11SA15R
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Glyphosate, pathways to modern diseases IV: cancer and related pathologies
Anthony Samsel1, * and Stephanie Seneff 2 , **
1
Research Scientist, Deerfield, NH 03037, USA
2
Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA
Glyphosate is the active ingredient in the pervasive herbicide, Roundup, and its usage,
particularly in the United States, has increased dramatically in the last two decades, in step with
the widespread adoption of Roundup®-Ready core crops. The World Health Organization
recently labelled glyphosate as “probably carcinogenic.” In this paper, we review the research
literature, with the goal of evaluating the carcinogenic potential of glyphosate. Glyphosate has a
large number of tumorigenic effects on biological systems, including direct damage to DNA in
sensitive cells, disruption of glycine homeostasis, succinate dehydrogenase inhibition, chelation
of manganese, modification to more carcinogenic molecules such as N-nitrosoglyphosate and
glyoxylate, disruption of fructose metabolism, etc. Epidemiological evidence supports strong
temporal correlations between glyphosate usage on crops and a multitude of cancers that are
reaching epidemic proportions, including breast cancer, pancreatic cancer, kidney cancer,
thyroid cancer, liver cancer, bladder cancer and myeloid leukaemia. Here, we support these
correlations through an examination of Monsanto’s early studies on glyphosate, and explain how
the biological effects of glyphosate could induce each of these cancers. We believe that the
available evidence warrants a reconsideration of the risk/benefit trade-off with respect to
glyphosate usage to control weeds, and we advocate much stricter regulation of glyphosate.
Keywords: cataracts, CYP 450 enzymes, glyphosate, gut microbiome, interstitial disease,
kidney cancer, non-Hodgkin’s lymphoma, pancreatic cancer
1. INTRODUCTION
Health Organization (WHO) revised its assessment of
Glyphosate is the active ingredient in the pervasive glyphosate’s carcinogenic potential in March 2015,
herbicide, Roundup. Its usage on crops to control weeds relabelling it as a “probable carcinogen” [2, 3].
in the United States and elsewhere has increased
Table 1. Pearson’s coefficients between time trends in various
dramatically in the past two decades, driven by the cancers and glyphosate applications to corn and soy crops,
increase over the same time period in the use of over the interval from 1990–2010, along with corresponding
genetically modified (GM)1 crops, the widespread P-values, as determined from hospital discharge data and
emergence of glyphosate-resistant weeds among the GM death data maintained by the US Centers for Disease Control
(CDC). Table adapted from Swanson et al. 2014 [1].
crops (necessitating ever-higher doses to achieve the
same herbicidal effect), as well as the increased adoption Disease R P
of glyphosate as a desiccating agent just before harvest. Thyroid cancer (incidence) 0.988 ≤7.6 × 10–9
GM crops include corn, soy, canola (rapeseed) and sugar Liver cancer (incidence) 0.960 ≤4.6 × 10–8
beet [1]. Crop desiccation by glyphosate includes application Bladder cancer (deaths) 0.981 ≤4.7 × 10–9
to non-GM crops such as dried peas, beans and lentils. It Pancreatic cancer (incidence) 0.918 ≤4.6 × 10–7
should be noted that the use of glyphosate for pre-harvest Kidney cancer (incidence) 0.973 ≤2.0 × 10–8
staging for perennial weed control is now a major crop Myeloid leukaemia (deaths) 0.878 ≤1.5 × 10–6
management strategy. The increase in glyphosate usage
in the United States is extremely well correlated with the Sri Lanka’s newly elected president, Maithripala
concurrent increase in the incidence and/or death rate of Sirisena, banned glyphosate imports as one of his first
multiple diseases, including several cancers [1]. These acts following election. This action was based on studies
include thyroid cancer, liver cancer, bladder cancer, by Jayasumana et al. that provided compelling evidence
pancreatic cancer, kidney cancer and myeloid leukaemia, that glyphosate was a key factor in the chronic kidney
as shown in Table 1, reproduced from [1]. The World disease that was affecting an alarming number of young
*
E-mail: anthonysamsel@acoustictracks.net
**
Corresponding author. E-mail: seneff@csail.mit.edu
1
Usually called genetically engineered (GE) in the USA.
Journal of Biological Physics and Chemistry 15 (2015) 121–159 © 2015 Collegium Basilea & AMSI
Received 5 August 2015; accepted 24 August 2015 121 doi: 10.4024/11SA15R.jbpc.15.03
122 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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agricultural workers in the northern region [4, 5], and was exposures to EDCs are associated with human diseases
probably further motivated by the WHO reevaluation of and disabilities. We conclude that when nonmonotonic
its carcinogenic potential. Kidney disease is a risk factor dose-response curves occur, the effects of low doses
for multiple cancers, with kidney dialysis being associated cannot be predicted by the effects observed at high doses.
with increased risk of Kaposi’s sarcoma by more than Thus, fundamental changes in chemical testing and safety
50-fold, with 3- to 10-fold increased risk of kidney cancer, determination are needed to protect human health.”
and 2- to 9-fold increased risk of thyroid cancer. Many Glyphosate is toxic to many microbes as well as to
other cancers also show more modest risk increases [6]. most plants, and one likely effect of chronic low-dose
A study of rats fed GM maize and/or Roundup in oral exposure to glyphosate is a disruption of the balance
their water over their entire lifespan revealed significantly among gut microbes towards an over-representation of
increased risk of massive mammary tumours in the pathogens [11]. This leads to a chronic inflammatory
females, along with kidney and liver damage in the males state in the gut, as well as an impaired gut barrier and
[7]. Most of the tumours were benign, but there were many other sequelae. It has become increasingly
three metastases (in female animals) and two Wilm’s apparent that chronic inflammation increases cancer risk
tumours found in the kidneys of males, which had to be and, in fact, many inflammatory conditions, such as
euthanized early due to the excessive tumours, which Crohn’s disease, hepatitis, schistosomiasis, thyroiditis,
grew to more than 25% of their body size. The exposed prostatitis and inflammatory bowel disease are known
animals also had a shortened life span compared to the cancer risk factors [12].
controls. In this paper, we review the research literature on
The hormone oestrogen was declared to be a human glyphosate, with particular emphasis on evidence of
carcinogen by the National Toxicology Program in 2003 carcinogenic potential, which includes glyphosate’s
[8]. Glyphosate has been demonstrated to have induction of metabolic disorders, oxidative stress and
oestrogenic effects at minute dosages, in in vitro DNA damage, known precursors to cancer development.
experiments on mammary tumour cells [9]. Glyphosate We begin with a section that summarizes our own findings
was able to induce proliferation in these cells in following perusal of large numbers of documents that
concentrations of parts per trillion,2 and it did so through were provided to one of us (Samsel) by the US Environ-
binding affinity to the oestrogen receptor and inducing mental Protection Agency (EPA), according to the
activation of the oestrogen response element (ERE). The Freedom of Information Act, which provided detailed
fact that an oestrogen antagonist, ICI 182780, could inhibit information on Monsanto’s own early experimental animal
glyphosate’s action demonstrated rather conclusively that it studies on glyphosate.
was mediated through oestrogen mimicry. This section motivates and inspires subsequent
Traditional concepts in toxicology are centred on sections where we seek to explain the likely mechanisms
Paracelsus’ dictum that “the dose makes the poison”, by which glyphosate might cause the tumours observed in
meaning that one should expect an increasing risk of Monsanto’s studies as well as explaining the strong
toxicity as the level of exposure is increased. However, statistical correlations with human cancers. Following a
the generality of this concept has been challenged due to section that provides direct evidence of DNA damage,
the realization that endocrine-disrupting chemicals the next four sections discuss metabolic disorders linked
(EDCs) often show a greater potential to cause cancer at to glyphosate that are known to increase cancer risk,
very low doses than at higher doses; i.e., the relationship including succinate dehydrogenase inhibition, glycation
between dose and response is nonmonotonic, with higher damage, N-nitrosylation, and disrupted glycine homeostasis.
doses producing a lower toxic effect than lower doses. In The subsequent eight sections successively address
fact, levels of exposure well below the lowest level used cancer of the colon, liver, pancreas and kidney,
in standard toxicology studies can be carcinogenic, as melanoma, thyroid cancer, breast cancer, and lymphoma.
discussed by Vandenberg et al. [10]. These authors In each section we provide evidence of a link to
concluded their abstract as follows: “We illustrate that glyphosate from the research literature and propose
nonmonotonic responses and low-dose effects are plausible explanations for a causal link. We finally
remarkably common in studies of natural hormones and conclude with a summary of our findings.
EDCs. Whether low doses of EDCs influence certain
human disorders is no longer conjecture, because
epidemiological studies show that environmental
2
U.S. trillion, i.e. 1012.
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Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 123
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4. MONSANTO’S EARLY STUDIES 3. Focal tubular nephrosis, a degenerative disease of the
renal tubules of the kidney. This nephrosis is a noninflam-
One of us (Samsel) petitioned the EPA for copies of
matory nephropathy that features damage of the renal
documents originating from Monsanto, dating from the
tubules [21].
1970s through the 1980s, which described experiments
4. Interstitial mononuclear cell infiltrate characteristic of
conducted by Monsanto to evaluate whether glyphosate
inflammatory lesions, which consist of white blood
is safe for human consumption. In this section, we
cells that clear debris from an injury site.
provide a summary of our findings related to those
Mineral deposits can be indicative of kidney stones,
documents, especially with respect to indications of
which may be calcium oxalate deposits inside the kidney,
kidney damage, tumorigenicity, bioaccumulation, and
as we shall discuss more fully later in this paper.
glyphosate metabolites.
A 1983 chronic feeding study in mice [16] found a
carcinogenic response to glyphosate in both male and
4.1 Kidney damage
female mice. There was also an increased incidence of
Classification of types of kidney damage, which are chronic interstitial nephritis in male animals. The study,
indicative of kidney disease, are noted below, based on lasting 18 months, involved feeding glyphosate by diet using
information contained in Monsanto’s glyphosate studies concentrations of 1000, 5000 and 30 000 ppm. The
on rats and mice [13–18]. In [13], changes in the kidneys incidence of kidney tumours in the control animals was
associated with chronic progressive neuropathy were 0/49, as was also noted in the lowest dose group. However,
noted mostly in males, but also in some female animals of the mid-dose and high-dose groups produced incidences of
both control and treated groups. There was also neoplasms at 1/50 and 3/50 respectively, which caused the
mineralization and mineralized debris found in the pelvic EPA Oncogenicity Peer Review Committee to temporarily
epithelium of the kidney, most often in females. classify glyphosate as a Class C carcinogen.
Following submission of the study, the EPA Monsanto, dissatisfied with the action, consulted
subsequently asked Monsanto for a histological re- another pathologist who, upon further examination, found
examination of the low- and mid-dose male animals, a small tumour in the control. This was followed by the
which resulted in establishing a no observable effect level EPA using a number of pathologists to re-examine
(NOEL). In response, Monsanto submitted an addendum additional kidney sections from the mice to check the
[14] to the pathology report. The results of the addendum validity of the findings. However, their re-examination did
summarized the examination of the kidneys and found not find any additional tumours nor confirm the tumour in
minimal tubular dilatation accompanied by interstitial
the control animal. There were no tumours present in any
fibrosis in all test groups. Statistically significant
additional sections. EPA asked for the decision to be
increases in tubular dilatation of the kidney were noted. A
externally refereed by the Federal Insecticide, Fungicide,
50% increase in changes to the kidney of the low-dose
and Rodenticide Act (FIFRA) Scientific Advisory Panel,
group and, in the high-dose group, a fourfold increase in
who found the results were statistically significant even
incidence was found compared to the control.
after comparing the data to historical controls. However,
Interstitial renal fibrosis begins with an accumulation
the committee agreed to downgrade glyphosate to a Class
of extracellular matrix proteins, which is the result of
D compound, arguing inadequate evidence of oncogenicity,
inflammation and injury to the cells, which is found in
and further sealed the study as a trade secret of Monsanto.
every type of chronic kidney disease (CKD). Interstitial
Non-neoplastic changes included:
fibrosis is a progressive pathogenesis leading to end-stage
1. Renal tubular neoplasms (in male mice; none found in
renal failure [19].
females);
The results of the 1981 study [17] further found:
2. Chronic interstitial nephritis (in males);
1. Focal tubular hyperplasia, a hyperplasia of the tubular
3. Renal tubular epithelial basophilia and hyperplasias
epithelium of the kidney caused by repeated tubular
(decreased in males, but a dose-related increase
damage. It is characterized by an abnormal increase in
found in females);
the number of cells, which causes enlargement. Tubular
4. Proximal tubule epithelial cell basophilia and
epithelial hyperplasia precedes the pathogenesis of
hypertrophy (females).
tubular dilatation in acute tubular necrosis [20].
2. Focal tubular dilation, a swelling or flattening of the
4.2 Tumorigenicity
renal tubule, seen as a result of an ischaemic or toxic
event as in pharmaceutical, antibiotic or chemical A 26-month long-term study in rats conducted by Bio/
poisoning. This leads to acute tubular necrosis, a cause dynamics revealed multitudes of tumours in glands and
of acute kidney injury and kidney failure. organs [13]. They occurred (from highest to lowest
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124 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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incidence) in the following organs: pituitary, thyroid, Using these deviations effectively neutralized the
thymus, mammary glands, testes, kidney, pancreas, liver inconvenient results and thus allowed the product to be
and lungs. Pituitary, thyroid and thymus glands control brought to market. Had they not engaged in this
body and immune function, and disruption can induce deception, glyphosate may never have been registered for
disease, including cancer. These glands produce many use. EPA documents show that unanimity of opinion for
necessary hormones that control numerous biological product registration was not reached. Not all members of
processes. Tumorigenic growth also disrupts functionality the EPA glyphosate review committee approved the
of the glands and organs where the growth occurs. A registration of glyphosate. There were those who
Monsanto trade secret document [13] revealed that there dissented and signed “DO NOT CONCUR.”3
were statistically significant lymphocytic hyperplasias of The EC GLP document [24] notes: “Misdosing and/
the thymus as well as significant C-cell thyroid tumours. or cross-contamination of the test item is always a risk in
Thymus lymphoid hyperplasia occurs in Graves disease animal studies. These problems are usually detected by
and thymus hyperplasia is commonly observed with the presence of the test item and /or its metabolites in
computed tomography (CT) scans of thyroid cancer plasma or other biological samples from control animals.
patients [22], and is also associated with autoimmune It is recognized that dietary and topical studies might lead
disorders such as myasthenia gravis, lupus erythematosis, to a higher level and incidence of contamination of test item
scleroderma and rheumatoid arthritis [23]. in control animals. However, contamination of biological
It should be noted that significant incidence of samples from control animals has been observed also in
tumours was found during these investigations. However, studies using other routes of administration, e.g. gavage,
to create doubt and obscure the statistical significance of intravenous, intraperitoneal, subcutaneous or inhalation.
inconvenient findings, which may have prevented Exposure of the control animals to the test item may
product registration, Monsanto used experimental noise compromise or invalidate the study from a scientific point
from 3, 5, 7 and even 11 unrelated study controls to of view.”
effectively eliminate results, as needed. In some instances Thus, these unrelated historical controls were most
the experiments’ own control showed 0% incidence of likely corrupted studies, whether by technician error,
tumours, while the results for the glyphosate-treated contaminated water and /or feed, or other mistakes. This
groups were statistically significant. However, through explains Monsanto’s collusion with the EPA and the
the dishonest magic of comparing the findings to data subsequent hiding of the data from purview.
from unrelated historical controls, they were explained Data tables are presented in Tables 2 through 7,
away as a mystery and deemed not to be related to without the use of experimental noise from historical
administration of the glyphosate. controls. Only the data results of the experiment are shown.
Table 2. 1981 Bio/dynamics 26-month glyphosate feeding study [17]: interstitial cell tumours of the testes in Sprague
Dawley rats.
Glyphosate dose /mg kg–1 day–1 0 3 10 30
Terminal sacrifice 0/15 (0%) 2/26 (7.69%) 1/16 (6.25%) 4/26 (15.38%)
All animals 0/50 (0%) 3/50 (6%) 1/50 (2%) 6/50 (12%)
Table 3. 1981 Bio/dynamics 26-month glyphosate feeding study [17]. Incidence of kidney focal tubular dilatation (FTD) and
focal tubuler nephrosis (FTN) in Sprague Dawley rats.
Glyphosate dose /mg kg –1 day–1 0 3 10 30
FTD unilateral 2/10 (20%) 3/10 (30%) 2/9 (22%) 7/10 (70%)
FTD bilateral 0/10 (0%) 2/10 (20%) 1/9 (11%) 1/10 (10%)
FTN unilateral 1/10 (10%) 2/10 (20%) 1/9 (11%) 0/10 (0%)
FTN bilateral 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%)
3
The practice of introducing “experimental noise” by using data from unrelated historical controls is still in use today, but is
obviously really bad laboratory practice. The European Union Good Laboratory Practice (GLP) Working Group approved a
guidance document for GLP inspectors and test facilities in 2005; it is available at the European Commission (EC) GLP internet
site [24]. The document discusses the responsibilities of the study director and the principles of identifying misdosing as well as
corrective measures.
JBPC Vol. 15 (2015)
Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 125
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Table 4. 1981 Bio/dynamics 26-month glyphosate feeding study [17]: incidence of pancreatic
islet cell tumours in male Sprague Dawley rats.
Glyphosate dose /mg kg –1 day–1 0 3 10 30
Adenomas 0/50 (0%) 5/49 (10%) 2/50 (4%) 2/50 (4%)
Carcinomas 0/50 (0%) 0/49 (0%) 0/50 (0%) 1/50 (2%)
Adenomas and carcinomas 0/50 (0%) 5/49 (10%) 2/50 (4%) 3/50 (6%)
Hyperplasias 3/50 (6%) 2/49 (4%) 1/50 (2%) 0/50 (0%)
Table 5. 1990 Stout & Rueker 24 month glyphosate feeding study [15]: incidence of pancreatic islet cell tumours in male
Sprague Dawley rats.
Glyphosate dose (ppm) 0 2000 8000 20 000
Adenomas 1/43 (2%) 8/45 (18%) 5/49 (10%) 7/48 (15%)
P 0.170 0.018 0.135 0.042
Carcinomas 1/43 (2%) 0/45 (0%) 0/49 (0%) 0/48 (0%)
P 0.159 0.409 0.467 0.472
Adenomas and carcinomas 2/43 (5%) 8/45 (18%) 5/49 (10%) 7/48 (15%)
P 0.241 0.052 0.275 0.108
Hyperplasia 2/43 (5%) 0/45 (0%) 3/49 (6%) 2/48 (4%)
P 0.323 0.236 0.526 0.649
Table 6. 1990 Stout & Rueker 24 month glyphosate feeding study [15]: incidence of thyroid C-cell tumours in male Sprague
Dawley rats.
Glyphosate d ose (ppm) 0 2000 8000 20 000
Adenomas 2/54 (4%) 4/55 (7%) 8/58 (14%) 7/58 (12%)
P 0.069 0.348 0.060 0.099
Carcinomas 0/54 (0%) 2/55(4%) 0/58 (0%) 1/58 (2%)
P 0.452 0.252 1.000 0.518
Adenomas and carcinomas 2/54 (4%) 6/55 (11%) 8/58(14%) 8/58 (14%)
P 0.077 0.141 0.060 0.060
Hyperplasia 4/54 (7%) 1/55 (2%) 5/58 (9%) 4/58 (7%)
P 0.312 0.176 0.546 0.601
Table 7. 1990 Stout and Rueker 24 month glyphosate feeding study [15]: incidence of thyroid C-cell tumours in female
Sprague Dawley rats.
Glyphosate d ose (ppm) 0 2000 8000 20 000
Adenomas 2/57 (4%) 2/60 (3%) 6/59(10%) 6/55 (11%)
P 0.031 0.671 0.147 0.124
Carcinomas 0/57 (0%) 0/60 (0%) 1/59 (2%) 0/55 (0%)
P 0.445 1.000 0.509 1.000
Adenomas and carcinomas 2/57 (4%) 2/60 (3%) 7/59 (12%) 6/55 (11%)
P 0.033 0.671 0.090 0.124
Hyperplasia 10/57 (18%) 5/60 (8%) 7/59 (12%) 4/55 (7%)
P 0.113 0.112 0.274 0.086
In a long-term study conducted by Monsanto between low-, mid- and high-dose animals respectively, as compared
1987 and 1989 [15], glyphosate was found to induce a to long-term studies conducted on mice and rats in the
statistically significant (P < 0.05) cataractous lens formation, early 1980s. Over the course of the study, cataract lens
highest in male rats. Considerably higher doses of glyphosate, changes were seen in low-, mid- and high-dosed groups
i.e., 2000, 8000 and 20 000 ppm, were administered to of both male and female rats. A second pathology
JBPC Vol. 15 (2015)
126 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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examination also found statistically significant changes to the eyes. Monsanto documents also revealed an
(see Table 8). The pathologist concluded that there was a increased incidence of basophilic degeneration of the
glyphosate-treatment related response for lens changes posterior subcapsular lens (fibroses) in highly dosed males.
Table 8. Incidence and occurrence of ophthalmic degenerative lens changes by glyphosate [15].
Control Low-dose Mid-dose High-dose
Male rats 2/14 (14%) 3/19 (16%) 3/17 (18%) 5/17 (29%)
All Animals 4/60 (7%) 6/60 (10%) 5/60 (8%) 8/60 (13%)
At the conclusion and termination of the experiment, impacted as 5/20 (25%), as shown in Table 9. The study
further incidence of degenerative lens changes was again noted that “the occurrence of degenerative lens
revealed, as shown in Table 8. The ophthalmic examination changes in high dose male rats appears to have been
yielded no noticeable changes to the control animals (0/15 exacerbated by (glyphosate) treatment” [15]. Unrelated
or 0.0%); however, highly dosed males were significantly historical controls were used to negate all findings.
Table 9. Data on unilateral and bilateral cataracts (all types) and Y-suture opacities, excluding “prominent
Y suture”, following glyphosate exposure to rats. From Stout & Rueker (1990) [15].
Sex Group No. Examined No. Affected % Affected
Male N 15 0 0
1 22 1 5
2 18 3 17
3 20 5 25
Female N 23 0 0
1 24 0 0
2 17 1 6
3 19 2 11
Stout & Ruecker [15] noted in a two year study with mucosa. This was the only statistically significant occur-
chronic feeding of glyphosate in rats: “Histopathological rence of non-neoplastic lesions.” Incidence of lesions of the
examination revealed an increase in the number of mid-dose squamous mucosa are shown in Table 10. Again, Monsanto
females displaying inflammation of the stomach squamous used unrelated historical controls to negate these findings.
Table 10. Lesions of the stomach squamous mucosa in rats chronically exposed to glyphosate at three different
levels (adapted from Stout and Ruecker [15].
Controls Low Mid High
Glyphosate (ppm) 0 2000 8000 20 000
Males 2/58 (3.44%) 3/58 (5.17%) 5/59 (8.47%) 7/59 (11.86%)
Females 0/58 (0.00%) 3/60 (5.00%) 9/60 (15.00%) 6/59 (10.16%)
4.3 Bioaccumulation
tions. The 1988 Monsanto study disclosed: “A significantly
Ridley and Mirly [25] found bioaccumulation of 14C- greater percentage of the dose remained in the organs
radiolabelled glyphosate in Sprague Dawley rat tissues. and tissues and residual carcasses for the males than for
Residues were present in bone, marrow, blood and glands the females. Overall recoveries for group 5 animals were
including the thyroid, testes and ovaries, as well as major 92.8% and 94.2% for males and females respectively.”
organs, including the heart, liver, lungs, kidneys, spleen The study examined seven test groups of 3 to 5 animals
and stomach. Further details are shown in Table 11. A per sex/group that were administered a single radiolabelled
low-dose, oral absorption (10 mg/kg body weight) of the dose of glyphosate. Blood, expired air, faeces and urine
radiolabelled xenohormone indicated highest bioaccumula- were collected and analysed by liquid scintillation counting
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(LSC), and glyphosate with its metabolites analysed by two with a radiological β half-life of 7.5 and 14 days in male
methods of high pressure liquid chromatography (HPLC). and female animals, respectively. Bioaccumulation of
Three animals were used in groups sacrificed at the end of glyphosate found in bone was 0.748 ppm for males and
24 hours, and 5 animals were used for all other groups, which 0.462 ppm for females for group 6 animals. Group 5
were sacrificed at the end of the seven day study. Groups 3 animals retained 0.552 ppm and 0.313 ppm for males and
and 7 received a 10 mg/kg intravenous dose, while group 4 a females, respectively. Males also had higher levels of
high oral dose (1 g/kg). Groups 1, 2, 5 and 6 each received a glyphosate in their blood. Approximately 0.27% of the
single oral 10 mg/kg radiolabelled dose. Group 6 animals orally administered dose was found in expired CO2 of the
received multiple low doses of 10 mg/kg of nonradiolabelled group 1 rats sacrificed after 24 hours. Table 11 shows
glyphosate for 14 days prior to administration of a single the mean average and percentage distribution of
10 mg/kg radiolabelled dose. radioactivity in ppm that were found in tissues and organs
Oral absorption of glyphosate was 30% and 35%, of groups 4, 5 and 6 of the orally dosed animals.
Table 11. Distribution and bioaccumulation of 14C radiolabelled glyphosate in blood, bone, glands,
organs and other tissue of Sprague Dawley rats. Data obtained from Ridley & Mirly, 1988 [25] (see
text for details).
Glyphosate mean (ppm) Group 4 Group 5 Group 6
M ale / Female Male / Female Male / Female
BLOOD
Blood plasma 0.129 / 0.127 0.00158 / 0.00114 0.00178 / 0.00152
Red blood cells 0.517 / 0.275 0.00845 / 0.00424 0.00763 / 0.00474
Whole blood 0.328 / 0.166 0.00454 / 0.00269 0.00476 / 0.00288
Bone 30.6 / 19.7 0.552 / 0.313 0.748 / 0.462
Bone marow 4.10 / 12.50 0.0290 / 0.00639 0.0245 / 0.0231
GLANDS
Thyroid 1.50 / 1.24 0.000795 / 0.000358 0.00703 / 0.00955
Testes/ovaries 0.363 / 0.572 0.00276 / 0.00326 0.00529 / 0.00813
ORGANS
Brain 0.750 / 0.566 0.00705 / 0.00551 0.0144 / 0.0110
Eye 0.655 / 0.590 0.00215 / 0.000298 0.00405 / 0.00337
Heart 0.590 / 0.518 0.00622 / 0.00398 0.00804 / 0.00632
Kidney 1.94 / 1.35 0.0216 / 0.0132 0.0327 / 0.0196
Liver 1.91 / 1.37 0.0298 / 0.0135 0.0407 / 0.0257
Lung 1.54 / 1.13 0.0148 / 0.0120 0.0211 / 0.0167
Spleen 2.61 / 2.98 0.0119 / 0.00727 0.0155 / 0.0130
Uterus – / 0.618 – / 0.00517 – / 0.00185
DIGESTIVE SYSTEM
Stomach 2.38 / 2.36 0.00795 / 0.00367 0.0377 / 0.0239
Small intestine 1.90 / 1.55 0.216 / 0.0183 0.0441 / 0.0257
Colon 11.0 / 9.20 0.0342 / 0.0159 0.0429 / 0.0298
FAT/MUSCLE
Abdominal fat 0.418 / 0.457 0.00364 / 0.00324 0.00557 / 0.00576
Testicular/ovarian fat 0.442 / 0.037 0.00495 / 0.00347 0.00721 / 0.00563
Abdominal muscle 0.262 / 0.214 0.00232 / 0.00160 0.00278 / 0.00216
Shoulder muscle 0.419 / 0.423 0.00388 / 0.00667 0.00783 / 0.00590
Nasal mucosa 1.71 / 1.79 0.00485 / 0.0226 0.0316 / 0.0125
Residual carcass 8.78 / 7.74 0.106 / 0.0870 0.157 / 0.101
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4.4 Glyphosate metabolites acid (AMPA), methylaminomethylphosphonic acid
(MAMPA), N-formylglyphosate, N-acetylglyphosate, N-
Howe, Chott & McClanahan [26] identified, characterized
nitrosoglyphosate and an unknown compound tagged as
and quantified glyphosate and its metabolites after
“Compound #11”. Metabolites found in the dosing solutions
intravenous and oral administration of the radiolabelled
administered to rats of these experiments would be
compound. They employed several analytical tools, including
expected in all glyphosate-based products. CX analysis
LSC, strong anion exchange (SAX), cation exchange
was used to identify AMPA and MAMPA and IPC was
(CX) and ion pair chromatography (IPC). CX and IPC
used to identify all other nonbasic glyphosate metabolites.
methods of HPLC were used primarily for the identification
Results are presented in Table 12. Metabolites were also
of glyphosate and its metabolites contained in urine and
found in the urine and faeces of both male and female
faeces. Metabolites of glyphosate found during analysis
rats, as shown in Table 13 for orally dosed groups 4, 5 and 6.
include the nonbasic compounds aminomethylphosphonic
Table 12. Glyphosate and its metabolites: Analysis of dose solutions expressed as % of total. Table adapted from
Howe et al. [26].
N-acetyl- N-formyl- N-nitroso- Compound
Dose group Glyphosate AMPA MAMPA
glyphosate glyphosate glyphosate #11
1: Oral 98.21 0.63 0.26 <0.04 0.49 <0.05 <0.06
10 mg/kg
3: Intravenous 99.14 0.36 0.00 <0.02 0.36 <0.01 0.03
10 mg/kg
4: Oral 98.88 0.57 0.31 <0.03 0.14 <0.02 0.04
1000 mg/kg
5: Oral 99.41 0.17 0.00 <0.03 0.18 <0.03 0.03
10 mg/kg
6: Preconditioned 99.36 0.19 0.07 <0.03 0.21 <0.02 <0.02
Oral 10 mg/kg
Table 13. Glyphosate and its metabolites: Analysis of faeces and urine from male and female rats expressed as % of total.
Table adapted from Howe et al. [26].
AMPA MAMPA N-Acetyl- N-Formyl- N-Nitroso- Compound
Dose group Glyphosate
(A) (M) glyphosate glyphosate glyphosate #11
4
Dose solution 98.88 0.57 0.31 <0.03 0.14 <0.02 0.04
Male urine 97.76 1.25 A+M 0.10 0.20 0.09 0.46
Male faeces 98.64 0.82 A+M <0.03 <0.04 0.13 0.16
Female urine 97.71 1.39 A+M <0.05 0.25 0.09 0.33
Female faeces 98.68 0.88 A+M <0.04 <0.04 0.11 0.17
5
Dose solution 99.41 0.17 0.00 <0.03 0.18 <0.03 0.03
Male urine 99.05 0.32 A+M <0.05 0.12 0.11 0.31
Male faeces 98.78 0.56 A+M < 0.06 <0.10 0.21 0.16
Female urine 98.65 0.30 A+M <0.06 0.25 0.11 0.58
Female faeces 98.23 0.64 A+M <0.05 <0.09 0.22 0.16
6
Dose solution 99.36 0.19 0.07 <0.03 0.21 <0.02 <0.02
Male urine 99.24 0.29 A+M <0.05 <0.11 0.08 0.18
Male faeces 98.31 0.90 A+M <0.06 <0.10 0.24 0.17
Female urine 98.84 0.26 A+M <0.04 0.12 0.15 0.51
Female faeces 98.27 0.93 A+M <0.05 <0.10 0.22 0.23
In vivo metabolization of glyphosate to AMPA was all of the nonbasic compounds found during analysis of
found in the excreta in quantities ≤ 0.4%. The bone was excreta, AMPA followed by N-nitrosoglyphosate were
the site of highest bioaccumulation and it retained 0.02 to most prevalent. Total N-nitrosoglyphosate levels found in
0.05% of the oral dose and 1% of the intravenous dose. the animals ranged between 0.06–0.20% of the given
Repetitive dosing of group 6 animals did not significantly dose. Faecal samples contained 0.10–0.32% and urine
change the metabolization or excretion of glyphosate. Of 0.06–0.15% of N-nitrosoglyphosate. Stability studies
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Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 129
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revealed that the majority of the N-nitrosoglyphosate factor in the observed pathologies, one of which was
found in the faeces was not completely due to presence acinar cell atrophy, present in the pancreas of 6.9% of the
of the compound as a contaminant of glyphosate, nor was males and 5.0% of the female rats. The authors noted a
it due to animal metabolism, but rather was due to the decrease in size and number of acini and increased
chemical reaction of glyphosate with nitrites contained in the amounts of interstitial tissue, suggesting fibrosis, along
excreta. Glyphosate readily reacts with oxides of nitrogen with increased infiltration of lymphocytes and
(e.g., NO2) to form the metabolite N-nitrosoglyphosate. macrophages. Since this is quite similar to the pathology
This engenders concern because N-nitroso compounds observed with glyphosate exposure to rats, a possibility is
are carcinogens. Nitrous acid occurring in sweat excreta that glyphosate contamination in their feed or water
of the skin could be problematic in the presence of supply contributed to the pathology, perhaps in part by
glyphosate and may be responsible for the rise of some chelating manganese; this transition metal is known to
skin cancers. N-nitrosoglyphosate, the product of chemical stimulate protein synthesis in acini isolated from both
reaction between glyphosate residues and nitrites in the diabetic and normal rats and, in the case of diabetic rats,
colon, may in fact be a causal agent in the alarming increase the effect was shown to be specific to manganese
in colorectal cancer. We discuss N-nitrosoglyphosate in §8. (cobalt, nickel, barium, strontium and magnesium failed to
Colvin, Moran & Miller [27] evaluated the metabolism exert the effect) [31].
of 14C-AMPA in male Wistar rats. A 6.7 mg/kg dose of To test for the hypothesis of glyphosate
radiolabelled AMPA was administered orally, of which 20% contamination in rat feed, we used HPLC to test for
was found unchanged in the urine of the animals and 74% in glyphosate and AMPA levels in three distinct rat chow
the faeces. Recovery from excreta totalled 94% of the products, containing corn, soy and wheat middlings, and
dose. In another study, Sutherland [28] fed Sprague Dawley found significant levels of both chemicals in all products
rats a single radiolabelled dose of N-nitrosglyphosate and examined. We also tested for choline and folic acid. As
successfully quantified the metabolite in the urine and shown in Table 14, our laboratory analysis of standard
faeces. Male and female animals received 3.6 mg/kg and rodent diets found no detectable folic acid. Folic acid
4.7 mg/kg, excreting 2.8% (faeces) 88.7% (urine) and (folate) is supplied not only through diet but also,
10.7% (faeces), 80.8% (urine) respectively. Both male and particularly, by commensal bacteria via the shikimate
female rats retained 8.5% of the N-nitrosoglyphosate dose, pathway [32]. Therefore, glyphosate evidently disrupts
while 90.5% was eliminated in excreta. folic acid production both in exposed plant food sources
and in the human gut, leading to deficiencies. Folate is a
5. THE ISSUE OF CONTROL RATS’ DIET cofactor in many important biologic processes, including
“Historical control data” show that 13–71% of the lab remethylation of methionine and single carbon unit donors
animals used to conduct toxicity tests on various chemicals during DNA biosynthesis. This impacts gene regulation,
would spontaneously present with mammary tumours, and transcription and genomic repair. Folate deficiency
26– 93% develop pituitary tumours. Their kidney function enhances colorectal carcinogenesis, in part through
is also frequently impaired. A recent study by Mesnage et impaired DNA methylation [33]. Folate deficiency has
al. [29] sought to evaluate whether toxic chemicals present also been implicated in the development of several
in the feed that is standard fare for these animals might be cancers, including cancer of the colorectum, breast,
causative for this surprisingly high background rate of ovary, pancreas, brain, lung and cervix [34]. Folate
disease. Nine out of 13 samples of commonly used deficiency during gestation is linked to neural tube defects
laboratory rat feeds tested positive for glyphosate. Thus, such as anencephaly and spina bifida.
these “spontaneous” disease manifestations may well be A synthetic form of choline, choline chloride, has been
due to the toxic chemicals in the feed in the control animals added to formulated lab chow diets for decades, as
rather than to some underlying genetic defects, and this indicated from historical references available from
fact raises serious questions about the validity of any manufacturers such as Purina. A 2010 European patent
studies based on such exposed animals as a control group. application describes the addition of choline chloride to
A 1995 paper by Dixon et al. describes a thorough glyphosate formulations to act as a bioactivator and to
analysis of the frequencies of various organ pathologies enhance penetration of glyphosate into the cells of the target
related to cancer and other diseases in “control” animals weed [35]. A study of 47, 896 male health professionals in
not subjected to any explicit administration of the toxic the US found that high choline intake was associated with
chemical under investigation [30]. The paper gave no an increased risk of lethal prostate cancer [36]. Our
information on the rats’ feed or supplements, which samples all tested positive for choline (see Table 14).
would have been important as a possible confounding
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130 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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Table 14. Evidence of glyphosate contamination, and levels of folate and choline, in Purina rat chow products
as determined from authors’ own analyses.
Glyphosate /mg kg–1 AMPA /mg kg–1 Folate /mg g–1 Choline /mg g–1
Purina Rat Chow 5002 0.65 0.35 0 4.827
Purina Chow 5K75 0.57 0.27 0 5.328
Purina Chow 5LG3 0.37 0.10 0 5.919
The American Veterinary Medical Foundation notes now found in cats and lead to the destruction of the
that “Cancer is the leading cause of death in older pets, jawbone. Mammary tumours, a common cancer found in
accounting for almost half of the deaths of pets over 10 dogs and cats, are also on the rise. We suspect that
years of age.” According to the Morris Animal Foundation, glyphosate may be a causal agent related to the rise of pet
established in 1948, one in four dogs will die of cancer cancers, and used HPLC to analyse 9 popular brands of
and over 22 000 cats will be diagnosed with aggressive dog and cat food. We found significant levels of both
sarcomas. Oral cancer squamous cell carcinomas are glyphosate and AMPA in all pet foods tested (Table 15).
Table 15. Glyphosate and AMPA residues found in various dog food and cat food products, as measured
from samples tested by the authors.
Glyphosate /mg kg—1 AMPA /mg kg —1
Purina Cat Chow Complete 0.102 0.12
Purina Dog Chow Complete 0.098 0.076
Kibbles-n-Bits Chefs Choice Am Grill 0.30 0.24
Friskies Indoor Delights 0.079 0.11
9 Lives Indoor Complete 0.14 0.12
Rachael Ray Zero Grain 0.022 Trace (< 0.02)
Iams Proactive Health 0.065 Trace (< 0.02)
Rachael Ray Nutrish Super Premium 0.14 0.14
Purina Beyond Natural - Simply Nine 0.047 0.031
Clearly, it is imperative that future studies on the first step leading to cancer. We examine evidence based
potential toxicity of any environmental chemical address on sea urchins, children in Malaysia, in mouse models,
the issue of the possible toxicity of chemicals contaminat- both in vitro and in vivo, in human lymphocytes, and in
ing the diet of the control animals, and/or the potential fish. We conclude with a paragraph on folate deficiency,
impact of nutritional imbalances. Feeding the control its probable link to glyphosate exposure, and folate’s
animals an unhealthy diet leads to an increased risk of essential rôle in DNA maintenance.
cancer in the control group making it much harder to see Cell cycle disruption is a hallmark of tumour cells and
a signal in the experimental group. Furthermore, since human cancers. A study on sea urchins investigated
oestrogenic chemicals are often more toxic at extremely several different glyphosate-based pesticide formulations,
low doses than at mid-range doses, it is easy to see why the and found that all of them disrupted the cell cycle. The
control group may manifest a significant incidence of cancer. sprays used to disseminate pesticides can expose people
in the vicinity to 500 to 4000 times higher doses than those
6. EVIDENCE OF DNA DAMAGE FROM THE RESEARCH needed to induce cell cycle disruption [37].
LITERATURE A study on children living near rice paddy farms in
According to the IARC’s report [2], while there exists Malaysia revealed DNA strand breaks and chromosome
only limited direct evidence of carcinogenicity of breakage associated with reduced blood cholinesterase
glyphosate in humans, strong evidence exists to show that levels [38], which were attributed to exposure to
glyphosate can operate through two key features of organophosphate insecticides. The study did not specify
carcinogens: induction of chromosomal damage and exactly to which pesticides the children were exposed,
induction of oxidative stress. In this section, we review but glyphosate is a general-purpose herbicide whose use
the evidence that glyphosate can damage DNA, a crucial in rice paddies in Sri Lanka led to widespread kidney
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Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 131
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failure among young agricultural workers there, ultimately dehydrogenase (SDH) enzyme, cytochrome b556, the
resulting in a ban on glyphosate usage in Sri Lanka [4, 5]. avoprotein subunit and the hydrophobic subunit, reducing
While glyphosate is technically an organophosphonate their activity three- to fourfold [48]. Roundup cytotoxicity
rather than an organophosphate, a study on the fish in human cells is mediated in part through inhibition of
Prochilodus lineatus has demonstrated that it suppresses SDH, a key enzyme in mitochondrial complex II [49–51].
cholinesterase in both muscle and brain [39]. A theoretical study of the mechanism of inhibition
Bolognesi et al. [40] studied the genotoxic potential suggests that glyphosate binds at the succinate binding
of both glyphosate in isolation and Roundup, in both site with a higher binding energy than succinate, thus
mouse in vivo studies and in vitro studies of human blocking substrate bioavailability [52]. Roundup has also
lymphocytes. In the mouse studies they found evidence been shown to depress complexes II and III [53].
of DNA strand breaks and alkali-labile sites in liver but Both SDH (complex II) and fumarate hydratase (FH)
especially in kidney, as well as in bone marrow. Roundup (complex III) are tumour suppressors. Their suppressive
was found to be more toxic than glyphosate, with damage mechanism can be understood through the effects of
occuring at lower concentrations. They also demonstrated enhanced glycolysis following their inhibition [54].
dose-dependent sister chromatid exchanges in human Mutations in SDH lead to the development of
lymphocytes exposed to glyphosate and to Roundup. paraganglioma (tumours originating in the ganglia of the
A recent study on a 96-hour Roundup exposure to sympathetic nervous system), and phaeochromocytoma
the economically important tropical fish tambaqui found (neuroendocrine tumours of the adrenal glands), and
disturbed gill morphology, inhibited cholinesterase activity mutations in FH cause renal cell carcinoma. Neuroblastoma
in the brain and DNA damage in erythrocytes [41]. They is the most common extracranial solid tumour in infants
found a sixfold increase in a genetic damage indicator and young children [55]. An increase in growth rate and
(GDI) in erythrocytes, using the “comet” assay method. invasiveness in neuroblastomas is linked to impaired
Similarly, the comet assay applied to goldfish erythrocytes succinate dehydrogenase function [56].
revealed DNA damage following exposure to glyphosate Succinate and fumarate will accumulate in
[42], and studies on exposure of eels to realistic mitochondria when SDH and/or FH are suppressed, and
concentrations of Roundup and the principal individual they leak out into the cytosol. Two newly recognized
components, glyphosate and the surfactant polyethoxylated signalling pathways result in enhanced glycolysis in a
amine (POEA) in isolation, confirmed DNA damage in “pseudohypoxic response”, as well as resistance to
erythrocytes [43, 44]. apoptotic signals [54]. A characteristic feature of tumour
Folate deficiency mimics radiation in damaging cells is their increased use of glycolysis as a source of
DNA through single- and double-strand breaks as well as energy, even in the presence of available oxygen, a
oxidative lesions [45]. It is estimated that 10% of the US phenomenon referred to as the Warburg effect [57, 58].
population is at risk from folate deficiency-induced DNA Malignant, rapidly growing tumour cells typically have
damage. Cancer of the colorectum in particular is linked glycolytic rates up to 200 times higher than those of their
to folate deficiency [45, 34], which causes reduced normal tissues of origin, even when oxygen is plentiful.
bioavailability of cytosine methylation capacity in DNA,
inappropriately activating proto-oncogenes and inducing 8. GLYOXAL, METHYLGLYOXAL AND GLYOXYLATE
malignant transformation. Folate is also itself crucial for In this section, we discuss the potent toxicity of multiple
DNA synthesis and repair. Folate deficiency can also metabolites of fructose that are plausibly present in foods
lead to uracil misincorporation into DNA and subsequent derived from glyphosate-resistant crops, or as a contaminant
chromosome breaks [34]. Folate is an essential B vitamin, in glyphosate-based products, or as a breakdown product
but it can be synthesized by gut microbes, particularly generated endogenously following glyphosate exposure.
Lactobacillus and Bifidobacterium [46]. Glyphosate is These include glyoxylate, glyoxal and methylglyoxal. We
a patented antimicrobial agent, and these two species show that these molecules are genotoxic and can induce
are more vulnerable than others to growth inhibition by cancer. We surmise that their toxicity is enhanced by
glyphosate [47]. Furthermore, folate is derived from glyphosate exposure diminishing bioavailability of vitamin E,
chorismate, a product of the shikimate pathway that
an antioxidant.
glyphosate disrupts [48].
Vitamin E, a tocopherol, is derived from the shikimate
pathway, which glyphosate disrupts [59]. One of the best
7. SUCCINATE DEHYDROGENASE INHIBITION
characterized functions of tocopherols is to protect biological
A study on Escherichia coli revealed that glyphosate membranes against oxidative stress. Superoxide dismutase
suppressed three different components of the succinate (SOD) catalyses the conversion of superoxide anion
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132 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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( O2– ), a reactive oxygen species (ROS), to hydrogen can be expected that similar problems will occur in gut
peroxide (H2O2) and molecular oxygen (O2). Nicotinamide microbes exposed to glyphosate, as well as human cells,
adenine dinucleotide phosphate (NADPH) oxidase can and this may explain the increased levels of methylglyoxal
also produce ROS, which leads to proteinuria and observed in association with diabetes [74].
haematuria [60]. H2O2 induces haem degradation in red
blood cells, particularly when glutathione is deficient [61].
ROS causes irreversible DNA impairment, damage to
lipid membranes and promotes the toxic carbonyl,
malondialdehyde [62, 63]. Excessive lipid peroxidation
induced with ingestion of glyphosate residues likely leads
to an overload of maternal and foetal antioxidant defence
systems following liver damage, as shown in rat studies
by Beuret et al. [64].
Glyoxal and methylglyoxal are very potent glycating
agents, considerably more reactive than either glucose or
fructose [65, 66]. They attack the amine groups in amino
Figure 1. Possible pathways of fructose metabolism in E. coli.
acids, peptides and proteins to form advanced glycation Genes are pgi, phosphoglucose isomerase; pc, fructose B-
end products (AGEs), and they cause carbonyl stress in phosphate kinase; fdp, fructose diphosphatase; and fda,
the presence of oxidizing agents such as O2– and H2O2 fructose diphosphate aldolase. PEP, phosphoenolpyruvate.
[66]. A study linking AGEs to cancer showed that Adapted from Fraenkel, 1968 [71].
methylglyoxal–bovine serum albumin (methylglyoxal- A study comparing rats fed a high-fructose
BSA) induced significant DNA damage [67]. Cancer compared to a high-glucose diet revealed that those rats
incidence is increased in association with chronic renal fed fructose experienced a significant increase in body
failure, and this is likely due to the binding of AGEs to weight, liver mass and fat mass compared to the glucose-
receptors for advanced glycation end products (RAGE), fed rats [75]. This was accompanied by a reduction in
leading to increased intracellular formation of ROS [67]. physical activity, although the total number of calories
Extremely high levels of methylglyoxal are found in consumed remained equivalent. We suspect that this
commercial carbonated beverages sweetened with high phenomenon may be largely due to the presence of
fructose corn syrup (HFCS), but not in those that are glyphosate and methylglyoxal contamination in the fructose
sweetened with artificial sweeteners [68]. Since HFCS is (which was likely derived from the GMO Roundup-
derived from glyphosate-resistant corn, it is conceivable Ready HFCS). A study exposing male Sprague Dawley
that the methylglyoxal was produced in the plant in rats to a high-fructose diet during an interval over a period
response to glyphosate exposure. There is a plausible of four months showed elevated serum levels of
biological mechanism for this, caused by the accumulation methylglyoxal, along with several indicators of diabetes
of excessive amounts of phosphoenolpyruvate (PEP) as a and metabolic syndrome, including expression of RAGE,
consequence of the disruption of the enzyme, 5- NF-kB, mediators of the renin angiotensin system and
enolpyruvyl-shikimate-3-phosphate (EPSP) synthase, elevated blood pressure [76]. At physiological concentra-
that uses PEP as substrate for the first step in the tions, methylglyoxal can modify plasmid DNA and cause
shikimate pathway [69]. PEP suppresses glycolysis by mutations and abnormal gene expression [77].
binding to the active site in the enzyme, triose phosphate Glyphosate formulations are trade secrets, but a 2006
isomerase (TPI) [70], outcompeting the natural substrates. Monsanto patent proposed using oxalic acid (oxalate) as an
Furthermore, PEP reacts with fructose to initiate its additive to increase the toxicity of glyphosate to weeds
conversion to triose phosphate, also known as [78]. Oxalate inhibits pyruvate kinase and this leads to an
glyceraldehyde 3-phosphate (glyceraldehyde 3-p), as elevation in PEP along with a reduction in production of
illustrated in Fig. 1 [71]. Glyceraldehyde 3-p is highly lactate and pyruvate. The synthesis of PEP in rat livers
unstable and it spontaneously breaks down to exposed to 0.1 mM oxalate more than doubled [79], which
methylglyoxal [72]. Severe impairment of TPI due to likely induces excess exposure to methylglyoxal as
genetic defects leads to sharp increases in methylglyoxal discussed above, causing liver stress. The effects of
and protein glycation, as well as oxidation and nitrosation oxalate would be synergistic with the effects of glyphosate
damage [73]. Inhibition of glycolysis will increase the inhibition of the shikimate pathway in gut microbes, which
residence time of glyceraldehyde 3-p and increase its can be expected to also increase PEP levels, since PEP is
chances to spontaneously degrade to methylglyoxal. It substrate for the enzyme that glyphosate disrupts.
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Several anaerobic bacteria, including Oxalobacter [88]. An earlier US patent application disclosed a similar
formigenes, Eubacterium lentum, Enterococcus process whereby aminomethylphosphonic acid is reacted
faecalis and Lactobacillus acidophilus can metabolize in an aqueous medium with glyoxal in the presence of
oxalate in the gut [80]. However, both oxalate sulfur dioxide to produce glyphosate. Methylglyoxal is
decarboxylase and oxalate oxidase, enzymes involved in cytotoxic, and it has been shown to arrest growth and
oxalate metabolism, depend on manganese as a cofactor react with nucleotides, increasing the incidence of sister
[81], and manganese is chelated by glyphosate, making it chromatid exchanges, a step towards tumorigenesis [93].
unavailable to gut microbes [82, 83]. Methylglyoxal also decreases protein thiols, especially
Elevated serum glyoxylate has been found to be an glutathione, an essential antioxidant. In in vitro studies,
early marker for diabetes risk [84]. The conversion of glyphosate has also been shown to reduce glutathione
glyoxylate to oxalate by the enzyme lactate dehydroge- levels in mammalian cells, possibly mediated through
nase is inhibited by oxalate [85, 86]. Hence glyoxylate, methylglyoxal [94]. Methylglyoxal induces DNA
derived from glyphosate breakdown, can be expected to mutations mainly at G:C base pairs, and it severely
accumulate in the presence of excess oxalate. Glyoxylate inhibits DNA replication by inducing cross-links between
can be derived from glyoxal, and both glyoxal and DNA and DNA polymerase [95]. The mutagenicity of
glyoxylate have been proposed as key reactants in the methylglyoxal is suppressed by sulfur-containing molecules,
production of glyphosate, as described in multiple patents such as sulfite, cysteine and glutathione [96]. Glyphosate
from the mid-1980s [87, 88]. Furthermore, glyphosate has been shown to deplete methionine levels by 50% to
can itself be metabolized to AMPA and glyoxylate by 65% in a glyphosate-sensitive carrot plant line [97].
microbial action along two distinct pathways, via glycine Methionine is an essential sulfur-containing amino acid
oxidase or via glyphosate oxidoreductase [89]. In vitro crucial for maintaining levels of cysteine, glutathione and
exposure of hepatocytes to glyoxal showed hepatotoxicity sulfate. Most bacteria possess biosynthetic pathways for
induced by lipid peroxidation, ROS, and collapsed methionine [98], and it is possible that glyphosate disrupts
mitochondrial membrane potential [90, 91]. their ability to supply this critical nutrient to the host.
LDH is also known to be involved in tumour Glyoxalase is a key enzyme in the pathway that
metabolism. A Monsanto study conducted by Johnson on detoxifies methylglyoxal. Mouse studies have demonstrated
rabbits found that extremely high doses of glyphosate that its overexpression can reduce AGE production and
(5000 mg/kg) severely downregulated production of oxidative damage associated with hyperglycaemia [99],
LDH, reducing values in both male and female animals, thus demonstrating a direct link between methylglyoxal
whereas a fivefold lower dose (1000 mg/kg) upregulated and these pathologies. Glyoxalase is upregulated in
LDH similarly in both males and females compared to the association with rapid cell proliferation [100] and also in
experimental control [92]. Glyphosate was administered association with some cancers, including gastric cancer
by dermal absorption to three groups, each of 5 male and [101] and prostate cancer [102] (gastric cancer is the
5 female rabbits. Doses of 100, 1000 and 5000 mg/kg second highest cause of cancer-related mortality worldwide
were held in place by occlusion for 6 hours/day, five [103]). Overexpression of glyoxalase I is associated with
days/week for 21 days. A control group of the same increased gastric wall invasion and lymph node metastasis
numbers of animals and sex did not receive the [101]. Glyphosate exposure has been shown experimentally
compound. Results for the control, low-, mid- and high- to induce increased expression of glyoxalase activity in
dose groups were 250, 169, 291 and 76 for male animals Arachis hypogaea (groundnut), which was engineered
and 189, 149, 258 and 28 for female animals, respectively. to be glyphosate-tolerant [100]. In addition, the observed
Not understanding glyphosate’s nonmonotonic dose- upregulation of redox-regulated kinases, phosphatases
response relationship caused Johnson to dismiss this and transcription factors shows the importance of redox
haematological finding. A similar pattern of LDH couples to reorganize growth and metabolic needs under
regulation was recorded by Stout & Ruecker in 1990 in stress conditions, such as exposure to glyphosate.
experiments with albino rats [15]. Mitogen-activated protein kinase (MAPK) phosphatases
A Monsanto patent application from 1985 describes (MKPs) play an important rôle in the development of
the invention as follows: “glyphosate and various glyphosate cancer in humans [104].
derivatives can be produced with very high selectivity by
the reductive alkylation of aminomethylphosphonic acid, 9. N-NITROSOGLYPHOSATE AND N-NITROSOSARCOSINE
its salts or its esters, in an aqueous medium with a carbonyl As was shown by Monsanto’s own studies [26],
compound, such as, for example, glyoxal, glyoxylic acid, a glyphosate readily reacts with nitrogen oxides to form N-
glyoxylate salt, or a glyoxylate polyacetal salt or ester” nitrosoglyphosate (NNG), which is of great concern due
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134 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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to its toxicity [105]. N-nitroso compounds (NOCs) can cell lines (including prostate, ovarian, cervical and lung
induce cancer in multiple organs in at least 40 different cancer) demonstrated that glyphosate at doses ranging
animal species, including higher primates [106–108]. In in from 15 to 50 mM was cytotoxic to tumour cells, and that
vitro studies on human liver slices, the mechanism of cytotoxicity to normal cell lines required higher doses
action was shown to be nucleic acid alkylation [109]. (e.g., 100 mM). It was hypothesized that the mechanism
Schmahl and Habs commented: “N-nitroso compounds of action involved impaired glycine synthesis due to
can act carcinogenically in a large number of animal glyphosate acting as a glycine mimetic.
species; there is no rational reason why human beings In direct contradiction, however, glycine has been
should be an exception, all the less so since in vitro shown to prevent tumorigenesis [122] and it is a potent
experiments have shown N-nitroso compounds are anti-angiogenic nutrient that suppresses tumour growth,
metabolized in the same way by human livers as by the possibly through activation of a glycine-gated chloride
livers of experimental animals” [108, p. 240]. Several channel [123]. Impaired glycine synthesis likely has other
different nitrosylated compounds have been targeted as adverse effects as well, such as the possibility that
potential carcinogenic agents, although it is conceded that glyphosate interferes with glycine conjugation of benzene-
the long lag time between exposure and tumour based compounds. In particular, this is a mechanism used
development makes it difficult to recognize the links by gut microbes, particularly Bifidobacteria, to detoxify
[110]. Dietary N-nitrosyl compounds especially are phenolic compounds, producing hippurate (benzoylglycine),
thought to increase the risk of colon cancer and rectal a glycine conjugate of benzoic acid, as a mechanism for
carcinoma [111, 112]. detoxification [124]. Glycine has been shown to be a
The Food and Agricultural Organization of the limiting factor for hippurate production [125]. We stated
United Nations (FAO) has set a strict upper limit of 1 earlier that glyphosate preferentially harms Bifidobacteria
ppm NNG [113]. The accepted methodology for measuring [46], and studies have shown reduced counts of
contamination levels, proposed by Monsanto in 1986 Bifidobacteria in obese rats along with reduced excretion
[114], has complicated instrumentation and operation of hippurate [126]. Obese humans have also been shown
conditions and is relatively insensitive [105]. New to have reduced urinary hippurate [127]. Furthermore,
advanced methodologies offer safer and more reliable lower urinary hippurate is linked to ulcerative colitis,
testing methods [115, 105]. particularly Crohn’s disease [128]. A Swedish study of
One of the pathways by which some bacteria break over 21 000 Crohn’s disease patients identified increased
down glyphosate is by first using carbon-phosphorus risk of a broad range of cancers, including liver, pancreatic,
lyase (C-P lyase) to produce sarcosine as an immediate lung, prostate, testicular, kidney, squamous cell skin
breakdown product [89, 116]. Nitrosylated sarcosine is well cancer, nonthyroid endocrine tumours and leukaemia
recognized as a carcinogenic agent. Injection of 225 mg/kg [129]. Crohn’s and inflammatory bowel disease have
of nitrososarcosine into mice at days 1, 4 and 7 of life led been increasing in incidence in the USA in step with the
to the development of metastasizing liver carcinomas in increase in glyphosate usage on corn and soy crops (R =
later life in 8 out of 14 exposed animals [117]. 0.938, P ≤ 7.1 × 10–8) [1].
Elevated levels of sarcosine are also linked to
prostate cancer, particularly metastatic prostate cancer 11. COLON AND LIVER CANCER
[118]. An unbiased metabolomic survey of prostate
As shown in Table 1, the incidence of liver cancer in the
cancer patients identified elevated levels of serum or
USA has increased substantially in the past two decades,
urinary sarcosine as a marker of aggressive disease
pari passu with the increase in glyphosate usage on corn
[119] (prostate cancer is the most commonly diagnosed
and soy crops (P ≤ 4.6) × 10–8.
cancer in men in the USA, and it afflicts one in nine men
Nonalcoholic steatohepatitis (NASH) is a fatty liver
over the age of 65 [120]). In both in vitro and in vivo
disease that has been linked to excess dietary fructose
prostate cancer models, exposure to sarcosine, but not
[130]. We hypothesize that it is due primarily to the
glycine or alanine, induced invasion and intravasation [119].
disruption in gut metabolism of fructose due to glyphosate
blocking the shikimate pathway, as discussed previously.
10. IMPAIRED GLYCINE SYNTHESIS
Fructose, which should have been processed in the gut
Perhaps surprisingly, a recent study has proposed that leading to production of aromatic amino acids, instead is
glyphosate might serve a useful rôle in cancer treatment delivered to the liver, which converts it into fat for either
due to its ability to inhibit glycine synthesis [121]. Glycine local storage or distribution within low-density lipid
is essential for the synthesis of DNA and, therefore, for particles (LDL). NASH affects a large proportion of the
cell proliferation. In vitro studies on 8 different cancer US population and is increasing in prevalence worldwide
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with adoption of a “Western diet” [131]. NASH causes endotoxin produced by gut microbes, such as lipopolysac-
cirrhosis and increases risk of liver cancer [131, 132]. charides (LPS) leads to inflammation in the liver along
Hepatocellular carcinoma (HCC) is the most common with hepatic fibrosis [138]. Several types of chronic liver
cause of obesity-related cancer deaths among middle-aged disease are associated with increased levels of bacterial
men in America. The consumption of refined carbohydrates LPS in the portal and/or systemic circulation [139].
in soft drinks has been postulated to be a key factor in the Acute hepatic porphyrias are disorders caused by
development of NASH [130]. As we have seen, soft enzyme defects in haem biosynthesis [140], and they are
drinks containing HFCS are very high in methylglyoxal. risk factors for liver cancer [141–143]. Glyphosate has
A study from 1988 on children with severe chronic been shown to disrupt haem synthesis, by suppressing the
liver disease revealed that those children with low vitamin enzyme that activates the first step, combining glycine
E levels were susceptible to H2O2-induced haemolytic with succinyl coenzyme A to form δ-aminolevulinic acid
anaemia [133]. We earlier discussed the rôle of glyphosate [144]. An often-overlooked component of glyphosate’s
in depleting vitamin E. Haemolysis leads to haemochroma- toxicity to plants is inhibition of chlorophyll synthesis
tosis (release of free iron from haem). The endocrine [145], as δ-aminolevulinic acid is also a precursor to
glands, heart, liver, testes and pancreas are all affected chlorophyll as well as haem.
by haemochromatosis. Damage to pancreatic islet β-cells γ-glutamyl transferase (GGT) is a membrane-bound
from iron deposition can lead to cellular death and enzyme that decomposes glutathione into cysteinyl
functional impairment associated with diabetes [134]. glycine and glutamate; it is highly expressed in the liver.
Other effects of haemochromatosis include bone and joint Excess serum GGT has been linked to both oxidative
pain, arthritis, cardiomyopathy and testicular problems. stress [146] and increased cancer risk [147] as well as
The liver synthesizes substantial amounts of haem, many other diseases [148]. In a study on 283 438 people
which is needed primarily for the cytochrome P450 who were divided into five subgroups based on GGT
(CYP) enzymes, which perform many important rôles, level, a hazard ratio of 18.5 for risk of hepatic carcinoma
including bile acid synthesis, hormone activation and was ascertained for the highest level compared to the
breakdown, and detoxifying many carcinogenic agents, lowest [149]. Another study based in Korea found an
including phenolic and other organic xenobiotics as well increased risk of multiple cancers in association with
as drugs and bilirubin. Glyphosate likely contributes to the elevated GGT: most especially liver cancer, but also
destruction of CYP enzymes both through H2O2 attack at cancer of the esophagus, larynx, stomach, bile ducts,
their haem centre as well as through direct interference lungs and colon [150]. GGT induces generation of
via nitrosylation at the active site by glyphosate [11]. reactive oxygen species through interactions of cysteinyl
CYP-mediated drug metabolism is impaired in patients glycine with free iron [151, 152].
with liver disease, particularly CYP1A, CYP2C19, and Exposure to Roundup at low doses increased GGT
CYP3A [135], and this makes these individuals even expression in rat testis and Sertoli cells [94]. A
more susceptible to liver damage. comparison between goats fed GM Roundup-Ready
Inflammation and metabolic disorders are intimately solvent-extracted soybean vs goats fed a conventional
linked, and both are characteristic features of diabetes soy equivalent revealed that the male kids born to the
and obesity [136]. Diabetes and obesity are linked to goats fed the GM soy had elevated expression of GGT in
dramatically higher risk of cancer, particularly of the liver both liver and kidney (P < 0.01) [153]. A study has shown
and gastrointestinal tract [137]. This is directly linked to that 70% of GM Roundup-ready soy samples had
bile acid dysregulation and dysbiosis of the gut significant levels of glyphosate, whereas the conventional
microbiome. Elevated levels of cytotoxic secondary bile soy did not [154].
acids and inflammation induced by an immune response to Exposure of Wistar rats to the herbicide Glyphosate-
gut pathogens induce heightened oxidative DNA damage, Biocarb over a period of 75 days resulted in liver damage,
increased cell proliferation and enterohepatic carcinogenesis including elevated serum alanine aminotransferase (ALT)
[137]. Temporal patterns of glyphosate use on corn and and aspartate aminotransferase (AST), suggesting
soy crops strongly correlate with the increase in both irreversible hepatocyte damage, as well as large deposition
diabetes and liver cancer observed over the same time of reticulin fibres containing collagen type III [155],
interval [1]. suggesting liver fibrosis [156], which is a major risk factor
Gut dysbiosis, due in part to glyphosate’s antimicrobial for hepatocarcinogenesis.
effects, leads to gut inflammation and impairment of the Excessive retinoic acid signalling in the liver is
gut barrier function. This means that pathogens will expected due to the interference of glyphosate with liver
escape the gut and infiltrate the liver. Exposure to CYP enzymes [11, 157, 158], because the CYP2C gene
JBPC Vol. 15 (2015)
136 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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family is needed to metabolize retinoic acid in the liver A two-year study of glyphosate toxicity to rats
[159]. The action of retinoic acid is likely mediated reported by the EPA in 1991 showed several signs of
through sonic hedgehog signalling [160]. Studies on mice tumours, which were ultimately dismissed partly because
have revealed that hedgehog signalling induces fibrosis of a lack of a dose–response relationship, and in part
and hepatocellular carcinoma [161]. Studies on tadpoles because it was argued that historical controls (but not the
have demonstrated that glyphosate produces teratogenic controls in the study) demonstrated tumours at comparable
effects characteristic of excessive retinoic acid signalling, rates, but under very different and uncontrolled dietary
and these effects were reversed by a retinoic acid and lifestyle practices [170]. The most frequently
antagonist [162]. observed tumours were pancreatic islet cell adenomas in
males, thyroid C-cell adenomas and/or carcinomas in
12. PANCREATIC CANCER males and females, and hepatocellular adenomas and
carcinomas in males. Both low-dose and high-dose, but
Pancreatic cancer is one of the cancers whose incidence
not mid-dose, males had a statistically significant
is going up in step with the increase in glyphosate usage
increased incidence of pancreatic islet cell adenomas.
on corn and soy crops (R = 0.918; P ≤ 4.6 × 10–7.) [1]. As
of 2002, pancreatic adenocarcinoma was the fourth
leading cause of cancer death in the USA, with an overall
5-year survival rate of less than 5% [163]. We have
already noted that excess methylglyoxal exposure can
lead to diabetes. Direct evidence of this was obtained
when methylglyoxal injection into Sprague Dawley rats
caused pancreatic β-cell dysfunction [164]. We earlier
discussed the rôle of excess iron deposition in the
destruction of pancreatic β cells [134].
Glyphosate’s metal chelation effects led to severe
manganese deficiency in cows [83]. Rats fed a diet Figure 2. Incidence of nephritis and kidney failure reports in the
deficient in manganese showed significantly lower US CDC’s hospital discharge data from 1998 to 2010 normalized
concentrations of manganese in liver, kidney, heart and to counts per million population each year. This includes all
pancreas compared to controls [165]. Pancreatic insulin reports of ICD-9 codes from 580 to 589.
content was reduced by 63%, and insulin output was
correspondingly reduced, suggesting that manganese 13. KIDNEY CANCER
deficiency may play a direct rôle in insulin-deficient Chronic kidney disease (CKD) and cancer are closely
diabetes and islet cell stress. linked in reciprocal fashion: cancer or its treatment can
Acinar cell carcinoma is the second most common cause CKD and patients with CKD have increased risk
type of pancreatic cancer, characterized histologically by of cancer. Dialysis patients have an increased risk
zymogen-like granules as well as fibrillary internal ranging from 10% to 80%; kidney transplant recipients
structures in the tumour cells [166]. A comparison have a 3- to 4-fold increased risk of cancer [6]. The
between mice fed GM soy and wild soy demonstrated number of patients with kidney failure treated by dialysis
alterations in pancreatic acinar cells including smaller and transplantation increased dramatically in the USA
zymogen granules and less zymogen content in one from 209 000 in 1991 to 472 000 in 2004 [171]. There
month-old mice, along with reduced production of α- have been concurrent increases in earlier stages of
amylase [167]. The authors did not consider possible chronic kidney disease such as albuminuria and impaired
effects of glyphosate contamination, even though another glomerular filtration [172]. Since 2004, this trend has
study has shown significant glyphosate residues in GM worsened. Figure 2 shows the trend over time in the US
soy as compared to conventional soy treated with Centers for Disease Control (CDC)’s hospital discharge
glyphosate [154]. Pancreatic atrophy of the acinar cells data4 for ICD-9 codes 580-589, including acute and
along with degranulation and intracellular fibrillation is a chronic glomerulonephritis, nephritis and nephropathy,
fundamental aspect of the childhood wasting disease acute and chronic renal failure, renal sclerosis, and
kwashiorkor [168], which is linked to disrupted gut disorders resulting from impaired renal function. There
microbes [169], and may also be in part attributable to has been an alarming rise in the frequency of these
glyphosate poisoning. conditions, especially since 2006.
4
ftp://ftp.cdc.gov/pub/Health Statistics/NCHS/Datasets/NHDS
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Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 137
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Studies on rats show that CYP 2B1 plays a pivotal unfolded protein response leading to overproduction of
rôle as an important site for ROS production through ROS. Overexpression of Keap1 protein causes proteasomal
cytotoxicity in the glomeruli [173]. The breakdown of the degradation of Nrf2, thus suppressing Nrf2-dependent
CYP haem protein through attack by H2O2 leads to the stress protection. As a consequence, the cellular redox
release of catalytic iron, which, in turn, generates more balance is altered toward lens oxidation and cataract
potent tissue-damaging oxidants such as the hydroxyl formation [179].
radical. Glyphosate’s induction of excess H2O2 as discussed There is a link between cholestasis and cataracts via
earlier would cause an increase in the bioavailability of poor absorption of nutrients that protect the lens from
catalytic free iron to work synergistically with H2O2 to UV damage. Studies on short-term exposure of catfish to
cause toxicity. sublethal levels of Roundup revealed toxicity to the gills,
Methylglyoxal and other glycating agents may be a liver and kidneys [181]. The observed elevated levels of
significant factor in the development of kidney disease. unconjugated bilirubin and alanine aminotransferase
Twelve weeks of administration through drinking water of (ALT) are indicative of cholestasis, likely in part a
methylglyoxal to Dahl salt-sensitive rats led to an increase consequence of impaired CYP enzyme function.
in systolic blood pressure and significantly increased Cholestasis impairs the absorption of fat-soluble vitamins
urinary albumin excretion, glomerular sclerosis, tubular and previtamins such as the carotenoids [182]. Lutein
injury, myocardial collagen content and cardiac perivascular and zeaxanthin are carotenoids that play an important rôle
fibrosis [174]. Renal markers of AGE production, in the lens and macular region of the retina to protect
oxidative stress and inflammation were all elevated. from oxidative damage due to sunlight exposure [183,
Acquired cystic kidney disease (ACKD) can lead to 184]. They are highly lipophilic and, therefore, like the
renal tumours, and the tumours often accumulate calcium fat-soluble vitamins, depend on adequate bile flow for
oxalate crystals [175]. These tumours are often gastrointestinal absorption. Cholestatic patients have
associated with distinctive morphological features, where greatly reduced serum levels of these nutrients [182].
the tumour cells have ill-defined cell membranes, Tryptophan is a product of the shikimate pathway
abundant granular eosinophilic cytoplasm, large nuclei that glyphosate suppresses. A tryptophan-free diet
and prominent nucleoli. In another study identifying induces cataracts in young Wistar rats, along with a
intratumoral calcium oxalate crystal deposition in two significant decrease in lens weight and water-soluble lens
cases of high-grade renal carcinomas, the authors protein [185]. Kynurenine is a breakdown product of
suggested a relationship between tumour growth and tryptophan, and it has been suggested that kynurenine
oxalate crystal deposition [176]. This suggests a rôle for and its glycoside derivatives in the ocular lens protect the
oxalic acid added to glyphosate-based formulations. retina from UV light by absorbing UV radiation [186].
An in vitro study on rat testis and Sertoli cells Kynurenine is present in excessive concentrations in
demonstrated that Roundup triggers calcium-mediated cataracts [186].
cell death associated with reductions in levels of the Melanoma is one of the types of cancer that have
antioxidant glutathione, along with thiobarbituric acid been linked to glyphosate exposure in agriculture. An
reactive species (TBARS) and protein carbonyls indicative age-adjusted analysis revealed an 80% increased risk of
of protein oxidation and glycation damage [94]. Adminis- melanoma associated with glyphosate use in a study on
tration of L-buthionine(S,R)-sulfoximine (BSO), a specific pesticide applicators in Iowa and North Carolina [187]. It
inhibitor of glutathione synthesis, to rats caused reduced is possible that impaired supply of the aromatic amino
glutathione levels in the kidneys and a marked increase in acids, tryptophan and tyrosine due to disruption of the
pathologies linked to polycystic kidney disease [177]. shikimate pathway in gut microbes plays a rôle in
increased risk to melanoma.
14. CATARACTS AND MELANOMA In vitro, exposure to 0.1 mM glyphosate induced
As we showed previously, Monsanto’s own studies hyperproliferation in human skin keratinocytes (HaCaT)
revealed increased risk of cataracts following exposure to cells, suggesting carcinogenic potential [188]. The
Roundup. Early-onset cataracts are associated with mechanism involves increased ROS expression and the
insufficient antioxidative activity and, therefore, are a emptying of intracellular calcium stores, which facilitates
potential risk of cancer, as verified in a recent nationwide basal cell or squamous cell carcinomas. Cells accumulated
study based in Taiwan [178]. in S-phase of the cell cycle, while mitochondrial apoptotic
Methylglyoxal is implicated in cataract development signalling pathways were downregulated.
[179, 180]. Methylglyoxal induces endoplasmic reticulum Melanin plays an important protective rôle in the skin
stress in human lens epithelial cells, and activates an against UV exposure, and dark-skinned races have
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138 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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significantly reduced risk of skin melanoma because of the tumour’s ability to deplete tryptophan and avoid
their naturally higher levels of melanin [189]. immune surveillance, but might also lead to accelerated
Melanosomes are tissue-specific organelles in pigment DNA damage within the tumour and increased risk of
cells that resemble lysosomes, in which melanin is metastasis [209].
synthesized and stored [190]. L-tyrosine is the precursor
to melanin synthesis, and the pathway involves the 15. THYROID CANCER
intermediary, L-dopa. Both L-tyrosine and L-dopa, when
The incidence of thyroid cancer in the United States has
supplied to cells with melanogenic potential, increase not
increased dramatically in the past two decades, in step
only the synthesis of melanin but also the formation of
with the increase in glyphosate usage on corn and soy
melanosomes within the cells [191].
crops (R = 0.988, P ≤ 7.6 × 10–9) [1]. It is not clear how
While blacks have protection against skin cancer
glyphosate might increase risk of thyroid cancer beyond
due to the high concentration of melanin in their skin, dark
the general factors already described previously in this
skin also appears to be a risk factor for autism. A study
paper, but it is possible that impaired selenium
based in Los Angeles showed that children born to black
incorporation into selenoproteins plays a rôle.
foreign-born women had a substantially increased risk for
Selenium is an important trace element involved in
low-functioning autism [192]. A similar observation has
the protection of cells from oxidative stress, and it is
been made in Sweden [193] and the UK [194]. One
particularly important for the thyroid. Low serum levels
possibility is that increased demand for melanin in the skin
of selenium are associated with increased risk of thyroid
depletes the supply of tyrosine for dopamine synthesis.
cancer, and probably play a rôle in carcinogenesis. All
Genetic mutations in dopamine transport proteins have
three of the deiodinases that convert thyroxine (T4) into
been linked to autism [195, 196]. The defect features a
triiodothyronine (T3) contain selenocysteine, as do
persistent reverse transport of dopamine (substrate efflux
glutathione peroxidase and thioredoxin reductase, which
from the synapse), which reduces the amount of time
are important antioxidant enzymes essential for
extracellular dopamine is available for signalling effects
protecting thyrocytes from oxidative damage [210].
[195]. Other genes of the dopaminergic network are also
The microbiome plays an important rôle in
linked to autism, including syntaxin [197] and enzymes
incorporating free selenium into selenoproteins, especially
involved in dopamine metabolism [198]. Hence, we
selenocysteine. Lactobacillus reuteri is a popular species
hypothesize that reduced bioavailability of tyrosine (due
in probiotics, shown to be effective against diarrhoea in
to disruption of the shikimate pathway in gut microbes)
children [211], and to inhibit the prooxidant cytokine TNF-α
for either dopamine synthesis or melanin synthesis leads
in humans [212]. This species has been found to be
to different outcomes (autism vs melanoma) depending
especially effective in its ability to produce selenocysteine,
on race-related skin colour.
and has been proposed to have therapeutic benefit in
Tryptophan is an essential amino acid for lymphocyte
cases of selenium deficiency [213]. Lactobacillus is
activation and proliferation, which promotes surveillance
especially vulnerable to glyphosate due to its crucial and
and elimination of tumour cells [199, 200]. Tryptophan is
unusual need for manganese as an antioxidant [214, 215],
also produced by gut microbes via the shikimate pathway
so it is plausible that diminished Lactobacillus representation
that glyphosate disrupts, suggesting that glyphosate exposure
in the gut could lead to an impaired supply of selenocysteine
to gut microbes could impair tryptophan bioavailability to the
for the thyroid.
human host. The enzyme indoleamine 2,3-dioxygenase
(IDO) catalyses the degradation of tryptophan to
16. BREAST CANCER
kynurenines. Tumours of the lung [201], colon [202],
liver [203], breast [204] and uvea [205], as well as skin Breast cancer accounts for one third of cancer diagnoses
melanoma [206], overexpress IDO, and it is believed that and 15% of cancer deaths in women in the United States.
this leads to an ability to evade immune surveillance by T- As mentioned previously, an in vitro study has confirmed
cells via depletion of tryptophan bioavailability in the that glyphosate stimulates proliferation of human breast
surrounding milieu [205]. It is interesting that IDO offers cancer cells when present in concentrations of parts per
significant protection from UV damage by producing trillion [9].1 This effect is specific to hormone-dependent
tryptophan-based filters that protect the cornea, lens and cell lines, and is mediated by the ability of glyphosate to
retina from UV-induced photo-oxidation [207, 208]. It act as an oestrogenic agent.
may well be that tumours exploit IDO for this purpose as One can obtain an estimate of the time trends in
well. Clearly, decreased bioavailability of tryptophan due breast cancer by looking at the CDC’s hospital discharge
to glyphosate’s effects on gut microbes would enhance data. The results show a steady decrease in breast cancer
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Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 139
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diagnoses up to 2006, followed by an increase from 2006 to A study on rats conducted by Séralini et al. [7]
2010 (the last year for which data are available). The divided the rats into four groups: (1) control, (2) GM maize
decrease can logically be explained by a growing without Roundup, (3) GM maize with Roundup, and (4)
awareness of the increased risk of breast cancer Roundup alone. The major tumours detected in the
associated with hormone replacement therapy (HRT). A female rats were mammary fibroadenomas and adenocarci-
Women’s Health Initiative (WHI) study, published in nomas. These authors summaraized their findings as:
2003, showed a 24% increase in invasive breast cancer “The Roundup treatment groups showed the greatest
risk associated with oestrogen/progestin therapy [216]. rates of tumour incidence, with 80% of animals affected
In direct response to this alarming report, HRT with up to 3 tumours for one female, in each group.” For
prescriptions in the United States decreased by 38% in the group that received Roundup in their drinking water,
2003. A large study on 1 642 824 women published in 2013, all but one of the females presented with mammary
based on the Breast Cancer Surveillance Consortium, hypertrophies and hyperplasias. The one exception suffered
revealed that HRT (commonly used to treat symptoms of from a metastatic ovarian carcinoma.
menopause) increased the risk of breast cancer by 20% Glyphosate may also indirectly increase risk of
in whites, Asians and hispanics, but not in blacks [217]. breast cancer by impairing metabolism of toxic phenolic
By forming separate records from the hospital compounds such as nonylphenols, diethylstilbestrol
discharge data for black and white women, it can be (DES), and Bisphenol A (BPA), all widely recognized to
confirmed that the breast cancer rates among blacks possess oestrogenic activity. Nonylphenols, also known
remained flat up to 2006, supporting the observation that as alkylphenols, are a family of organic compounds used
black women are not subject to increased risk from HRT. extensively as additives in laundry detergents, lubricating
This suggests that one can build a model to correct for the oils, paints, pesticides, personal care products and plastics,
influence of reduced use of HRT among white women in which are known to be xenoestrogenic [218]. DES is an
order to arrive at a time trend that might more closely oestrogenic compound linked to vaginal tumours in
capture any effects of glyphosate. A simple decaying women exposed in utero to this compound when it was
exponential model matches well for the Caucasian data mistakenly believed to be of therapeutic benefit. BPA,
from 1998 to 2006, and this model can be extended into commonly used in plastics production, is now widely
the time interval from 2006 to 2010, and then subtracted recognized as an endocrine disruptor. PCBs were widely
from the original plot, to yield a plot of the residual trends used as coolants and insulating fluids for transformers
for breast cancer. The resulting plot is shown in Fig. 3 and capacitors until their ban in 1979 by the US
alongside rates of glyphosate usage on corn and soy crops. government due to recognition of their toxicity due to
The correlation coefficient is 0.9375 (P-value ≤ 0.0001132). oestrogenic activity. However, they degrade very slowly,
and therefore are still environmental pollutants today.
Liver CYP enzymes play an important rôle in
metabolizing all of these xenoestrogenic compounds.
CYP1A1 is upregulated in response to PCB exposure,
and therefore it likely metabolizes these toxic phenols
[219]. High serum levels of PCBs in conjunction with at
least one (defective) exon 7 variant allele of CYP1A1
increased breast cancer risk [219]. CYP enzymes are
also involved with the metabolism of nonylphenols [220].
Similarly, BPA is mainly metabolized by the CYP2C
subfamily in the liver [221]. Thus, impaired CYP function
due to glyphosate exposure [11, 157, 158] can be
expected to interfere with metabolism of PCBs and
therefore increase their oestrogenic potential, leading
indirectly to increased risk of breast cancer.
Figure 3. Incidence of breast cancer in US hospital discharge data High dietary iron enhances the incidence of carcinogen-
from 1998 to 2010 normalized to counts per 1,000,000 population induced mammary cancer in rats and oestrogen-induced
each year, after subtraction of an exponential model accounting kidney tumours in hamsters [222]. Oestrogen facilitates
for the decline in the years up to 2006 in the Caucasian iron uptake by cells in culture. Elevated body iron storage
subpopulation [see text]. This includes all reports of ICD-9 codes
174 and 175. The red line shows trends in glyphosate usage on increases the risk of several cancers, including breast
corn and soy crops over the same time period. cancer in humans. Although it might be argued that
JBPC Vol. 15 (2015)
140 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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glyphosate’s chelating effects may protect from iron Bone marrow involvement is common in NHL and,
overload, glyphosate could increase the bioavailability of particularly for those of T-cell origin, it portends a poor
free iron due to its damaging effects on red blood cells prognosis [240]. An unpublished study by Monsanto in
[42, 223] working synergistically with its interference in 1983 confirmed that glyphosate administered by
haem synthesis [144], and by acting as an oestrogen intraperitoneal injection to rats reaches the bone marrow
mimetic to enhance iron uptake. Haem degradation by within 30 minutes [241]. In an experiment to assess
reactive oxygen species [224] will lead to the release of potential toxicity to bone marrow cells [242], a single
free iron, and we have previously discussed how intraperitoneal dose of glyphosate at concentrations of 25
glyphosate would induce oxidative stress. In fact, recent and 50 mg/kg was administered to Swiss albino mice.
evidence strongly suggests that GGT induces lipid Chromosal aberrations and micronuclei, analysed 24, 48,
peroxidation of red blood cell membranes leading to and 72 hours later, were shown to be significantly
haemolysis and the release of free iron from chelating increased compared to vehicle control (P < 0.05). Mitosis
agents [225]. This also results in impaired deformability rates were also decreased, indicating cytotoxic effects.
which impedes their passage through narrow capillaries. Multiple myeloma is the second most common
GGT was found to be enhanced up to 5.4-fold in the liver haematological malignancy in the USA after non-Hodgkin
in Séralini et al.’s long-term study of rats exposed to lymphoma; it constitutes 1% of all cancers [243]. In a
GMO’s plus Roundup [7]. prospective cohort study of 57 311 licensed pesticide
applicators in Iowa and North Carolina, a greater than
17. NON-HODGKIN’S LYMPHOMA twofold increased risk of multiple myeloma was associated
with ever-use of glyphosate [187].
Striking increases in the incidence of non-Hodgkin
Coeliac disease, along with the more general
lymphoma (NHL) cancer have occurred over the past
three decades, both in Europe [226] and America [227]. condition, gluten intolerance, has recently reached
Agricultural workers have a higher risk of NHL than the epidemic levels in the United States, and it has been
general population, but it is difficult to tease out the hypothesized that this heightened wheat sensitivity is a
effects of glyphosate compared to the myriad other toxic direct consequence of glyphosate contamination of the
chaemicals they are exposed to, which also confer wheat, due to the increasingly common practice of wheat
increased risk [228]. However, some studies have been desiccation with glyphosate just before harvest [158].
able to directly link glyphosate to NHL. A threefold Coeliac disease patients are at increased risk of cancer,
increased risk of NHL in association with glyphosate particularly non-Hodgkin lymphoma, and they have
exposure was found in a 2002 study from Sweden [229]. A statistically a shortened lifespan mainly due to this
later Swedish study in 2008 of over 900 cancer cases also increased cancer risk.
found a significant increased risk of NHL (OR 2.02) For coeliac disease patients, serum prolactin (PRL)
[230]. A Canadian study demonstrated a correlation levels are high in association with an unrestricted gluten-
between the number of days per year of glyphosate containing diet, and PRL has been proposed as a useful
exposure and the risk of NHL [231]. marker for coeliac disease [244]. PRL is an important
Increased exposure to superoxide is implicated as a regulatory hormone released by the pituitary gland, which
causal agent in oncogenesis [232], and manganese SOD is best known for inducing lactation. Bisphenol A, a well-
(Mn-SOD) is an important antioxidant defence agent in established oestrogenic agent, has been shown to lead to
mitochondria [233]. Mice engineered to be defective in hyperprolactinaemia and growth of prolactin-producing
Mn-SOD had increased DNA damage and higher cancer pituitary cells [245]. Prolonged exposure to Bisphenol A
incidence [234]. We mentioned earlier that Mn-SOD is during childhood may contribute to the growth of a
protective against pancreatic cancer. Mn-SOD expression prolactinoma, the most common form of cancer of the
was also found to be anomalously low in erythrocytes of pituitary. Oestrogen treatment of ovariectomized rats
patients suffering from NHL [235]. In vitro studies have induced a marked elevation of serum PRL levels [246],
shown that an Mn-SOD mimetic had an anti-proliferation and this was found to be due to oestrogen’s ability to
effect on human NHL Raji cells [236]. Glyphosate’s chelating reduce the capacity of PRL cells to incorporate dopamine
effects on manganese can be expected to interfere with into their secretory granules. Since glyphosate has been
Mn-SOD function [82]. Increased Mn-SOD expression confirmed to be oestrogenic, it is plausible that glyphosate
potentiates apoptosis of tumour cells exposed to contamination in wheat is the true source of the observed
dexamethasone [237]. Cationic manganese porphyrins, elevation of PRL in association with gluten ingestion
probably by acting as Mn-SOD mimetics, have also been among coeliac patients.
found to play a protective rôle in treating NHL [238, 239].
JBPC Vol. 15 (2015)
Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 141
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18. CONCLUSION soy crops. While these strong correlations cannot prove
causality, the biological evidence is strong to support
In this paper, we have reviewed the research literature on
mechanisms that are likely in play, which can explain the
glyphosate and on the biological processes associated
observed correlations through plausible scientific arguments.
with cancer, and we have provided strong evidence that
Glyphosate’s links to specific cancer types can often
glyphosate is likely contributing to the increased prevalence
be explained through specific pathologies. For example,
of multiple types of cancer in humans. Monsanto’s own
succinate dehydrogenase deficiency is linked to adrenal
early studies revealed some trends in animal models that
cancer [17]. Selenoprotein deficiency is likely contributory
should not have been ignored. Forty years of glyphosate
towards thyroid cancer. Glyphosate’s action as an
exposure have provided a living laboratory where humans
oestrogen mimetic explains increased breast cancer risk.
are the guinea pigs and the outcomes are alarmingly
Prostate cancer is linked to sarcosine, a by-product of
apparent.
glyphosate breakdown by gut microbes. Impaired
We have shown that glyphosate transforms exposed
fructose metabolism links to fatty liver disease, which is a
cells into a tumour-provoking state by suppressing crucial
risk factor for hepatic tumorigenesis. Impaired melanin
enzymes in the electron transport chain, such as succinate
synthesis by melanocytes due to deficiencies in the
dehydrogenase and fumarate hydratase. Glyphosate
precursor, tyrosine, a product of the shikimate pathway,
chelates manganese, reducing its bioavailability, and
can explain increased incidence of skin melanoma. This
manganese is an important catalyst for Mn-SOD, which
is compounded by tryptophan deficiency, as tryptophan is
protects mitochondria from oxidative damage, which can
also protective against UV exposure.
cause mutations in DNA. Glyphosate also causes impaired
Manganese deficiency stresses the pancreas and
metabolism of fructose, due to the accumulation of PEP
impairs insulin synthesis, and this could explain the recent
following blockage of the shikimate pathway. This leads
epidemic in pancreatic cancer. Increased oxalate, due in
to the synthesis of multiple short-chain sugars that are
part to the proprietary formulations, stresses the kidney
known to be highly potent glycating agents, such as
and contributes to risk of renal tumours. Glyphosate’s
methylglyoxal and glyoxalate. Glyphosate is readily
accumulation in bone marrow can be expected to disrupt
nitrosylated, and nitrosyl glyphosate is known to be
the maturation process of lymphocytes from stem cell
extremely toxic and carcinogenic. Microbial pathways
precursors. Glycine forms conjugates with organic benzene-
convert glyphosate into sarcosine, a known marker for
derived carcinogenic agents, and glyphosate likely
prostate cancer, likely due to its nitrosylated form.
interferes with this process. Glyphosate’s interference
An often overlooked aspect of glyphosate’s toxicity
with CYP enzyme function impairs detoxification of
is its interference with enzymes that have glycine as
multiple other carcinogenic agents, increasing their
substrate, due to mimicry. Phenolic compounds are
carcinogenic potential. Overall, the evidence of the carcino-
detoxified by gut microbes through glycine conjugation to
genicity of glyphosate is compelling and multifactorial.
produce products such as hippurate. Bifidobacteria are
important for the rôle they play in protecting from these APPENDIX: NEOPLASTIC INCIDENCE DATA FROM
xenobiotics through such conjugation. Reduced hippurate MONSANTO
is linked to Crohn’s diseases and inflammatory bowel
disease, which show epidemiological trends that match Two-Year Animal Studies
the increased use of glyphosate on core crops, and which In this section we present selected tables tabulating
are linked to increased risk of a broad range of cancers, tumours and malignancies, separately for male and female
most especially non-Hodgkin lymphoma. Lymphoma has rats, in the long-term study conducted by Lankas & Hogan
also been linked to glyphosate through studies of and reported on in an unpublished document in 1981 [17].
environmental exposure in agricultural settings. The rats were exposed to three different doses of
Multiple studies, both in vitro and in vivo, have shown glyphosate added to their feed (3, 10, and 30 mg kg–1 day–1)
that glyphosate damages DNA, a direct step towards and compared with unexposed controls.
tumorigenicity. These studies have been conducted on Similarly, we present tables tabulating all of the
sea urchins, fish, mice and various human cell types in tumours and malignancies that were found, separately for
vitro. Children in Malaysia living near rice paddies have male and female mice, in the long-term study conducted
evidence of DNA damage. by Knezevich & Hogan and reported on in an
Epidemiological studies strongly support links unpublished document in 1983 [18]. The mice were
between glyphosate and multiple cancers, with extremely exposed to three different doses of glyphosate added to
well matched upward trends in multiple forms of cancer their feed (1000, 5000 and 30 000 ppm) and compared
in step with the increased use of glyphosate on corn and with unexposed controls.
JBPC Vol. 15 (2015)
142 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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Table A1. Incidence of neoplastic findings in male rats with glyphosate administered by diet. Part I. Data extracted
from Lankas & Hogan (1981) [17].
–1 –1
Glyphosate /mg kg day 0 3 10 30
PITUITARY
Adenoma 16/48 (33%) 19/49 (38%) 20/48 (40%) 18/47 (36%)
Carcinoma 3/48 (6%) 2/49 (4%) 3/48 (6%) 1/47 (2%)
BRAIN
Glioma 1/49 (2%) 3/50 (6%) 0/50 (0%) 1/50 (2%)
HEART
Reticulum cell sarcoma 0/49 (0%) 0/49 (0%) 1/50 (2%) 0/50 (0%)
LUNG
Sarcoma 0/50 (0%) 0/50 (0%) 0/50 (0%) 0/50 (2%) 1/50 (2%)
Reticulum cell sarcoma 1/50 (2%) 1/50 (2%) 1/50 (2%) 1/50 (2%)
MSa Malignant mixed tumour 0/50 (0%) 1/50 (2%) 0/50 (0%) 0/50 (0%)
MANDIBULAR SALIVARY GLAND
Reticulum cell sarcoma 0/49 (0%) 0/49 (0%) 1/49 (2%) 0/49 (0%)
MEDIASTINAL LYMPH NODE
MSa Fibrosarcoma 0/39 (0%) 0/39 (0%) 1/32 (3%) 0/35 (0%)
Reticulum cell sarcoma 1/39 (3%) 0/39 (0%) 1/32 (3%) 0/35 (0%)
SPLEEN
Reticulum cell sarcoma 0/50 (0%) 0/50 (0%) 2/50 (4%) 1/50 (2%)
STOMACH
Squamous cell carcinoma, 0/50 (0%) 0/49 (0%) 0/48 (0%) 1/49 (2%)
Cardia
JEJUNUM
Reticulum cell sarcoma 0/49 (0%) 0/46 (0%) 1/48 (2%) 0/49 (0%)
KIDNEY
Tubular adenoma 1/50 (2%) 1/50 (2%) 0/50 (0%) 0/50 (0%)
Reticulum cell sarcoma 1/50 (2%) 1/50 (2%) 1/50 (2%) 0/50 (0%)
Lipoma 1/50 (2%) 1/50 (2%) 1/50 (2%) 0/50 (0%)
TESTES
Interstitial cell tumour 0/50 (0%) 3/50 (6%) 1/50 (2%) 6/50 (12%)
a
MS = metastatic.
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Table A2. Incidence of neoplastic findings in male rats with glyphosate administered by diet. Part II.
Data extracted from Lankas & Hogan (1981) [17].
–1 –1
Glyphosate /mg kg day 0 3 10 30
PROSTATE
Reticulum cell sarcoma 0/50 (0%) 0/47 (0%) 1/49 (2%) 0/49 (0%)
URINARY BLADDER
Papilloma 0/46 (0%) 1/45 (2%) 0/43 (0%) 0/46 (0%)
THYROID
C-cell carcinoma 0/47 (0%) 0/49 (0%) 1/49 (2%) 0/49 (0%)
Follicular adenoma 1/47 (2%) 2/49 (4%) 4/49 (8%) 4/49 (8%)
PARATHYROID
Adenoma 0/27 (0%) 2/30 (4%) 0/28 (0%) 0/27 (0%)
ADRENAL
Reticulum cell sarcoma 0/50 (0%) 0/50 (0%) 1/50 (2%) 0/50 (0%)
Pheochromo-cytoma 8/50 (16%) 8/50 (16%) 5/50 (10%) 11/50 (22%)
Cortical adenoma 2/50 (4%) 4/50 (8%) 1/50 (2%) 1/50 (2%)
SKIN
Basosquamous cell tumour 0/49 (0%) 0/48 (0%) 0/49 (0%) 1/49 (2%)
Sebaceous gland adenoma 0/49 (0%) 0/48 (0%) 0/49 (0%) 1/49 (2%)
PERIOCULAR TISSUE
Squamous cell carcinoma 0/0 (0%) 0/0 (0%) 1/1 (100%) 0/0 (0%)
SUBCUTANEOUS TISSUE
Fibrosarcoma 2/10 (20%) 1/12 (8%) 2/10 (20%) 3/7 (43%)
Fibroma 0/10 (0%) 3/12 (24%) 1/10 (10%) 2/7 (29%)
Neuro brosarcoma 0/10 (0%) 0/12 (0%) 0/10 (0%) 1/7 (14%)
Lipoma 1/10 (10%) 2/12 (17%) 0/10 (0%) 0/7 (0%)
Osteogenic sarcoma 0/10 (0%) 0/12 (0%) 1/10 (10%) 0/7 (0%)
Malignant mixed tumour 0/10 (0%) 1/12 (8%) 0/10 (0%) 0/7 (0%)
MEDIASTINAL TISSUE
Reticulum cell sarcoma 0/7 (0%) 0/1 (0%) 0/4 (0%) 1/2 (50%)
ABDOMEN
Lipoma 0/0 (0%) 0/0 (0%) 0/0 (0%) 1/1 (100%)
ABDOMINAL CAVITY
Reticulum cell sarcoma 0/0 (0%) 0/0 (0%) 1/1(100%) 0/0 (0%)
LUMBAR LYMPH NODE
MS a Islet cell carcinoma 0/0 (0%) 0/0 (0%) 0/0 (0%) 1/1 (100%)
SACRAL LYMPH NODE
Reticulum cell sarcoma 0/1 (0%) 1/3 (33%) 0/3 (0%) 0/3 (0%)
a
MS = metastatic.
JBPC Vol. 15 (2015)
144 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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Table A3. Incidence of neoplastic findings in female rats with glyphosate administered by diet. Part I.
Data extracted from Lankas & Hogan (1981) [17].
–1 –1
Glyphosate /mg kg day 0 3 10 30
PITUITARY
Carcinoma 8/48 (17%) 7/48 (15%) 5/50 (10%) 12/49 (24%)
BRAIN
Invasive pituitary carcinoma 0/50 (0%) 0/49 (0%) 1/50 (2%) 1/50 (2%)
Malignant lymphoma 0/50 (0%) 0/49 (0%) 0/50 (0%) 1/50 (2%)
Glioma 0/50 (0%) 0/49 (0%) 0/50 (0%) 1/50 (2%)
CERVICAL SPINAL CORD
Malignant lymphoma 0/50 (0%) 0/50 (0%) 0/50 (0%) 1/50 (2%)
HEART
Malignant lymphoma 0/50 (0%) 0/50 (0%) 0/50 (0%) 1/50 (2%)
LUNG
Reticulum cell sarcoma 2/49 (4%) 2/50 (4%) 1/49 (2%) 3/50 (6%)
Malignant lymphoma 0/49 (0%) 1/50 (2%) 0/49 (0%) 1/50 (2%)
Adenocarcinoma 0/49 (0%) 0/50 (0%) 0/49 (0%) 1/50 (2%)
Carcinoma 0/49 (0%) 0/50 (0%) 1/49 (2%) 0/50 (0%)
LIVER
Reticulum cell sarcoma 2/50 (4%) 2/50 (4%) 1/50 (2%) 2/50 (4%)
Malignant lymphoma 0/50 (0%) 0/50 (0%) 1/50 (2%) 2/50 (4%)
Hepatocellular carcinoma 1/50 (2%) 0/50 (0%) 0/50 (0%) 2/50 (4%)
MESENTERIC LYMPH NODE
Malignant lymphoma 0/42 (0%) 0/39 (0%) 0/48 (0%) 1/47 (2%)
Reticulum cell sarcoma 0/42 (0%) 0/39 (0%) 0/48 (0%) 2/47 (4%)
PANCREAS
Islet cell carcinoma 0/50 (0%) 1/50 (2%) 1/50 (2%) 1/49 (2%)
MANDIBULAR SALIVARY GLAND
Metastatic fibrosarcoma 0/48 (0%) 0/50 (0%) 1/49 (2%) 0/49 (0%)
THYMUS
Malignant lymphoma 0/25 (0%) 0/32 (0%) 1/37 (3%) 1/34 (3%)
Thymoma 0/25 (0%) 0/32 (0%) 1/37 (3%) 0/34 (0%)
MEDIASTINAL LYMPH NODE
Reticulum cell sarcoma 0/33 (0%) 1/29 (3%) 0/37 (0%) 0/30 (0%)
Malignant lymphoma 0/33 (0%) 0/29 (0%) 1/37 (3%) 2/30 (7%)
SPLEEN
Malignant lymphoma 0/50 (0%) 0/50 (0%) 1/50 (2%) 2/50 (4%)
Reticulum cell sarcoma 2/50 (4%) 2/50 (4%) 1/50 (2%) 5/50 (10%)
STOMACH
Malignant lymphoma 0/50 (0%) 0/50 (0%) 0/50 (0%) 1/50 (2%)
JEJUNUM
Leiomyosarcoma 0/50 (0%) 1/48 (2%) 0/49 (0%) 0/49 (0%)
ILEUM
Reticulum cell sarcoma 0/47 (0%) 0/49 (0%) 0/49 (0%) 1/48 (2%)
COLON
Reticulum cell sarcoma 0/50 (0%) 0/50 (0%) 0/49 (0%) 1/48 (2%)
URINARY BLADDER
Transitional cell tumour 0/50 (0%) 0/48 (0%) 0/48 (0%) 1/44 (2%)
JBPC Vol. 15 (2015)
Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 145
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Table A4. Incidence of neoplastic findings in female rats with glyphosate administered by diet. Part II.
Data extracted from Lankas & Hogan (1981) [17].
–1 –1
Glyphosate /mg kg day 0 3 10 30
OVARY
Granulosa cell tumour 8/49 (16%) 8/50 (16%) 6/48 (13%) 6/45 (13%)
Theca-granulosa cell tumour 0/49 (0%) 0/50 (0%) 0/48 (0%) 1/45 (2%)
UTERUS
Squamous cell carcinoma 0/50 (0%) 0/50 (0%) 0/49 (0%) 1/49 (2%)
Endometrial sarcoma 0/50 (0%) 0/50 (0%) 0/49 (0%) 1/49 (2%)
Adenoma 0/50 (0%) 0/50 (0%) 2/49 (4%) 1/49 (2%)
THYROID
C-cell adenoma 5/47 (10%) 3/49 (6%) 6/50 (12%) 3/47 (6%)
C-cell carcinoma 1/47 (2%) 0/49 (0%) 2/50 (4%) 6/47 (12%)
Metastatic fibrosarcoma 0/47 (0%) 0/49 (0%) 1/50 (2%) 0/47 (0%)
PARATHYROID
Adenoma 0/23 (0%) 0/25 (0%) 0/25 (0%) 1/23 (4%)
ADRENAL
Reticulum cell sarcoma 1/50 (2%) 1/50 (2%) 1/50 (2%) 3/49 (6%)
Pheochromo-cytoma 1/50 (2%) 2/50 (4%) 2/50 (4%) 2/49 (4%)
Cortical adenoma 5/50 (10%) 10/50 (20%) 6/50 (12%) 4/49 (8%)
Malignant lymphoma 0/50 (0%) 0/50 (0%) 0/50 (0%) 1/49 (2%)
MAMMARY GLAND (L&R)
Adenoma (L) 4(47) (8%) 7(46) (15%) 10(48) (20%) 5(44) (11%)
Adenoma (R) 4(47) (8%) 7(46) (15%) 8(48) (16%) 5(44) (11%)
Fibroadenoama (L) 33/47) (66%) 28(46) (61%) 27(48) (56%) 22(44) (50%)
Fibroadenoama (R) 24(47) (48%) 16(46) (35%) 20(48) (41%) 16/44 (36%)
EYE
Periocular fibrosarcoma 0/49 (0%) 0/48 (0%) 1/50 (2%) 0/47 (0%)
HARDERIAN GLAND
Malignant lymphoma 0/47 (0%) 0/45 (0%) 0/47 (0%) 1/44 (2%)
Invasive fibrosarcoma 0/47 (0%) 0/45 (0%) 1/47 (2%) 0/44 (0%
BONE MARROW
Malignant lymphoma 0/46 (0%) 0/44 (0%) 1/46 (2%) 1/45 (2%)
Reticulum cell sarcoma 1/46 (2%) 0/44 (0%) 1/46 (2%) 3/45 (6%)
SUBCUTANEOUS TISSUE
Lipoma 0/4 (0%) 0/6 (0%) 0/1 (0%) 2/2 (100%)
Reticulum cell sarcoma 0/4 (0%) 2/6 (33%) 0/1 (0%) 0/2 (0%)
MEDIASTINAL TISSUE
Reticulum cell sarcoma 0/2 (0%) 1/1 (100%) 0/2 (0%) 0/2 (0%)
MESENTERY
Reticulum cell sarcoma 0/5 (0%) 0/5 (0%) 0/2 (0%) 2/7 (29%)
MANDIBULAR LYMPH NODE
Malignant lymphoma 0/2 (0%) 0/3 (0%) 0/6 (0%) 1/6 (17%)
URETER
Transitional cell carcinoma 0/0 (0%) 0/0 (0%) 1/1 (100%) 1/1 (100%)
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146 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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Table A5. Incidence of neoplastic findings in male mice with glyphosate administered by diet. Part I. From Knezevich
& Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.
Glyphosate (ppm) 0 Low (1000) Mid (5000) High (30 000)
BRAIN
MS Lymphoblastic lymphosarcoma 0/49 (0%) 0/50 (0%) 1/50 (2%) 0/50 (0%)
with leukaemic manifestations
HEART
MS Lymphoblastic lymphosarcoma 0/47 (0%) 1/49 (2%) 2/49 (4%) 1/50 (2%)
with leukaemic manifestations
LUNGS
BN Bronchiolar-alveolar adenoma 5/48 (10%) 9/50 (18%) 9/50 (18%) 9/50 (18%)
MG Bronchiolar-alveolar 4/48 (8%) 3/50 (6%) 2/50 (4%) 1/50 (2%)
adeno-carcinoma
MS Lymphoblastic lymphosarcoma 1/48 (2%) 4/50 (8%) 3/50 (6%) 1/50 (2%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/48 (0%) 1/50 (2%) 0/50 (0%) 0/50 (0%)
LIVER
MG Hepatocellular adenocarcinoma 5/49 (10%) 6/50 (12%) 6/50 (12%) 4/50 (8%)
BN Hepatocellular adenoma 0/49 (0%) 0/50 (0%) 1/50 (2%) 0/50 (0%)
MG Hepatocellular carcinoma 0/49 (0%) 0/50 (0%) 0/50 (0%) 2/50 (4%)
MS Histiocytic sarcoma 0/49 (0%) 1/50 (2%) 0/50 (0%) 0/50 (0%)
MS Liposarcoma 0/49 (0%) 0/50 (0%) 1/50 (2%) 1/50 (2%)
MS Lymphoblastic lymphosarcoma 1/49 (2%) 4/50 (8%) 2/50 (4%) 2/50 (4%)
with leukaemic manifestations
MESENTERIC LYMPH NODES
MG Histiocytic Sarcoma 0/40 (0%) 1/50 (2%) 0/46 (0%) 0/49 (0%)
with leukaemic manifestations
MG Lymphoblastic lymphosarcoma 1/40 (2%) 2/50 (4%) 1/46 (2%) 0/49 (0%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/40 (0%) 0/50 (0%) 1/46 (2%) 2/49 (4%)
with leukaemic manifestations
MG Lymphoblastic lymphosarcoma 0/40 (0%) 1/50 (2%) 0/46 (0%) 0/49 (0%)
MEDIASTINAL LYMPH NODES
MS Histiocytic sarcoma 0/45 (0%) 1/49 (2%) 0/41 (0%) 0/49 (0%)
MS Lymphoblastic lymphosarcoma 1/45 (2%) 2/49 (4%) 1/41 (2%) 2/49 (4%)
with leukaemic manifestations
MG Lymphoblastic lymphosarcoma 0/45 (0%) 0/49 (0%) 2/41 (5%) 0/49 (0%)
with leukaemic manifestations
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Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 147
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Table A6. Incidence of neoplastic findings in male mice with glyphosate administered by diet. Part II. From
Knezevich & Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.
Glyphosate (ppm) 0 Low (1000) Mid (5000) High (30 000)
SPLEEN
MG Hemangio-endothelioma 0/48 (0%) 0/49 (0%) 1/50 (2%) 0/49 (0%)
MS Histiocytic sarcoma 0/48 (0%) 1/49 (2%) 0/50 (0%) 0/49 (0%)
MS Lymphoblastic lymphosarcoma 1/48 (2%) 2/49 (4%) 2/50 (4%) 0/49 (0%)
MG Lymphoblastic lymphosarcoma 0/48 (0%) 2/49 (4%) 0/50 (0%) 1/49 (2%)
with leukaemic manifestations
PANCREAS
MS Histiocytic Sarcoma 0/48 (0%) 1/48 (2%) 0/50 (0%) 0/49 (0%)
MS Lymphoblastic lymphosarcoma 0/48 (0%) 0/48 (0%) 1/49 (2%) 0/50 (0%)
with leukaemic manifestations
KIDNEYS
BN Renal tubule adenoma 0/49 (0%) 0/49 (0%) 1/50 (2%) 3/50 (6%)
MS Histiocytic sarcoma 0/49 (0%) 1/49 (2%) 0/50 (0%) 0/50 (0%)
MS Composite lymphosarcoma 1/49 (2%) 0/49 (0%) 0/50 (0%) 0/50 (0%)
MS Lymphoblastic lymphosarcoma 1/49 (2%) 3/49 (6%) 2/50 (4%) 2/50 (4%)
with leukaemic manifestations
ADRENAL GLANDS
BN Cortical adenoma 1/48 (2%) 2/49 (4%) 0/50 (0%) 1/48 (2%)
MS Lymphoblastic lymphosarcoma 0/48 (0%) 1/49 (2%) 0/50 (0%) 0/48 (0%)
with leukaemic manifestations
BN Lymphoblastic lymphosarcoma 0/48 (0%) 0/49 (0%) 1/49 (2%) 0/48 (0%)
with leukaemic manifestations
HARDERGIAN GLAND
BN Adenoma 1/47 (2%) 0/48 (0%) 0/45 (0%) 0/48 (0%)
MG Liposarcoma 0/47 (0%) 0/48 (0%) 1/45 (2%) 0/48 (0%)
BONE MARROW
MS Lymphoblastic lymphosarcoma 1/40 (2%) 2/45 (4%) 1/47 (2%) 1/49 (2%)
with leukaemic manifestations
LYMPH NODE
MS Histiocytic sarcoma 0/0 (0%) 1/3 (33%) 0/2 (0%) 0/2 (0%)
MS Composite lymphosarcoma 0/0 (0%) 0/3 (0%) 1/2 (50%) 0/2 (0%)
MS Lymphoblastic lymphosarcoma 0/0 (0%) 1/3 (33%) 1/2 (50%) 0/2 (0%)
with leukaemic manifestations
MG Lymphoblastic lymphosarcoma 0/0 (0%) 0/3 (0%) 0/2 (0%) 1/2 (50%)
with leukaemic manifestations
TESTES
BN Interstitial cell tumor 1/49 (2%) 0/48 (0%) 2/50 (4%) 0/50 (0%)
MS Lymphoblastic lymphosarcoma 0/49 (0%) 1/48 (2%) 0/50 (0%) 0/50 (0%)
with leukaemic manifestations
BN Lymphoblastic lymphosarcoma 0/49 (0%) 0/48 (0%) 1/50 (2%) 0/50 (0%)
with leukaemic manifestations
JBPC Vol. 15 (2015)
148 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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Table A7. Incidence of neoplastic findings in female mice with glyphosate administered by diet. Part I. From Knezevich
& Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.
C ontrols Low Mid High
Glyphosate (ppm) 0 Low (1000) Mid (5000) High (30 000)
BRAIN
MS Lymphoblastic lymphosarcoma 0/50 (0%) 0/49 (0%) 1/50 (2%) 0/50 (0%)
with leukaemic manifestations
HEART
MS Lymphoblastic lymphosarcoma 0/50 (0%) 0/50 (0%) 2/50 (4%) 0/49(0%)
with leukaemic manifestations
LUNGS
BN Bronchiolar-alveolar adenoma 10/49 (20%) 9/50 (18%) 10/49 (20%) 1/50 (2%)
MG Bronchiolar-alveolar adenocarcinoma 1/49 (2%) 3/50 (6%) 4/49 (8%) 4/50 (8%)
BN Granulosa cell tumour 0/49 (0%) 1/50 (2%) 0/49 (0%) 0/50 (0%)
MS Lymphoblastic lymphosarcoma 1/49 (2%) 2/50 (4%) 5/49 (10%) 1/50 (2%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/50 (0%) 0/50 (0%) 0/49 (0%) 1/50 (2%)
LIVER
MG Hepatocellular adenocarcinoma 1/49 (2%) 2/50 (4%) 1/49 (2%) 0/49 (0%)
BN Hepatocellular adenoma 0/49 (0%) 1/50 (2%) 0/49 (0%) 0/49 (0%)
MS Leiomyosarcoma 0/49 (0%) 1/50 (2%) 0/49 (0%) 0/49 (0%)
MS Granulocytic leukaemia 0/49 (0%) 3/50 (6%) 0/49 (0%) 0/49 (0%)
MG Hemangioendiothelioma 0/49 (0%) 0/50 (0%) 2/49 (4%) 0/49 (0%)
MS Composite lymphosarcoma 2/49 (4%) 1/50 (2%) 0/49 (0%) 4/49 (8%)
MS Lymphoblastic lymphosarcoma 1/49 (2%) 4/50 (8%) 4/49 (8%) 1/49 (2%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/49 (0%) 0/50 (0%) 0/49 (0%) 2/49 (4%)
MESENTERIC LYMPH NODES
MS Leimyosarcoma 0/49 (0%) 1/49 (2%) 0/48 (0%) 0/48 (0%)
MS Granulocytic leukaemia 0/49 (0%) 1/49 (2%) 0/48 (0%) 0/48 (0%)
MG Lymphoblastic lymphosarcoma 0/49 (0%) 3/49 (6%) 1/48 (2%) 1/48 (2%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 1/49 (2%) 1/49 (2%) 3/48 (6%) 0/48 (0%)
with leukaemic manifestations
MS Composite lymphosarcoma 1/49 (2%) 1/49 (2%) 1/48 (2%) 3/48 (6%)
MG Lymphoblastic lymphosarcoma 0/49 (0%) 0/48 (0%) 0/48 (0%) 2/48 (4%)
MS Lymphoblastic lymphosarcoma 0/49 (0%) 0/49 (0%) 0/49 (0%) 1/49 (2%)
MS Haemangioendothelioma 0/49 (0%) 0/49 (0%) 0/49 (0%) 1/49 (2%)
JBPC Vol. 15 (2015)
Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 149
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Table A8. Incidence of neoplastic findings in female mice with glyphosate administered by diet. Part II. From
Knezevich & Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.
Controls Low Mid High
Glyphosate (ppm) 0 Low (1000) Mid (5000) High (30 000)
MEDIASTINAL LYMPH NODES
MS Leimyosarcoma 0/42 (0%) 1/48 (2%) 0/39 (0%) 0/47 (0%)
MS Granulocytic leukaemia 0/42 (0%) 1/48 (2%) 0/39 (0%) 0/47 (0%)
MS Liposarcoma 1/42 (2%) 0/48 (0%) 0/39 (0%) 0/47 (0%)
MS Composite lymphosarcoma 1/42 (2%) 1/48 (2%) 0/39 (0%) 2/47 (4%)
MS Lymphoblastic lymphosarcoma 0/42 (0%) 1/48 (2%) 3/39 (8%) 0/47 (0%)
with leukaemic manifestations
MG Lymphoblastic lymphosarcoma 1/42 (2%) 1/48 (2%) 2/39 (5%) 0/47 (0%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/42 (0%) 1/48 (2%) 0/39 (0%) 1/47 (2%)
SALIVARY GLAND
MS Leiomyosarcoma 0/50 (0%) 0/50 (0%) 1/50 (2%) 0/47 (0%)
SPLEEN
MG Hemangio-endothelioma 1/50 (2%) 0/48 (0%) 2/49 (4%) 1/49 (2%)
MG Granulocytic leukemia 0/50 (0%) 3/48 (6%) 0/49 (0%) 0/49 (0%)
MS Hemangio-endiothelioma 0/50 (0%) 0/48 (0%) 0/49 (0%) 1/49 (2%)
MS Lymphoblastic lymphosarcoma 1/50 (2%) 2/48 (4%) 2/49 (4%) 0/49 (0%)
with leukaemic manifestations
MG Lymphoblastic lymphosarcoma 0/50 (0%) 0/48 (0%) 2/49 (4%) 0/49 (0%)
with leukaemic manifestations
MG Composite lymphosarcoma 1/50 (2%) 1/48 (2%) 1/49 (2%) 5/49 10%)
MS Lymphoblastic lymphosarcoma 0/50 (0%) 0/48 (0%) 0/49 (0%) 1/49 (2%)
STOMACH
MG Leiomyosarcoma 0/48 (0%) 0/49 (0%) 1/50 (2%) 0/50 (0%)
MG Gastric adenosarcoma 0/48 (0%) 0/49 (0%) 1/50 (2%) 0/50 (0%)
PANCREAS
MS Granulocytic leukaemia 0/47 (0%) 1/47 (2%) 0/49 (0%) 0/50 (0%)
MS Composite lymphosarcoma 2/47 (4%) 1/47 (2%) 0/49 (0%) 1/50 (2%)
MS Lymphoblastic lymphosarcoma 1/47 (2%) 1/47 (2%) 1/49 (2%) 0/50 (0%)
with leukaemic manifestations
KIDNEYS
MS Leiomyosarcoma 0/50 (0%) 1/50 (2%) 0/50 (0%) 0/50 (0%)
MS Granulocytic leukaemia 0/50 (0%) 1/50 (2%) 0/50 (0%) 0/50 (0%)
MS Composite lymphosarcoma 2/50 (4%) 1/50 (2%) 1/50 (2%) 2/50 (4%)
MS Lymphoblastic lymphosarcoma 1/50 (2%) 2/50 (4%) 3/50 (6%) 1/50 (2%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/50 (0%) 0/50 (0%) 0/50 (0%) 1/50 (2%)
JBPC Vol. 15 (2015)
150 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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Table A9. Incidence of neoplastic findings in female mice with glyphosate administered by diet. Part III. From
Knezevich & Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.
Controls Low Mid High
Glyphosate (ppm) 0 Low (1000) Mid (5000) High (30 000)
URINARY BLADDER
MS Granulocytic leukaemia 0/47 (0%) 1/43 (2%) 0/49 (0%) 0/48 (0%)
MS Composite lymphosarcoma 1/47 (2%) 1/43 (2%) 0/49 (0%) 0/48 (0%)
MS Lymphoblastic lymphosarcoma 1/47 (2%) 2/43 (4%) 2/49 (4%) 0/48 (0%)
with leukaemic manifestations
OVARIES
MG Teratoma 0/47 (0%) 1/47 (2%) 0/50 (0%) 0/47 (0%)
MG Granulosa cell tumour 0/47 (0%) 1/47 (2%) 0/50 (0%) 0/47 (0%)
MS Leiomyosarcoma 0/47 (0%) 1/47 (2%) 0/50 (0%) 0/47 (0%)
MS Lymphoblastic lymphosarcoma 0/47 (0%) 1/47 (2%) 0/50 (0%) 0/47 (0%)
with leukaemic manifestations
MS/BN Lymphoblastic lymphosar- 1/47 (2%) 0/47 (0%) 2/50 (4%) 0/47 (0%)
coma with leukaemic manifestations
UTERUS
MS Leiomyoma 2/49 (4%) 1/48 (2%) 1/49 (2%) 1/50 (2%)
MG Leiomyosarcoma 2/49 (4%) 3/48 (6%) 2/49 (4%) 3/50 (6%)
MG Endometrial stromal cell carcinoma 0/49 (0%) 1/48 (2%) 0/49 (0%) 0/50 (0%)
MS Haemangioma 0/49 (0%) 1/48 (2%) 0/49 (0%) 0/50 (0%)
MG Haemangio-endiothelioma 0/49 (0%) 0/48 (0%) 0/49 (0%) 1/50 (0%)
MS Lymphoblastic lymphosarcoma 0/49 (0%) 3/48 (6%) 1/49 (2%) 0/50 (0%)
with leukaemic manifestations
CERVIX
MG Leiomyosarcoma 0/0 (0%) 2/2 (100%) 0/0 (0%) 0/1 (0%)
THYROID
MS Follicular adenoma 0/43 (0%) 0/37 (0%) 1/49 (2%) 0/48 (0%)
SKIN
MG Fibrosarcoma 0/45 (0%) 1/45 (2%) 1/49 (2%) 0/48 (0%)
MAMMARY
MG Ductal adenocarcinoma 2/38 (5%) 4/36 (11%) 2/40 (5%) 1/38 (3%)
MS Lymphoblastic lymphosarcoma 0/38 (0%) 0/36 (0%) 1/40 (3%) 0/38 (0%)
with leukaemic manifestations
BONE MARROW
MS Lymphoblastic lymphosarcoma 0/46 (0%) 1/49 (2%) 3/47 (6%) 1/49 (2%)
with leukaemic manifestations
MS Lymphoblastic lymphosarcoma 0/46 (0%) 0/49 (0%) 0/47 (0%) 2/49 (4%)
MS Composite lymphosarcoma 0/46 (0%) 0/49 (0%) 0/47 (0%) 1/49 (2%)
JBPC Vol. 15 (2015)
Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 151
______________________________________________________________________________________________________
ACKNOWLEDGMENTS 77-2063. Submitted to EPA for evaluation. (31 March 1981).
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This work benefited from discussions with Yi-Wan Chen, generation reproduction study in rats with glyphosate.
Nancy Swanson, Bob Davidson, James Beecham and R.D. #374; Special Report MSL-1724. EPA Registration No
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