, environmental, and socioeconomic consequences of GM
soy cultivation in producer countries [7]. More recently, concerns
expanded to include potential risks to animal and human health posed
by glyphosate residues in the animal feed and human food chain [8,9].
Residues of up to 17 mg/kg of glyphosate have been found in harvested
soybean crops [10].
As the existing EU approval of glyphosate dated from 2002 [11]
and was valid for ten years, a new review was due in 2012. In response
to a Parliamentary question, John Dalli, EU Commissioner for health
and consumer policy, stated that the date might be brought forward if
the new evidence justied it [12].
German Authorities and Industry Respond
Commissioner Dalli gave the task of assessing Paganelli et al.’s
ndings to the German regulatory authorities. As the “rapporteur”
member state for glyphosate, Germany was responsible for liaising
between industry, the European Commission, and the member states
in the authorisation process. In October 2010 Germany’s Federal Oce
for Consumer Protection and Food Safety, BVL, issued an anonymous
rebuttal of the study, which stated:
ere is a huge and reliable database for developmental toxicity
of glyphosate and no evidence of teratogenicity has been obtained.
In particular, studies in rats and rabbits failed to reveal craniofacial
malformations as would be expected if a substance aects mainly
the neural crest [13].
While the identity of the “huge and reliable database” is not dened
by BVL, the studies on rats and rabbits to which BVL referred were
those commissioned by manufacturers of glyphosate herbicides and
summarised in Germany’s 1998 dra assessment report on glyphosate.
Germany’s summary of, and commentary on, these largely unpublished,
non-peer-reviewed industry-sponsored studies in the dra assessment
report form the basis of the EU’s current authorisation of glyphosate,
which dates from 2002 [11].
BVL concluded that Paganelli et al.’s ndings “do not put the
current risk assessment for glyphosate and glyphosate-based PPP
[plant protection products pesticides] into question with regard to
human health” [13].
Based on BVL’s assessment, Commissioner Dalli said there was no
need to restrict or ban glyphosate [14]. e Commission did not bring
the glyphosate review forward, or even keep to the expected date of 2012.
Instead, in November 2010 it issued a Directive delaying the review
of glyphosate until 2015 [15]. In response to a query from Friends of
the Earth Germany as to the reason for the delay, BVL replied that the
Commission and the European Food Safety Authority (EFSA) had too
heavy a workload to review glyphosate and had not nalized the rules
for renewing the approval of certain pesticides, including glyphosate
(personal communication from BVL to Friends of the Earth Germany).
BVL’s response to Paganelli et al. was followed in 2011 by a similar
response from industry. Employees of Monsanto, Dow, and Syngenta,
all manufacturers of glyphosate herbicides, published a letter in the
same journal that published Paganelli et al.’s original paper [16].
e Monsanto/Dow/Syngenta letter, published alongside a reply
from Andres Carrasco, lead author of the Paganelli et al. Paper [17],
stated: “Glyphosate does not cause adverse reproductive eects in
adult animals or birth defects in ospring of these adults exposed to
glyphosate, even at very high doses” [16].
Claims of No Teratogenicity Assessed
In order to test BVL’s claim of the absence of teratogenicity in
the industry studies on glyphosate, we obtained from the German
authorities the dra assessment report on glyphosate that they
compiled in 1998. e industry toxicological data summarised in the
dra assessment report are not publicly available and are claimed by
Monsanto to be commercially condential, though Pesticide Action
Network Europe is pursuing disclosure through the courts (personal
communication).
Examination of the dra assessment report revealed that the
industry toxicological studies on rabbits and rats that BVL said showed
“no evidence of teratogenicity” did, in fact, report malformations from
glyphosate exposure [12].
In the dra assessment report, the German authorities
concluded, based on the industry studies, “Glyphosate does not cause
teratogenicity”, but added that higher doses of glyphosate caused
“reduced ossication and a higher incidence of skeletal and/or visceral
anomalies” in rats and rabbit foetuses, as well as a reduced number of
viable fetuses [18]. e latter is consistent with increased incidence of
malformations. e German authorities do not dene what they mean
by “higher” doses, but the industry-sponsored teratogenicity studies
typically use three doses: low, mid, and high dose. For details of the
dose levels used, see Table 1.
However, in the industry-sponsored studies, malformations were
found not only at high, maternally toxic doses, as the Commission’s
health and consumer aairs division, DG SANCO, stated in its 2002
review report on glyphosate [11], but also at lower doses. In some cases,
eects at lower doses were statistically signicant [12], though statistical
signicance at lower doses is dicult to obtain in standardised industry
studies performed for regulatory purposes, which use small numbers of
animals per group.
Table 1, below, shows the range of malformations found in the
industry teratogenicity studies on glyphosate, as summarised by
the German authorities in the dra assessment report. e studies
were conducted as long ago as the 1980s and 1990s. Many of the
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 3 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
malformations found are consistent with descriptions of retinoic
acid-induced teratogenesis in the literature. For example, the
increased heart malformations and abnormalities noted in the dra
assessment report are cited as characteristic of retinoic acid-induced
teratogenicity by Lammer et al. [19], Kessel [20], and Huang et al.
[21]. e supernumerary, distorted, and rudimentary ribs noted in
the dra assessment report are consistent with Kessel’s (1992) citation
of the generation of supernumerary ribs and rib malformations as
characteristic of retinoic acid-induced teratogenicity [20]. Absent
postcaval lobe of the lungs, as mentioned in the dra assessment
report, is consistent with the lung dysmorphogenesis caused by
retinoic acid administration or deprivation as cited in Malpel [22],
Wilson et al. [23], Shenefelt [24] and Dickman et al. [25]. e reduced
ossication of cranial centres and sacro-caudal vertebral arches, as well
as the undened skeletal malformations, cited in the dra assessment
report are consistent with the cranial and skeletal malformations cited
by Lammer et al. [19], Kessel [20] and Huang et al. [21] as characteristic
of retinoic acid-induced teratogenicity.
General Observations on the Dra Assessment Report
Maternal toxicity
roughout the dra assessment report, German regulators
dismissed ndings of malformations in industry studies by claiming
that the eects were due to maternal toxicity. In its 2002 report
that forms the basis of the EU authorisation of glyphosate, the EU
Commission’s health and consumer division, DG SANCO, followed the
German regulators’ lead, discounting the developmental abnormalities
on the grounds that they were conned to “maternally toxic doses”
[11], though how this conclusion was reached is unclear.
e general reasoning behind this conclusion is that poisoning
of the mother with any substance (including commonly ingested
substances like salt and caeine) could aect the development of the
foetus and therefore such malformations are not a direct and specic
eect of the substance on the foetus. Germany and DG SANCO argued
that the studies report maternal toxicity and therefore the foetal
abnormalities were due to maternal toxicity. However, the studies
failed to dierentiate between maternal toxicity and compound-specic
teratogenicity. At the high doses used, both could be taking place.
It is unfortunate that the standardised industry studies performed
for regulatory purposes use only a small number of animals per group.
Given this restriction, relatively high doses of the test compound are
used and maternal toxicity eects are common. ere is a high risk that
this type of study design can miss compound-specic eects that occur
at low- and medium- frequency.
An equally valid conclusion that could be drawn from the industry
studies is that maternal toxicity could be obscuring a compound-
specic teratogenic eect and may not be the only cause of the
observed malformations. is argues that another study should have
been conducted employing larger groups of animals and lower, more
realistic doses administered over a longer, preferably lifelong, period
before the possibility of compound-specic teratogenic eects could
be eliminated and before glyphosate could be deemed free from
teratogenic eects.
Paumgartten (2010) supports this conclusion, stating that in cases
of maternal toxicity, it is not possible to know whether an eect on the
embryo is due to non-specic maternal poisoning or to a direct action
of the chemical at doses that also adversely aect the mother. In the
latter case, the chemical would be a developmental toxin [26].
Dallegrave et al. (2007) demonstrated that this issue is relevant to
glyphosate formulations. e authors examined the eects of Roundup
on reproduction in male and female ospring of rats treated during
pregnancy and lactation with doses of Roundup that were too low
to induce maternal toxicity. ey found that Roundup at these doses
induced adverse reproductive eects in male ospring, showing that
this herbicide formulation is a reproductive toxin at non-maternally
toxic doses [27].
is argues for the need to redesign regulatory tests to use larger
groups of animals and more realistic doses over longer exposure
periods, preferably beginning exposures prenatally.
Nonlinear Dose-Response
roughout the dra assessment report, German regulators
assumed that only eects that follow a linear dose-response relationship
are valid. But this assumption is not supported by current knowledge.
Dose-response relationships can be complex and nonlinear, especially
where the endocrine system is involved. A large body of evidence
indicates that for some compounds, toxic eects are found at low doses
but not at higher doses, and that dierent toxic eects can be found at
dierent doses [28-31].
Roundup and glyphosate have been found to be endocrine
disruptors [27,32], and therefore, nonlinear dose-responses may apply
for some endpoints. Indeed, a neurotoxicity study found not only that
Roundup was more toxic than glyphosate and produced eects at
concentrations as low as 10 ppb or 0.01 micrograms/L (equivalent to
a glyphosate concentration of 0.5 nM), but also found “unusual” dose-
response relationships with both substances, suggesting that low-dose
eects may not be predictable from eects at high doses [33].
We conclude that it is not in accord with current scientic
understanding to dismiss ndings of increased developmental
malformations on the grounds of a nonlinear dose-response
relationship. However, given that that current practice by regulatory
agencies assumes that the dose-response relationship should be linear,
we indicate, where relevant in Table 1, where such a relationship is
observed.
Historical control data
e German regulators repeatedly discounted ndings of
malformations in industry studies by referring to historical control data
instead of the concurrent controls measured in the studies themselves.
However, the use of this historical control data set is questionable
from two perspectives. First, the dra assessment report fails to disclose
the historical control data used. It does not provide the individual
data points or statistical measures of the variability within the dataset.
Second, the dra assessment report fails to present evidence that
demonstrates the validity of this historical control dataset.
e use of historical, instead of concurrent, controls is contrary to
rigorous scientic methodology, which is designed to tightly control
for variables. It articially introduces variables into the dataset,
potentially masking any eect caused by the substance being tested.
Potential variables include:
• strain of animal, involving a dierent genetic background and
sensitivity.
• substance tested, introduced by dierent manufacturing
processes and storage conditions.
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 4 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
Study
author and
date
Submitter company Experimental animal/
exposure route
Doses
used
mg/kg
bw/d
Effects found Dose-related effects/Statistical
signicance
Suresh,
1993 Feinchemie Rabbits/gavage 0, 20, 100,
500 Dilated heart
Linear dose-response relationship.
Signicantly elevated at all doses, including
low dose
Unspecied “major visceral malformations”
Linear dose-response relationship.
Increased in all treatment groups,
signicantly increased at highest dose
Extra 13th rib
Linear dose-response relationship.
Statistically signicant increase at highest
dose
Brooker et
al., 1991 Monsanto/Cheminova Rabbits/gavage 0, 50, 150,
450
Heart malformations (only type specied is
interventricular septal defect)
Effect found at highest dose. No information
provided by Germany on statistical
signicance
Embryonic deaths Signicant at all doses, though no clear
dose/response relationship
Bhide and
Patil, 1989 Barclay/Luxan Rabbits/route
unstated
0, 125,
250, 500 Heart malformation (ventricular septal defect)
Linear dose-response relationship. No
statistical analysis provided by authors.
Increased heart malformations found in all
treatment groups
Lungs: postcaval lobe absent
Linear dose-response relationship. No
statistical analysis provided by authors.
Dose-dependent increases found in all
treatment groups
Kidneys absent
Linear dose-response relationship. No
statistical analysis provided by authors.
Dose-dependent increases found in all
treatment groups
Rudimentary 14th rib, unilateral
No statistical analysis provided by authors.
Dose-dependent increases found in mid-
and high-dose groups
Number of viable foetuses per litter decreased
and number of non-viable implants increased
Linear dose-response relationship in case of
non-viable implants. No statistical analysis
provided by authors. Effects found at high
dose level.
Tasker et al.,
1980 Monsanto/Cheminova Rabbits/gavage 0, 75, 175,
350 Increased number of deaths in dams
Linear dose-response relationship. 1, 2,
and 10 deaths in low, mid- and high-dose
treatment groups respectively (no. of rabbits
per group: 16 or 17). 75 mg/kg stated by
Germany to be NOAEL
Anon., 1981 Alkaloida Rats and rabbits/oral
feeding
0, 10.5,
50.7,
255.3
Increased number of foetal deaths Effect seen at two upper dose levels
Zhu et al.,
1984 Barclay Mice/gavage 80, 420,
1050
Germany comments that there is “No evidence
of dose-related toxic effects” and “no …
structural malformations” but that description of
experiment was “poor”
Data not provided by Germany
Brooker et
al., 1991 Monsanto/Cheminova Rats/gavage
0, 300,
1000,
3500
Distortions affecting thoracic ribs
Dose-dependent increases found in
mid- and high-dose groups. Statistically
signicant at high dose
Reduced ossication of one or more cranial
centres
Dose-dependent increases found in mid-
and high-dose groups.
Reduced ossication of sacro-caudal vertebral
arches
Dose-dependent increases found in mid-
and high-dose groups
Unossied sternebrae Increases found in all treated groups,
statistically signicant at high dose
Skeletal variations
Dose-dependent increases found in all
treated groups, statistically signicant in
mid-dose and high-dose groups.
Tasker and
Rodwell,
1980
Monsanto/Cheminova Rats/gavage
0, 300,
1000,
3500
Unossied sternebrae Increase found at highest dose level
Unspecied malformations Increase at highest dose level
No. of viable foetuses per litter and mean foetal
weight decreased Effects found at highest dose level
Early resorption of embryos Data not provided by Germany
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 5 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
total number of foetuses with major visceral anomalies was
high in all treated groups, including the low dose level of 20
mg/kg glyphosate, and was signicantly increased at the
highest dose level of 500 mg/kg. e percentage of foetuses
with dilated heart was signicantly elevated at all dose levels.
Skeletal variations, anomalies and malformations were found
but there was no clear dose-response pattern. ere was a
dose-related increase in the occurrence of an extra 13th rib in
all glyphosate-treated groups; in the high dose group this was
statistically signicant.
e German regulators dismissed the ndings on the grounds that
the actual number of foetuses with dilated heart was small, that there was
no increase in foetuses with heart dilation in the mid-dose over the low-
dose group, that almost no other so organ malformations occurred,
and that the supposed consequences of this heart malformation were
“equivocal”. ey concluded that the low dose of 20 mg/kg bw/d and
even the mid dose of 100 mg/kg bw/d were NOAELs (No Observable
Adverse Eect Levels) [37].
b. e UK’s Pesticides Safety Directorate (PSD) commented,
“e increased incidences of abnormalities are of concern,
particularly the heart eects which are also reported in other
rabbit studies with glyphosate… e interpretation of this
nding must rely on comparison with historical control data”
[38].
c. In fact, no NOAEL was found in this study, as a statistically
signicant increase in the dilated heart malformation was
found even at the lowest dose of 20 mg/kg. erefore, the
German regulators should have asked for further tests at
lower doses to establish a true NOAEL. eir comment that
the number of foetuses with abnormalities was small merely
identies a shortcoming of the standardised industry studies
performed for regulatory purposes. Larger numbers of animals
are preferable. If the number of animals used is small, any eect
will only be seen in a few animals and statistical signicance
will be dicult to obtain. is is especially true at lower doses,
where observable eects will be smaller and/or less frequent.
e German regulators’ dismissal of the heart malformations on
the grounds that no other so organ malformations were found is
invalid, as toxic agents can have organ-specic eects. eir argument
that the heart dilation malformation had “equivocal” consequences and
could therefore be dismissed is scientically and clinically indefensible.
• diet for the experimental animals, which can vary in
composition and contaminants.
• pathogens in the environment.
• year and laboratory in which the experiments were performed,
for unknown reasons [34].
In order to demonstrate that the use of these historical control data
for glyphosate is valid, German regulators must disclose the datasets
used and demonstrate the relevance of each data point included in
the dataset. In the absence of such documentation, we consider the
conclusions of the dra assessment report to be questionable.
Several reviews state that concurrent control groups are the
most valid controls and warn against the biasing eect of conducting
comparisons with historical control data [34-36]. Cue (2011) stated
that using such data can lead to Type II errors [36]. In the case of
glyphosate, this would be a false negative, in which a nding of toxicity
was overlooked.
In rare instances, the use of historical control data is acceptable,
such as where eects observed are borderline, showing only a marginal
increase over concurrent controls, or in the case of rare tumours, where
data other than historical data is unavailable. Nevertheless, extreme
care must be taken in selecting the data points included in the historical
control dataset. Specically, all sources of variability in the historical
control data must be identied and controlled for [34]. ere is no
evidence in the dra assessment report that the German regulators did
this in the case of glyphosate.
Analysis of industry-sponsored studies from the dra
assessment report
Below we analyse selected industry-sponsored teratogenicity
studies from the German regulators’ dra assessment report (see Table
1 for a summary of all the industry teratogenicity studies cited in the
dra assessment report). For each study analysed, we present: (a) a
condensed version of the German regulators’ summary of the ndings;
(b) the comments of the UK’s Pesticides Safety Directorate (PSD),
where relevant; and (c) our comments.
Increased skeletal, visceral, and heart malformations
With regard to a study in rabbits by Suresh:
a. e German regulators stated that this study found that the
Suresh,
1991 Feinchemie Rats/gavage 0, 1000
Increase in delayed ossication (caudal
vertebral arch, forelimb proximal and hindlimb
distal phalanges) found in treatment group, but
increase in delayed ossication of skull found in
control group
Conicting data led Germany to conclude
that the NOAEL for developmental toxicity
was 1000 mg/kg
Bhide, 1986 Barclay/Luxan Rats/gavage 0, 100,
500
No effects found but Germany commented
that “serious reporting deciencies” and lack of
statistical analysis led it to consider the study as
supplementary information only
In spite of lack of reliable data, Germany
derived a NOAEL for developmental toxicity
of 500 mg/kg
Anon., 1981 Alkaloida Rats and rabbits/oral
feeding
22, 103,
544
Germany commented that description of study
is so “poor” that it only considered the study
as supplementary information. There were
“no malformations recorded” and effects on
foetuses were “not observed” but it is unclear
from Germany’s summary whether this was due
to poor reporting by the study’s authors or if
there was an actual absence of effects
In spite of lack of reliable data, Germany
derived a NOAEL for developmental toxicity
of 544 mg/kg
Source for all studies: Rapporteur member state Germany (1998) Monograph on glyphosate, German Federal Agency for Consumer Protection and Food Safety (BVL).
Vol 3-1 Glyphosat 05: pp. 9–20
Table 1: Malformations, embryonic deaths, and maternal deaths in industry-sponsored teratogenicity studies on glyphosate.
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 6 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
Increased heart malformations and embryonic deaths
With regard to a study in rabbits by Brooker et al.:
a. e German regulators stated that this study on the eects
of glyphosate on pregnancy in rabbits found a signicant
increase in embryonic deaths in all treatment groups.
However, they argued that comparison with historical control
data showed that the incidence in the concurrent control
group was untypically low and that therefore the increase
was not signicant. In addition, they questioned its biological
signicance, arguing that a clear dose-response relationship
was not shown. e German regulators did, however, state that
an increase in late embryonic deaths at the highest dose level
had been reported in another study. ey noted the increased
incidence of heart malformations in the high dose group, but
stated that this was within the range of historical control data.
ey added that anomalies of the heart were found in other
teratogenicity studies with glyphosate in rabbits, but concluded
that a possible eect on the occurrence of visceral anomalies
was “equivocal” [39].
b. e UK PSD commented: “e increased levels of embryonic
death/post-implantational loss at all dose levels are of concern,
as are the reports of heart defects… a more robust argument
should be presented before these ndings can be dismissed”
[38].
c. Again, the German regulators used historical control data and
an inappropriate model for toxicity dose-response to dismiss
heart malformations. We believe that this conclusion was
not justied and that the increase in late embryonic deaths
required investigation because malformed foetuses are oen
spontaneously aborted or are born dead. e relevance of this
observation to humans is suggested by a study of farm families
in Ontario, Canada, which found a higher than normal rate of
miscarriages and pre-term deliveries associated with glyphosate
herbicide exposure [40].
Decrease in viable foetuses, increase in malformations
With regard to a study in rabbits by Bhide and Patil:
a. e German regulators stated that this study found a decreased
number of viable foetuses per litter and increased embryonic
deaths. e number of visceral and skeletal malformations was
increased in the high-dose group [41].
b. e UK PSD commented: “Another study with equivocal
evidence of heart defects” [42].
c. Dose-dependent increases in lung and kidney malformations
were found across all treatment groups. Increased frequency
of heart malformations was found in all treatment groups.
Increased skeletal (rudimentary 14th rib) malformations,
typical of retinoic acid embryopathy, were found in the mid-
dose and high-dose groups.
German regulators incorrectly stated that the teratogenic NOAEL
was the mid dose of 250 mg/kg bw/d. In fact, the data showed increases
in most defects even at the low dose of 125 mg/kg bw/d. e authors
of this study did not provide an analysis of statistical signicance and
groups of only 15 animals were used, making it dicult to achieve
statistical power at lower doses. e data presented in this study suggest
that it would be more appropriate to declare the mid dose, possibly even
the low dose of 125 mg/kg, as the LOAEL (lowest observed adverse
eect level) and to state that no NOAEL was found.
Increased foetal deaths
With regard to a study in rats and rabbits by Anon:
a. e German regulators stated that this oral feeding study was
poorly recorded and was only considered as supplementary
information. No malformations were recorded, but there were
more foetal deaths at the two upper dose levels (50.7 and 255.3
mg/kg bw/d). ey stated that it was dicult to understand
why an increase in foetal deaths would occur at doses far below
those at which foetal eects were found in gavage studies
and concluded that it was “doubtful” whether this eect was
treatment-related [43].
b. e UK PSD commented, “ough this study is questioned
[by German regulators] for showing evidence of foetotoxicity
at lower doses than other studies, the study by Brooker (see
above) may also indicate foetotoxicity at 50 mg/kg bw/d” [42].
c. e German regulators’ assumption that low-dose ndings
were non-treatment-related because oral feeding resulted in
dierent eects than gavage is not defensible. As was pointed
out by the UK’s PSD, another study supported this study’s
ndings [42]. ere is no explanation in the dra assessment
report as to whether, or how, this disagreement was resolved,
and thus the issue remains open for discussion.
Increased unossied sternebrae
With regard to a study in rats by Tasker and Rodwell:
a. e German regulators stated that this study found a higher
number of foetuses with malformations at the highest dose
level (3500 mg/kg bw/d), but considered that this was within
the range of historical control data and not treatment-
related. Specically, there were more foetuses with unossied
sternebrae in the high-dose group. While they accepted that
this eect was treatment-related, they concluded that it was
“rather a developmental variation than a malformation” [44].
b. e German regulators again used historical control data
to dismiss evidence of teratogenicity. Given the ndings of
malformations in other studies, this is not justied. To dene
unossied sternebrae as a “developmental variation” rather
than a malformation is scientically unjustiable. Unossied
sternebrae in the rat are clearly dened as a skeletal deformity
in e Handbook of Pesticide Toxicology [45].
Increased skeletal malformations
With regard to a study in rats by Brooker et al.:
a. e German regulators stated that this gavage study in rats
found increased incidence of reduced ossication and increased
skeletal malformations at the mid and high doses but added
that the results were within the range of historical control
data. ey stated that maternal toxicity was a confounding
factor and described the signicance of the malformations as
“equivocal” [46].
b. Again, the German regulators used historical control data and
maternal toxicity to minimize the signicance of malformations.
However, these malformations are consistent with the ndings
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 7 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
of Paganelli et al. and are associated with disturbances in the
retinoic acid signalling pathway [1].
PSD’s conclusion
e UK PSD’s overall conclusion on the industry-sponsored rabbit
teratogenicity studies was: “Taken in isolation, none of the ndings …
would be clearly of concern. However, overall there is an indication
of a pattern” (our emphasis). e PSD asked the German regulatory
authorities to make available the historical control data against which
they compared the ndings of these studies [42], but we have been
unable to locate any published statement indicating whether the PSD
saw this data or, if it did, how it responded.
Following the deliberations of the German regulators and the UK’s
PSD, the issue of glyphosate-mediated teratogenicity was considered by
the EU Commission’s ECCO scientic review panel. e ECCO panel
noted “the incidence of heart malformations”, but dismissed them on
the grounds that they were “within the range of the historical control
data” [47]. Again, it is unclear from the panel’s statement whether it saw
the historical control data and, if so, whether it systematically assessed
the validity of that data set. Subsequently, in 2002, the EU Commission
authorised glyphosate.
Misleading “Safe” Level Set For Glyphosate?
e central purpose of a pesticide risk assessment is to establish
an Acceptable Daily Intake (ADI), a level of exposure deemed safe for
humans over a long period. In the case of glyphosate, the ADI was
calculated from the dataset provided by industry-sponsored studies,
some of which are discussed above. e level that should be used to
set the ADI is the highest dose at which no adverse eect is observed
(NOAEL), which is also lower than the lowest dose at which adverse
eects are observed (LOAEL). is level should be selected from “the
most appropriate study in the most sensitive species”, as the German
regulators note [48].
e German regulators set the ADI for glyphosate at 0.3 mg/kg
bw/d [49]. is ADI was accepted by the European Commission in its
nal report [11].
But this ADI is incorrect. e German authorities arrived at this
ADI by excluding certain studies from the ADI process. First, they
excluded the mid-term teratogenicity studies on rabbits discussed
above, on the grounds that only long-term studies should be used to
set safe chronic exposure levels. Second, they claimed that the most
sensitive species for chronic exposure was the rat [50], providing
another reason to exclude the rabbit teratogenicity studies.
However, while mid-term studies are generally discounted in ADI
calculations because they are considered less sensitive than long-term
studies, in this case, the mid-term rabbit studies found toxic eects at
lower doses than the long-term studies in rats. erefore, the mid-term
rabbit studies were found to be more sensitive, and the rabbit was a
more appropriate species. ese data clearly indicate that the rabbit
studies should have been used to set the ADI.
e exclusion of the toxicity studies in rabbits has introduced
signicant bias into the data used by the German regulators to calculate
the ADI. e German authorities cited as their starting point for
establishing the ADI a LOAEL of 60 mg/kg bw/d from a two-year study
in rats, which found signicant toxicity at that level (Suresh et al., 1996).
is was stated to be the lowest dose at which toxicity was observed.
ey then identied the highest NOAEL below that level 31 mg/kg
bw/d – as the one from which the ADI should be calculated. Applying
the usual 100-fold safety factor, the German regulators proposed an
ADI for glyphosate of 0.3 mg/kg bw/d [49].
e German authorities ignored the LOAEL of 20 mg/kg identied
by Suresh et al. in rabbits, a value three times lower than their chosen
LOAEL of 60 mg/kg bw/d [51].
e reason given by the German regulators for not adopting the 20
mg/kg LOAEL (Suresh et al., 1993) for setting the acceptable operator
(applicators’) exposure level (AOEL), is that it is a mid-term rather
than long-term experiment and therefore more suitable for setting this
type of level [52].
However, we propose that given the greater sensitivity of the rabbit
model system to glyphosate exposure, the LOAEL of 20 mg/kg bw/d
(Suresh et al., 1993) should have been the starting point for the ADI
and for the applicators’ AOEL. Indeed, this study found no NOAEL,
as even the lowest dose produced toxic eects [51]. If the LOAEL of
20 mg/kg were used, employing the same procedure as the German
regulators, the highest NOAEL below this dose from their approved
list of studies is 10 mg/kg [49]. Applying the customary 100-fold safety
factor to this value results in a more objectively accurate ADI of 0.1 mg/
kg bw/d, one-third of the ADI suggested by the German authorities
and subsequently adopted by the EU Commission.
e ADI According To Peer-Reviewed Studies
Two mammalian toxicological studies suggest that the LOAEL for
glyphosate should be even lower than the ADI of 0.1 mg/kg bw/d that
we derive from the industry-sponsored studies.
Romano et al. (2010) found that Roundup is a potent endocrine
disruptor and disturbed the reproductive development of rats with
exposure during puberty. Adverse eects, including delayed puberty
and reduced testosterone production, were found at all dose levels,
including the LOAEL of 5 mg/kg. ere was a clear dose-response
relationship [53].
Benedetti et al. (2004) found that Glyphosate-Biocarb caused
“irreversible” damage to rat liver cells, including at the LOAEL of 4.87
mg/kg, with a clear dose-response relationship [54].
No dose below these LOAELs was tested in these two studies
[53,54], so the NOAEL will be lower. Hypothetically, if the NOAEL
were conservatively assumed to be 2.5 mg/kg bw/d, applying the 100-
fold safety margin would result in an ADI of 0.025 mg/kg bw/d. is is
twelve times lower than the ADI proposed by the German regulators,
which is currently in force in the EU and used as a basis for the
maximum residue limit for food and feed.
ese studies used a species (rats) and exposure route (oral) that
are accepted by industry, EU regulators and the Organisation for
Economic Cooperation and Development (OECD). ey tested specic
glyphosate formulations, so it is not known whether their ndings can
be extrapolated to other formulations. However, this raises the crucial
question of why formulations are approved on the basis of industry
tests on, and a regulatory assessment of, only the isolated ingredient,
glyphosate.
Papers Defending Glyphosate’s Safety
In their rebuttal of Paganelli et al.’s study, the authors from
Monsanto/Dow/Syngenta state:
e GLP [Good Laboratory Practice] studies that Paganelli
et al. infer as untrustworthy “industry-funded studies” have been
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 8 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
exhaustively reviewed by multiple government scientic regulators,
oen comprised of academic expert scientists and all of which
have strongly supported the conclusions put forth in those studies.
Glyphosate does not cause adverse reproductive eects in adult animals
or birth defects in ospring of these adults exposed to glyphosate, even
at very high doses [16].
Given the evidence we present here from both academic and
industry-sponsored studies, this argument is unconvincing. e data
clearly show that glyphosate does cause adverse reproductive eects
and malformations in laboratory animals.
Even if one accepts the position proposed by Monsanto/Dow/
Syngenta, that only studies conducted according to GLP should be
considered, this argument does not stand up to scrutiny, as some of
the studies in the industry dossier on glyphosate are too old to utilize
GLP [55].
Williams et al. (2000), in a paper that is frequently cited as evidence
of the safety of Roundup and glyphosate, also cite the GLP status of
industry studies to back their claim that glyphosate is not a reproductive
toxin. However, some of the studies that they cite are, in fact, non-
GLP: for example, Schroeder (1981) and Tasker (1980) [55]. Moreover,
they fail to cite other studies from the same industry dossier – Suresh
(1993), Brooker (1991), and Bhide and Patil (1989) [56], which found
teratogenic eects from glyphosate, as detailed above.
It is important to note that GLP is not a measure of scientic
reliability or validity, but a set of laboratory management rules
instituted by regulators in the 1970s and 1980s to combat fraud
in industry testing. Interestingly, the move to GLP standards was
prompted by a high-prole case of fraud involving toxicological tests
on glyphosate for regulatory purposes conducted by a laboratory under
contract to Monsanto in late 1970s. However, the implementation of
GLP failed to prevent a second major case of fraud, which came to
light in the 1990s. is case also involved glyphosate at a dierent
laboratory under contract to Monsanto, but this time involved residue
tests [57,58]. While Monsanto said it later replaced the fraudulent tests
[59], this history shows that industry-sponsored testing can be prone to
fraud and that GLP cannot be assumed to prevent it.
Both Williams et al. (2000) and the authors from Monsanto/Dow/
Syngenta cite World Health Organisation (WHO) reports in support of
glyphosate’s safety [60,56,16]. However, the WHO relies on data from
industry studies [60], which, as shown above, in fact provide evidence
of teratogenicity.
In addition, the study by Williams et al. (2000) was co-authored
by Ian C. Munro, whose aliation was listed as the chemical industry
consulting rm Cantox [56]. Cantox states that its mission is to
“protect client interests while helping our clients … bring products
to market” [61]. Williams et al. published their paper in the journal
Regulatory Toxicology and Pharmacology, which was investigated by
a US Congressional Committee in 2008 over its industry sponsorship
in relation to its role in the FDA’s decision allowing the endocrine-
disrupting chemical bisphenol A in infant formula and other foods
[62,63].
A Monsanto-funded review by Williams et al. (2012), co-authored
by two representatives of the chemical industry consulting rm
Exponent, argued for the unreliability of Dallegrave’s study (2003)
partly on the claimed basis that the malformations found were artefacts
of histopathological xation and processing [64]. But these hypothetical
arguments could be countered by the clear dose-response relationship
(as required by regulators) found by Dallegrave [5]. Williams et al. also
argued that the malformations were only “signs of a developmental
delay that correct themselves within a brief period” [64]. e authors
failed to provide citations of any experimental evidence upon which
this claim was based and whether the malformations would indeed
“correct themselves” without resulting in lasting damage to the
developing central nervous system and other organs and systems. us
this assertion remains unsubstantiated.
e argument used by Williams et al. (2012), is similar to the
German authorities’ redenition of a malformation as a “developmental
variation” [44]. Indeed, in a discussion of an unpublished mammalian
toxicology study on glyphosate (IRDC, 1980a), Williams et al. followed
the German authorities in dening the observed unossied sternebrae
in treated rats as not a malformation but “a variation, possibly related
to the reduced foetal weights and a developmental delay” [64].
With regard to Paganelli et al.’s study [1], Williams et al. (2012)
stated that the glyphosate solution tested was not pH-adjusted and
thus the malformations “may have been due to the acidic nature of the
test compound” [64]. However, this hypothetical argument is spurious
since at the dilutions used, the pH of the buered test solution was not
changed by the addition of herbicide.
BVL’s Response to Dallegrave et al.
In its response to Paganelli et al. [1], BVL dismissed Dallegrave
et al.’s study, which found malformations in the ospring of rats
treated with Roundup, on the basis that “there were no craniofacial
malformations” [13]. But this is a misrepresentation of Dallegrave’s
study, which stated, “e most frequent skeletal alterations observed
were incomplete skull ossication and enlarged fontanel[le]” [5]. Both
are craniofacial malformations. erefore, contrary to BVL’s assertion,
Dallegrave et al.’s study provides clear evidence that a glyphosate
herbicide can cause craniofacial malformations.
Moreover, by focusing on craniofacial malformations, BVL ignored
the broad range of malformations associated with disturbances in the
retinoic acid signalling pathway during development, which were found
from glyphosate exposure by Dallegrave et al. [5], Paganelli et al. [1]
and in the industry studies (see above). For example, a malformation
found by Dallegrave et al. in a dose-dependent relationship was “caudal
vertebrae: absent” [5]. is malformation is associated with the retinoic
acid signalling pathway. Exposure of mouse embryos to retinoic acid
at a similar period of development has been found to produce agenesis
of caudal vertebrae, caused by the down-regulation of posterior Hox
genes [20].
Reports and Studies from South America
Paganelli et al. stated that they were prompted to conduct their
study by reports and studies indicating high rates of human birth
defects in regions of South America dedicated to growing GM Roundup
Ready soy [1].
For example, an epidemiological study carried out in Itapua,
Paraguay, found a higher rate of malformations in the ospring of
women exposed in pregnancy to pesticides, compared with controls.
e malformations observed included craniofacial defects, anencephaly,
microcephaly, hydrocephalus, myelomeningocele, cle palate, anotia,
polydactyly, syndactyly, and congenital heart defects [65].
Many of these malformations are of the same type as those
observed by Paganelli et al. in frogs and chickens, and are associated
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
Page 9 of 13
J Environ Anal Toxicol Toxicology of Pesticides ISSN:2161-0525 JEAT an open access journal
with the retinoic acid pathway. e authors do not mention glyphosate,
and most agrochemical applications use mixtures of pesticides, so a
sole causative agent cannot be identied. However, Itapua is an area of
intensive Roundup Ready soy cultivation [66].
A study commissioned by the provincial government of Chaco,
Argentina, a region of intensive GM soy production, showed a threefold
increase in birth defects in the province and a fourfold increase in
cancer in the locality of the agricultural town of La Leonesa in the last
decade, coinciding with the expansion of GM soy and the associated
application of pesticides. e authors named glyphosate as a pesticide
of concern and noted that complaints from residents were highest in
regions where GM crops are planted [67].
A study of birth defects in seven regions of Argentina found that
Cordoba, an area of intensive planting of GM soy where pesticides are
heavily used, had a higher incidence of spina bida, microtia, cle lip
with cle palate, polycystic kidney, postaxial polydactyly and Down’s
syndrome than other regions [68]. Many of these defects are of the type
associated with disturbances in the retinoic acid signalling pathway,
though it is not possible to identify a sole causative agent.
Epidemiological Studies in North America
Epidemiological studies carried out in North America show an
association between exposure to glyphosate herbicides and adverse
reproductive and developmental outcomes. In Canada, the Ontario
Farm Family Health Study found a higher than normal rate of
miscarriages and pre-term deliveries associated with glyphosate
exposure [40,69]. An epidemiological study carried out in the USA
found that the children of pesticide applicators exposed to glyphosate
herbicides had an increased incidence of ADHD (attention decit
hyperactivity disorder) [70]. e nding suggested that glyphosate
herbicide impacts neurological development.
Rull et al. provided evidence of an association between maternal
exposure to glyphosate herbicides and anencephaly, a type of neural
tube defect, as well as with neural tube defects (NTDs) in general
[71,72]–consistent with retinoic acid-linked teratogenicity. e study
found that maternal glyphosate herbicide exposure was associated
with anencephaly using one type of analytical model (polytomous
conventional multiple pesticide model), but not with another
(hierarchical polytomous or single pesticide model).
e data showed modest associations between glyphosate and
NTDs for both single and multiple pesticide models, with an odds ratio
(OR) of 1.5 for both. For the hierarchical model the OR was 1.4. e
authors’ criteria for signicant eects were that the OR should be greater
than or equal to 1.4 and the lower limit of the condence interval (CI)
should be greater than or equal to 0.9. e OR requirement was met for
glyphosate and NTDs using both models, but both models delivered
CIs of 0.8, just below the cut-o value [71,72].
ese results indicate a modest association between glyphosate
herbicide exposure and NTDs and are in disagreement with the
interpretation put forward by Williams et al. that the data shows “no
eect” on NTDs. Williams et al. disagree with Rull et al.’s classication
of glyphosate as an organophosphate [64], although chemically, it falls
into that category of compounds.
Some studies that Williams et al. (2012) cite in their review in
defence of the safety of glyphosate herbicides are unpublished industry-
sponsored studies [64]. It should be noted, however, that the industry
teratogenicity studies examined glyphosate and not the commercial
herbicide formulations, which are the substances under examination
in epidemiological and most laboratory studies from the peer-reviewed
literature. Crucially, these are also the substances to which humans are
exposed. Studies have found that, although glyphosate itself is toxic,
the formulations are more toxic than glyphosate alone [32,33,73,74].
Even the industry-sponsored studies on glyphosate alone show cause
for concern, as shown above.
Genotoxicity of Glyphosate
While the EU Commission’s 2002 review report on glyphosate
concludes that it is “not genotoxic” [11], it is dicult to understand
how this position can be maintained. Studies indicate that glyphosate
herbicides are genotoxic and thus have the potential to increase the risk
of birth defects and cancer. Cytogenetic monitoring of crop sprayers
in Cordoba, Argentina revealed that the number of chromosomal
aberrations in peripheral blood cells was signicantly higher in the
exposed group in comparison to the unexposed group. e pesticides
most commonly used by the exposed group were glyphosate,
cipermetrine, and atrazine [75].
An epidemiological study on Ecuadorian populations showed that
people exposed to aerial glyphosate spraying showed a higher degree of
DNA damage than a control population living 80 km away [76]. Mañas
et al. found that glyphosate was genotoxic in the comet assay in Hep-2
cells and in the micronucleus test at 400 mg/kg in mice [77].
Glyphosate herbicides and glyphosate’s main metabolite, AMPA,
altered cell cycle checkpoints in sea urchin embryos by interfering with
the DNA repair machinery [78-80]. e failure of cell cycle checkpoints
is known to lead to genomic instability and cancer in humans.
Glyphosate and AMPA have also been found to cause irreversible
damage to DNA that may increase the risk of cancer [77,81]. AMPA
damaged DNA in human cells at doses of 2.5-7.5mM and caused
chromosomal breaks at 1.8mM [81].
e surfactants and other adjuvants in glyphosate formulations
enhance the toxic eects of glyphosate, as they enable it to penetrate
more easily through the cell membrane [79,82]. e adjuvants alone
are also toxic [73].
Farm Family Exposure Study
e Monsanto/Dow/Syngenta authors cited the Farm Family
Exposure Study (FFES) [83], as evidence that the doses used by
Paganelli et al. and the suggestion of a link between glyphosate herbicide
exposure and birth defects in Argentina are unrealistic [16]. e FFES
measured urinary glyphosate concentrations for farmers, their spouses,
and their children. e study concluded that the maximum systemic
dose to spouses in the FFES was only 0.04 μg/kg body weight, with
more than 95% of the spouse exposures below the limit of detection
[83]. e Monsanto/Dow/Syngenta authors stated that this exposure
scenario was “similar” to that of the populations in Argentina and
other soy-producing regions of South America that were the focus of
concern in Paganelli et al.’s study [16].
However, it is dicult to envisage how these two scenarios are similar.
e US-based FFES measured urinary glyphosate concentrations the
day before, the day of, and for three days following a single glyphosate
application, which was carried out by tractor and boom sprayer. In
the US, it is usual for farmers to conduct spraying from the relatively
protected environment of an enclosed air-conditioned cab. People
living in South American GM soy-producing regions are exposed not
once but frequently during the growing season and application is oen
carried out from the air, leading to problems of dri.
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
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Moreover, any evaluation of the eects of pesticide exposures
must take into consideration the eects of repeated and continuous
exposures. Bolognesi (2003) found that chromosomal damage caused
by pesticides was temporary in short or time-limited exposures but
cumulative in continuous exposures to agrochemicals [84].
e FFES authors acknowledged that the nature of their study
may have led participating farmers to take extra care in their work.
erefore it may not have reected real conditions, even in the US
(a representative of the study was present with the farmer at the time
of application). Also, the FFES was sponsored by members of the
pesticide industry: Bayer, Dow, DuPont, FMC, Monsanto, Syngenta,
and the American Chemistry Council. One author, Acquavella, was
an employee of Monsanto; another was an employee of the industry
consulting rm, Exponent. ese links with the pesticide industry
create a risk of bias.
For these reasons, the FFES may not reect realistic conditions.
Mage (2006) stated in a critique of the FFES that a study that randomly
and frequently assesses glyphosate burdens in farm families over a long
period of time would provide a more realistic assessment of exposure
[85].
Our concerns are supported by another study, which is not
mentioned by the authors of the Monsanto/Dow/Syngenta rebuttal. In
a study investigating pesticide exposure in farm and non-farm families
in Iowa, USA, Curwin et al. (2007) found that 75% of farmers, 67% of
wives, and 81% of farmers’ children were carrying urinary burdens of
more than 900 ppb of glyphosate (0.9 mg/kg bw) [86]. In contrast, the
FFES reported average urinary burdens of glyphosate ranging from 1
to 6.4 ppb on dierent days of the study for farmers, and with averages
close to 0 ppb for wives and children (less than 25% of subjects were
reported to have any detectable urinary glyphosate burden) [83].
Court Cases on Glyphosate Herbicide Exposure
e safety of glyphosate herbicides has been successfully
challenged in several court cases. In New York in 1996, a court ruled
that Monsanto was no longer allowed to market Roundup as safe,
non-toxic, biodegradable or environmentally friendly [87]. In France
in 2007, Monsanto was forced to withdraw advertising claims that
Roundup was biodegradable and leaves the soil clean aer use [88]. In
March 2010, in a case brought by residents, a court in Santa Fe province,
Argentina instituted a regional ban on the spraying of glyphosate and
other agrochemicals in populated areas on grounds of “severe damage
to the environment and to the health and quality of life of the residents”
[89].
In June 2012 criminal charges were brought by aected residents
against two soy producers and a crop-spraying airplane pilot, in
a case heard by a court in Cordoba, Argentina. Plaintis charged
the defendants with malicious contamination over the spraying of
glyphosate and other agrochemicals in Ituzaingó, an area on the
outskirts of Cordoba reportedly characterized by a high incidence of
cancer and birth defects [90].
Relevance of Dierent Exposure Routes
BVL and Monsanto/Dow/Syngenta dismissed Paganelli et al.’s
study on the grounds that it used inappropriate exposure routes. ey
object to injection and culture on the grounds that they are “highly
articial”, “do not reect human exposure” [13], and are “irrelevant”
[16], to human risk assessment. is argument is also used by Williams
et al. (2012) in defence of the safety of glyphosate [64].
e standard that is being invoked is not named but is likely to be
the OECD standardised protocols for industry studies performed for
regulatory purposes, which prefer oral, dermal or inhalation exposure
routes [91].
OECD guidelines exist to guide industry on how to conduct
standardised tests performed for regulatory purposes, but it is not
credible to suggest that they represent the only valid or the most
scientically rigorous route to acquiring information about a chemical’s
toxicity.
In the case of Paganelli et al.’s study [1], injection of the treated
group with glyphosate and of the control group with water claried that
only one substance-glyphosate-could have caused the malformations.
e absence of malformations in the water-injected controls showed
that the trauma of injection did not cause the malformations.
Two studies comparing oral dosing with injection presented
ndings that challenge assumptions about dierent exposure routes:
• A study comparing the eects of bisphenol A (BPA)
administered to rats by oral dosing and injection found that
aer two hours, the level of active BPA in the blood was the
same between orally dosed and injected groups. Both exposure
routes resulted in the same pre-cancerous toxic eects on the
prostate seven months aer exposure. e study concluded
that the internal received dose, not route of exposure, is the
critical factor, and that therefore, the injection exposure route
should be acceptable for human risk assessment [92,93].
• A study comparing the toxicokinetics of glyphosate
administered to rats by oral dosing and injection found that
when given orally, glyphosate was more slowly absorbed but
took longer to clear from blood, leading to the possibility
that it could be distributed to the tissues, causing systemic
toxic eects [94]. e oral route is favoured by industry and
regulators on the claimed grounds that it better reects real
human exposures. us, based on this study, experiments
using injection could be assumed to result in less toxic eects
than those using oral methods.
While doses received by dierent tissues may vary according to
exposure route, this should be tested and not assumed. It seems critically
important to conduct biomonitoring studies on exposed populations
to discover how much glyphosate and its main metabolite, AMPA, is
present in tissues and to investigate the potential for bioaccumulation.
An in vitro study on human buccal cells attempted to mirror
human exposures to glyphosate herbicide through inhalation. e
study found that glyphosate and Roundup caused DNA damage in the
cells aer a single 20-minute exposure at a dose corresponding to a
450-fold dilution of the concentration used in agriculture. Roundup
was more toxic than glyphosate alone. e authors concluded that
inhalation may cause DNA damage in exposed individuals and that the
DNA damage was caused directly by the substances instead of being an
indirect result of cell toxicity [95].
While the Monsanto/Dow/Syngenta authors condemn in vitro
methods as “unvalidated”, this value judgement only raises the
question: validated by whom? We interpret this statement to mean that
these in vitro tests do not conform to OECD standardised protocols
for industry toxicological studies. However, outside the narrow context
of industry testing for regulatory purposes, such in vitro tests are an
important tool. For example, in the pre-clinical phase of pharmaceutical
drug development, if a potential drug gives a positive micronucleus test
Citation: Antoniou M, Habib MEM, Howard CV, Jennings RC, Leifert C, et al. (2012) Teratogenic Effects of Glyphosate-Based Herbicides: Divergence
of Regulatory Decisions from Scientic Evidence. J Environ Anal Toxicol S4:006. doi:10.4172/2161-0525.S4-006
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in vitro, then development is discontinued. Also, such in vitro tests
add valuable evidence to ndings from laboratory in vivo and human
epidemiological studies. Regarding glyphosate and Roundup, studies
of all these types suggest that both substances are genotoxic and have
toxic eects on development and reproduction.
Unrealistically High Doses?
In their response to Paganelli et al., the Monsanto/Dow/Syngenta
authors argue that the researchers used “inappropriately high” and
“unrealistic” doses, far higher than the already high doses that have
been shown in other studies not to cause malformations [16].
Considering rst Paganelli et al.’s frog embryo injection experiments,
calculations based on Monsanto/Dow/Syngenta’s own paper show that
the doses were not inappropriately high. e Monsanto/Dow/Syngenta
authors stated that a 400 mg/kg dose of glyphosate, delivered through
feeding, results in a blood concentration of 4.6 μg/ml. Animal studies
typically use between 50 and 500 mg/kg bw/d doses. Making a linear
extrapolation (as the Monsanto/Dow authors do for other purposes),
a 50 mg/kg dose should result in a blood concentration of 0.575 μg/
ml, or 575 μg/L. erefore, the range of blood concentrations achieved
in animal studies would be in the range of 575–5750 μg/L. Clearly,
the concentrations achieved in the frog embryos (690–950 μg/L) are
comparable to the blood concentrations typically achieved in animal
feeding studies.
Regarding Paganelli et al.’s frog embryo culture experiments, the
Monsanto/Dow/Syngenta authors stated that the concentrations used
were 9-15 times greater than the acute LC50 value for frog embryos of
the same species. Monsanto/Dow cites as its authority for this argument
a study by Edginton et al. [96], However, Edginton used a dierent
glyphosate formulation, with a potentially dierent LC50 value.
Moreover, the low mortality rate found by Paganelli et al. counters the
Monsanto/Dow/Syngenta authors’ claim that the doses used were even
close to the LC50 value.
Regarding Paganelli et al.’s experiments with chicken eggs, using
the Monsanto/Dow/Syngenta authors’ own estimate that 20μL of
a 1/4500 dilution of glyphosate-formulated product translates to 2
μg glyphosate injected into the egg, and assuming that the volume
of a chicken egg is approximately 35 ml, the actual concentration of
glyphosate within the egg would be 57 μg/L. is is much lower than the
blood concentrations of glyphosate that would be expected in animal
toxicity studies (575–5750 μg/L, see above), according to Monsanto/
Dow’s own calculation methods.
Further countering the claim that Paganelli et al. used unrealistically
high doses or doses higher than the LC50 value is new, as yet unpublished
data obtained by the same researchers. In these culture experiments
with embryos of Xenopus laevis, the same methodology was followed
as in the original culture experiments detailed in Paganelli et al. [1]
A dierent commercial formulation of Roundup was used (Gleba
from Gleba S.A., instead of the Roundup Classic used in the original
experiments) and batches of embryos were cultured in progressively
lower dilutions. e same malformations as were observed in the
original experiments were reproduced in a dose-dependent manner,
even at dilutions of 1/500,000 (4.30 μM). is dilution produced
developmental abnormalities in 17% of the embryos, with no lethality
[97].
Conclusion
Studies published in the peer-reviewed scientic literature have
raised major concerns regarding the potential for glyphosate and its
commercial formulations to cause birth defects and other reproductive
problems. In addition, a debate has emerged over the reported eects
on human health of herbicide application in regions that produce
GM glyphosate-tolerant crops and about the safety of food and feed
produced from these crops.
Regulatory authorities and industry aliates have defended the
use of glyphosate largely by citing the industry-sponsored toxicological
tests conducted for regulatory purposes, which they claimed showed
no evidence of teratogenicity. However, the German authorities’ dra
assessment report revealed that even these industry tests contained
clear evidence of glyphosate-mediated teratogenicity and reproductive
toxicity. Many of the malformations observed in these studies are of the
type associated with the retinoic acid signalling pathway. Paganelli et
al. [1] showed that this was the mechanism through which glyphosate
and Roundup exercise their teratogenic eects.
It is noteworthy that these industry tests were commissioned by
the same companies that stand to prot from regulatory authorization.
Regrettably, this system possesses an inherent risk of bias and makes
it especially important that the regulatory assessment is rigorous.
Yet in the EU, the evidence suggests that this was not the case. e
signicance of clear teratogenic eects of glyphosate in rabbits and rats
found in tests commissioned by industry were minimized by German
regulators. A scientically rigorous assessment was further impeded
by the outdated design of the standard tests, which are not suciently
sensitive to detect eects from realistic exposures. As a result, the
German authorities suggested, and the EU adopted, an acceptable daily
intake (ADI) for glyphosate that is unreliable and could potentially
result in exposures that cause harm to humans.
Another relevant factor is that the industry teratogenicity tests were
on glyphosate, the presumed active ingredient of the herbicide, and not
on the herbicide formulations as sold and used, even though studies
indicate that the formulations are more toxic for certain endpoints
than glyphosate alone.
A substantial body of evidence demonstrates that glyphosate
and Roundup cause teratogenic eects and other toxic eects on
reproduction, as well as genotoxic eects. From an objective scientic
standpoint, attempts by industry and government regulatory bodies to
dismiss this research are unconvincing and work against the principle
that it is the responsibility of industry to prove that its products are
safe and not the responsibility of the public to prove that they are
unsafe. e precautionary principle would suggest that glyphosate and
its commercial formulations should undergo a new risk assessment,
taking full account of the entirety of the peer-reviewed scientic
literature as well as the industry-sponsored studies. Experience to date
suggests that the new risk assessment should be conducted with full
public transparency by scientists who are independent of industry.
Disclaimer
The opinions expressed are those of the individual authors and do not reect
the policies of organizations with which they are associated.
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... According to the acute toxicity classification used in the United States, glyphosate is classified in category IV as a practically non-toxic substance [3] , but European Chemicals Agency classifies glyphosate as an eye irritant [4] as it may cause serious eye damage [2] . When it comes to chronic toxicity, studies have shown that exposure to glyphosate may be associated with QT interval prolongation and the occurrence of arrhythmias in humans [5] , oxidative-stress related organ damage [6] , hepatotoxic effects [7] , nephrotoxicity [8] , morphological changes in human erythrocytes [9] , increased risk of non-Hodgkin lymphoma [10] , compromised functioning of acetylcholinesterase with consequent deregulation in the transmission of nerve impulses [11] , DNA damage in human leukocytes [12] , teratogenic effects [13] , and endocrine disruption [6] , but there is no scientific consensus on whether the glyphosate should be considered as a hazardous substance or not. ...
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Glyphosate is a non-selective herbicide that targets the enzyme 5-enolpyruvyl-3-shikimate phosphate synthase. It has been used to effectively control perennial weed since 1974. There is some scientific evidence that supports concerns about glyphosate´s safety and potential health consequences for human health, such as eye irritation, cardiotoxicity, hepatotoxicity, nephrotoxicity, carcinogenicity, neurotoxicity, teratogenicity, mutagenicity and endocrine disruption, although there is no scientific consensus on this issue. Here, author summarized available up-to-date scientific evidence and explores the possible link between glyphosate maternal exposure and autism. Available up-to-date scientific evidence suggests that there may be a link between maternal glyphosate exposure and the increased risk for the development of autism in offspring, with possible pathophysiological mechanisms being increased levels of soluble epoxide hydrolase and Clostridium bacteria colonization of the intestinal tract, but more research is mandatory in order to establish the exact clinical relevance of here presented available scientific data.
... With the controversy surrounding GLY's safety, 67,68 it is never in our intention to consider or even use it for treatment. The role of melanin in mycetoma is still not very well understood, however, it is certain that it protects M. mycetomatis and increases resistance to antifungals. ...
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... Another limitation of the current regulatory toxicological evaluations is that they only require testing of individual active compounds, whereas testing of formulated products and combinations of pesticides is not usually required [129,132,[193][194][195]. Moreover, the reliance of regulators on industry-commissioned (rather than independent) toxicological evaluations has recently been criticized [205,206]. ...
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... Liczne badania dowodzą, iż glifosat oraz jego pochodne działają teratogennie, genotoksycznie oraz wywołują liczne toksyczne skutki w sferze reprodukcji [Robinson 2012]. Krüger i in. ...
... The daily intake of glyphosate was at maximum 15.4 µg/kg bw /day, which is only 3.1 % of the ADI of 0.5 mg/kg bw /day (EFSA, 2015), even when using a urinary excretion factor of only 1 % (Faniband et al., 2020;Zoller et al., 2020). Some argue that the current ADI is overestimated and should be 5-fold lower to account for a possible health impact of glyphosate and GBH (Antoniou et al., 2012;Myers et al., 2016) but even then, the herein quantified daily intakes would be far below the current ADI. These markedly low levels of glyphosate might be a result of stronger restrictions and consequently lower use in Germany, especially when compared with other countries like the USA. ...
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Since the 1970s, glyphosate has become the most used herbicide of the world. The general population is ubiquitously exposed to glyphosate. Its long-term toxicity, carcinogenic potential and other health effects are controversially discussed. Even though the possible health impacts of glyphosate are of global concern, no population-wide monitoring of glyphosate was done yet. This study presents the worldwide first population-representative data on glyphosate and its metabolite aminomethylphosphonic acid (AMPA) for children and adolescents. 2144 first-morning void urine samples of 3–17-year-old children and adolescents living in Germany were analysed for concentrations of glyphosate and AMPA in the German Environmental Survey for Children and Adolescents 2014–2017 (GerES V). In 52 % of the samples (46 % for AMPA) the urinary glyphosate concentrations were above the limit of quantification of 0.1 µg/L. The geometric mean concentrations were 0.107 µg/L (0.090 µg/gcreatinine) for glyphosate and 0.100 µg/L (0.085 µg/gcreatinine) for AMPA. No clear association between exposure to glyphosate or AMPA and vegetarian diet or consumption of cereals, pulses, or vegetables could be identified. The low quantification rate and the 95th percentiles for glyphosate and AMPA of around 0.5 µg/L demonstrate an overall low exposure of the young population in Germany.
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l principio di precauzione è citato nell’articolo 191 del trattato sul funzionamento dell’Unione europea (UE). Il suo scopo è garantire un alto livello di protezione dell’ambiente grazie a delle prese di posizione preventive in caso di rischio. Il campo di applicazione del principio è molto vasto e si estende anche alla politica dei consumatori, alla legislazione europea sugli alimenti, alla salute umana, animale e vegetale. La definizione deve avere un impatto positivo a livello internazionale, al fine di garantire un livello appropriato di protezione dell’ambiente e della salute. Tale principio è stato riconosciuto da varie convenzioni internazionali e figura in special modo nell'Accordo sulle misure sanitarie e fitosanitarie (SPS) nel quadro dell'Organizzazione mondiale del commercio (OMC). Nel 2012 l’opinione di tre comitati scientifici della Commissione Europea sulla tossicità delle miscele afferma che l’esposizione contemporanea a diverse sostanze chimiche può dare luogo ad effetti cumulativi tanto di tipo additivo, quanto di tipo sinergico. Ciò significa che la presenza di sostanze di origine differente, anche a dosi molto basse, moltiplica i rischi per la salute di intere generazioni di possibili utenti, magari colpiti da altre fonti di inquinamento o soggetti a problemi di origine genetica (SCHER, SCENIHR, SCCS, 2012, Toxicity and Assessment of Chemical Mixtures). Su queste basi si ritiene che tutte le sostanze presenti nelle liste qui presentate debbano essere immediatamente messe al bando nelle aree urbane anche se risultano avere qualità di “biocidi” per i quali manca ancora una normativa europea.
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Single and simultaneous toxic effects of glyphosate (Amega Up, 360 g L-1, 4%) and copper sulphate (0.01%) were studied in avian embryos treated either with injection directly into the air chamber or by immersion application for 30 min on day 0 of incubation. Alterations of the chicken embryos were evaluated during necropsy performed on day 19 of incubation, together with mortality, body weight and the type of developmental abnormalities. Based on the results, the injection application appeared to be more toxic than the immersion method, as it induced increased mortality and reduced the average body weight, and resulted in a higher incidence of congenital anomalies. Supposedly, a toxicodynamic interaction occurs between copper sulphate and glyphosate, which may reduce the vitality of embryos and thus decrease the number of offspring in wild birds.
Chapter
The toxicity of major herbicides on mammalian physiology is reviewed, with a focus on herbicides associated with agricultural systems employing genetically modified crops: glyphosate, 2,4-D, dicamba, glufosinate, quizalofop, sulfonylurea, imidazolinones, mesotrione, and isoxaflutole. Other products used in intensive agriculture worldwide are discussed: paraquat, atrazine, metolachlor, acetochlor, and alachlor. The frequent withdrawal of toxic ingredients creates the impression that herbicides are increasingly safe, but also implies that their initial assessment was insufficient. We highlight knowledge and technical gaps in the determination of safety thresholds: long-term effects of herbicides and their combinations at environmental levels (i.e., real-life exposure scenarios), epigenetics effects, and impacts on the gut microbiome are insufficiently tested. Most of the studies are focused on a few usual suspects (glyphosate, 2,4-D, atrazine), and the toxicology of some major herbicides remains underexplored. This amplifies the inescapable gap between the introduction of a new herbicide and the detection of its health effects.
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A preview genotoxic biomonitoring was carried out from a random sample in workers daily exposed to pesticides. Soy bean cultivation is the main activity of these rural workers from Córdoba. The total chromosomal aberrations (CA)/100 cells in the exposed group was 11.50±4.33 and 7.71±3.45 including and excluding gaps respectively, statistically different (p<0.05) from the reference group (5.25±2.77 and 2.58±1.83). The most commonly pesticides used by the exposed group were glyphosate, cipermetrine and atrazine. The total amount of aberrant cells in the exposed group was 11.21±3.87 and 7.50±3.00 including and excluding gaps respectively, statistically different (p<0.05) from the reference group (5.08±2.71 and 2.58±1.83 ). These findings showed the risk factor that represents pesticides exposure to human health in the studied group, compared with the reference group.
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The pesticide industry and EU regulators knew as long ago as the 1980s-1990s that Roundup, the world's best selling herbicide, causes birth defects – but they failed to inform the public.
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Soy production has rapidly expanded in Latin America in the last two decades. From 1990 to 2007, soy production increased from 16 to 61 million tonnes in Brazil and from 12 to 47 million tonnes in Argentina. Also Paraguay and Bolivia have started large-scale soy production. Soy in Latin America is primarily grown for export, with China and the EU being the worlds’ largest importers of soy products. Between 1997 and 2007, the share of genetically modi- fied (GM) soy in the total soy production increased from 23% to 95% in Argentina and from 2% to about 66% in Brazil. The only GM soy currently commercially grown in Latin America is soy with a trait leading to tolerance to the herbicide glyphosate. This GM soy line is also known as Roundup Ready® or RR soy. The use of RR soy has raised much discussion in debates about the socio-economic and environmental consequences of soy production. Many claims on RR soy have been made by various stakeholders, but they often lack science-based evidence. To support stakeholders to engage in effective debates on GM soy, an overview of the scientific literature about the agro-ecological sustainability of the cultivation of GM soy in Brazil and Argentina is pro- vided in this report. While socio-economic and institutional matters are evidently of great importance, they have not been within the scope of this study. In addition, almost all our data relate to the cultivation of RR soy. As all new GM events that will be commercially released in Latin America in the near future also relate to the use of broad-spectrum herbicides, the principles, practices and our findings related to RR soy may apply to a large extent to those events as well. Only when it concerns Bt soy, other issues need to be dealt with, which have not been extensively elaborated here. The development of GM soy deviated from conventional breeding because the desired trait was incorporated in the soy through biotechnological methods rather than the conventional process of crossing plants or using mutation breeding. RR soy was obtained through the direct incorporation of a specific DNA construct, containing a gene originating from Agrobacterium, resulting in the RR trait. By now, the RR trait has been incorporated, through conventional breeding, into a wide range of receiver varieties adapted to local conditions. Therefore the genetic diversity of GM soy is not necessarily different from conventional soy. No evidence was found that yields of GM soy differ consistently from yields of conventional soy. Differences that have been reported, either lower or higher yields of RR soy, are usually related to the genetic background of the GM varieties, and specific climatic or managerial conditions. There is no experience in large-scale cultivation of RR2 soy to reject or confirm the higher yields claimed for this soy type that will be released shortly. Co-existence of GM and conventional soy production chains is technically feasible if appropriate measures are taken to minimise cross pollination, herbicide drift and the admixture of GM and conventional soy during field operations and in various post-harvest steps. Co-existence in the field is easily achieved, because soy is a self-pollinator, with outcrossing levels on average in the order of 1%. This implies that adventitious GM presence due to outcrossing declines to close to zero at 2-5 meters from the GM field. The likelihood of GM soy traits dispersing and persisting outside agricultural fields is very small in Latin America. Potentially, the cultivation of RR soy can assist in lowering the environmental impact from herbicides, relative to conventional soy. Based on data of herbicide use in soy in the main soy cropping areas of Argentina (North Buenos Aires – South Santa Fe), we found substantial differences in the environmental impact from herbicides between conventional and zero tillage systems. Within a tillage system, we found a higher herbicide impact associated with RR soy, relative to conventional soy, primarily due to higher application rates of glyphosate in RR soy. We do not know how generally applicable this finding is, as another study found no such effect of GM soy across all production areas in Argentina. Nevertheless, the results warrant further research on actual herbicide use in GM and conventional soy. Various reasons could explain why the environmental impact from herbicide appears to have increased in RR soy in areas of Argentina. One of them is that the build up of resistance by weeds to glyphosate over time has stimulated farmers to increase glyphosate rates in RR soy to achieve acceptable weed control. The positive interaction between RR soy and the implementation of zero tillage practices may have further stimulated the use of herbicides in RR soy. It should be noted that most factors that could lead to increased herbicide application rates in GM soy also apply to conventional crops. Broad-spectrum herbicides, especially glyphosate, used as pre-emergence herbicides make up an important component of the weed management in conventional soy. Weeds can also develop herbicide resistance in conventional crops and in zero tillage practices that were introduced in large parts of Brazil and Argentina independent from GM crops. Zero tillage practices have been successfully introduced in Latin America to reduce soil erosion, to sustain or enhance soil quality and improve soil water balances. Moreover, zero tillage practices can save machinery, labour, time, and inputs, with the exception of herbicide use. A major difficulty associated with this practice is the control of weeds. Without tillage, weeds are not mechanically controlled anymore and other alternative control tools, especially chemical weed control, become more important. The availability of (broad-spectrum) herbicides has been at the base of the widespread adoption of zero tillage worldwide. Before the introduction of GM crops, broad-spectrum herbicides were used as pre-emergence herbicides at a large scale in zero tillage systems. In RR soy, glyphosate can also be applied post-emergence without risking crop damage, which has further eased weed control. While zero tillage techniques were already widely adopted in Latin America before the introduction of RR soy, the characteristics of RR soy have most likely facilitated the expansion of zero tillage practices. The recent increase in the scale of soy farming in Latin America has been driven by the need to benefit from economies of scale required to export grain bulk products at competitive prizes. The availability of vast areas of new lands at the agricultural frontiers, suitable farm machinery, and appropriate field management techniques facilitated the expansion of large scale operations. The characteristics of RR soy fitted well in these developments. The flexible timing of application of glyphosate as a post-emergence herbicide in RR soy, as well as the implementation of zero tillage techniques, which on its turn may have been facilitated by RR soy, likely aided an enlargement of the scale of farming. However, we found no evidence that the availability of RR soy was an essential or decisive factor in this process. Grain cultivation has always been large scale in Argentina, and scale enlargement in the soy cultivation in Argentina and Brazil started well before the introduction of GM soy. Monocropping soy or other crops may lead to agronomic difficulties in the long term. Whether or not additional crops are introduced in a crop rotation depends on opportunity costs. When income will be foregone because of lower margins of the alternative crop, the stimulant to rotate will be small. If the net benefits made from RR soy would be higher than those from conventional soy, the stimulant to cultivate soy as a monocrop would be higher in RR soy than in conventional soy. As with the scale farming, it is unlikely that the availability of RR soy has been an essential or decisive factor in allowing farmers to monocrop soy. Other (conventional) crops such as wheat and maize were widely cultivated as monocrops in the past in Argentina. Based on our assessments of the agro-ecological performance of RR soy and conventional soy in Argentina and Brazil, we recommend stakeholders in the debates about GM and conventional soy to put little emphasis on issues related to the scale or type of cultivation practices (i.e. monocropping, large-scale cultivation) or the expansion of soy production into areas which are environmentally sensitive, because these issues can not be unambiguously associated with GM soy. Notwithstanding, these issues are highly relevant for the discussion on sustainable soy production in general. Also the environmental effects of the GM construct itself appear to have little for the debate on the ecological impact of GM soy, while the co-existence of GM and conventional soy production chains can be achieved if appropriate measures are taken. We recommend to focus the GM soy discussion on the use of herbicides in GM and conventional farming systems and the environmental impact from these herbicides in the long term, specifically as related to the build-up of herbicide resistance in weeds.
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We analyzed the consequences of aerial spraying with glyphosate added to a surfactant solution in the northern part of Ecuador. A total of 24 exposed and 21 unexposed control individuals were investigated using the comet assay. The results showed a higher degree of DNA damage in the exposed group (comet length = 35.5 μm) compared to the control group (comet length = 25.94 μm). These results suggest that in the formulation used during aerial spraying glyphosate had a genotoxic effect on the exposed individuals.
Book
The Handbook of Pesticide Toxicology is a comprehensive, two-volume reference guide to the properties, effects, and regulation of pesticides that provides the latest and most complete information to researchers investigating the environmental, agricultural, veterinary, and human-health impacts of pesticide use. Written by international experts from academia, government, and the private sector, the Handbook of Pesticide Toxicology is an in-depth examination of critical issues related to the need for, use of, and nature of chemicals used in modern pest management. This updated third edition carries on the book's tradition of serving as the definitive reference on pesticide toxicology and recognizies the seminal contribution of Wayland J. Hayes, Jr., co-Editor of the first edition. Feature: Presents a comprehensive look at all aspects of pesticide toxicology in one reference work. Benefit: Saves researchers time in quickly accessing the very latest definitive details on toxicity of specific pesticides as opposed to searching through thousands of journal articles. Feature: Clear exposition of hazard identification and dose response relationships in each chapter featuring pesticide agents and actions Benefit: Connects the experimental laboratory results to real-life applications in human health, animal health and the environment. Feature: All major classes of pesticide considered. Benefit: Provides relevance to a wider variety of researchers who are conducting comparative work in pesticides or their health impacts. Feature: Different routes of exposure critically evaluated. Benefit: Connects the loop between exposure and harmful affects to those who are researching the affects of pesticides on humans or wildlife.
Article
) When genetically modified soya came in Argentina, it seemed like a heaven-sent solution to the country's agricultural problems. But now soya is being blamed for an environmental crisis that is threatening the country's fragile economic recovery. Branford investigates how it all went wrong. Full Text (2510 words) Copyright Reed Business Information UK Apr 17-Apr 23, 2004 [Headnote] When genetically modified soya came on the scene it seemed like a heaven-sent solution to Argentina's agricultural problems. Now soya is being blamed for an environmental crisis that is threatening the country's fragile economic recovery. Sue Branford discovers how it all went wrong A YEAR ago, Colonia Loma Senes was just another rural backwater in the north of Argentina. But that was before the toxic cloud arrived. "The poison got blown onto our plots and into our houses," recalls local farmer Sandoval Filemon. "Straight away our eyes started smarting. The children's bare legs came out in rashes." The following morning the village awoke to a scene of desolation. "Almost all of our crops were badly damaged. I couldn't believe my eyes," says Sandoval's wife, Eugenia. Over the next few days and weeks chickens and pigs died, and sows and nanny goats gave birth to dead or deformed young. Months later banana trees were deformed and stunted and were still not bearing edible fruit. The villagers quickly pointed the finger at a neighbouring farm whose tenants were growing genetically modified soya, engineered to be resistant to the herbicide glyphosate. A month later, agronomists from the nearby National University of Formosa visited the scene and confirmed the villagers' suspicions. The researchers concluded that the neighbouring farmers, like thousands of others growing GM soya in Argentina, had been forced to take drastic action against resistant weeds and had carelessly drenched the land -and nearby Colonia Loma Senes -with a mixture of powerful herbicides.