Glyphosate, pathways to modern diseases IV: cancer and related pathologies

Abstract

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.

Full text

© 2015 Collegium Basilea & AMSI
doi: 10.4024/11SA15R.jbpc.15.03
Journal of Biological Physics and Chemistry 15 (2015) 121–159
Received 5 August 2015; accepted 24 August 2015 121
11SA15R
________________________________________________________________________________________________________
1. INTRODUCTION
Glyphosate is the active ingredient in the pervasive
herbicide, Roundup. Its usage on crops to control weeds
in the United States and elsewhere has increased
dramatically in the past two decades, driven by the
increase over the same time period in the use of
genetically modified (GM)1 crops, the widespread
emergence of glyphosate-resistant weeds among the GM
crops (necessitating ever-higher doses to achieve the
same herbicidal effect), as well as the increased adoption
of glyphosate as a desiccating agent just before harvest.
GM crops include corn, soy, canola (rapeseed) and sugar
beet [1]. Crop desiccation by glyphosate includes application
to non-GM crops such as dried peas, beans and lentils. It
should be noted that the use of glyphosate for pre-harvest
staging for perennial weed control is now a major crop
management strategy. The increase in glyphosate usage
in the United States is extremely well correlated with the
concurrent increase in the incidence and/or death rate of
multiple diseases, including several cancers [1]. These
include thyroid cancer, liver cancer, bladder cancer,
pancreatic cancer, kidney cancer and myeloid leukaemia,
as shown in Table 1, reproduced from [1]. The World
Glyphosate, pathways to modern diseases IV: cancer and related pathologies
Anthony Samsel1, * and Stephanie Seneff 2,
**
1Research Scientist, Deerfield, NH 03037, USA
2Computer 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
*E-mail: anthonysamsel@acoustictracks.net
** Corresponding author. E-mail: seneff@csail.mit.edu
1Usually called genetically engineered (GE) in the USA.

Disease R P
Thyroid cancer (incidence) 0.988
≤
7.6 × 10
–
9
Liver cancer (incidence) 0.960 ≤4.6 × 1 0
–
8
Bladder cancer (deaths) 0.981
≤
4.7 × 10
–
9
Pancreatic cancer (incidence)
0.9 18
≤
4.6 × 10
–
7
Kidney cancer (incidence) 0.973 ≤2.0 × 10
–
8
Myeloid leukaemia (deaths) 0.878
≤
1.5 × 10
–
6
Health Organization (WHO) revised its assessment of
glyphosate’s carcinogenic potential in March 2015,
relabelling it as a “probable carcinogen” [2, 3].
Sri Lanka’s newly elected president, Maithripala
Sirisena, banned glyphosate imports as one of his first
acts following election. This action was based on studies
by Jayasumana et al. that provided compelling evidence
that glyphosate was a key factor in the chronic kidney
disease that was affecting an alarming number of young
Table 1. Pearson’s coefficients between time trends in various
cancers and glyphosate applications to corn and soy crops,
over the interval from 1990–2010, along with corresponding
P-values, as determined from hospital discharge data and
death data maintained by the US Centers for Disease Control
(CDC). Table adapted from Swanson et al. 2014 [1].

122 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
agricultural workers in the northern region [4, 5], and was
probably further motivated by the WHO reevaluation of
its carcinogenic potential. Kidney disease is a risk factor
for multiple cancers, with kidney dialysis being associated
with increased risk of Kaposi’s sarcoma by more than
50-fold, with 3- to 10-fold increased risk of kidney cancer,
and 2- to 9-fold increased risk of thyroid cancer. Many
other cancers also show more modest risk increases [6].
A study of rats fed GM maize and/or Roundup in
their water over their entire lifespan revealed significantly
increased risk of massive mammary tumours in the
females, along with kidney and liver damage in the males
[7]. Most of the tumours were benign, but there were
three metastases (in female animals) and two Wilm’s
tumours found in the kidneys of males, which had to be
euthanized early due to the excessive tumours, which
grew to more than 25% of their body size. The exposed
animals also had a shortened life span compared to the
controls.
The hormone oestrogen was declared to be a human
carcinogen by the National Toxicology Program in 2003
[8]. Glyphosate has been demonstrated to have
oestrogenic effects at minute dosages, in in vitro
experiments on mammary tumour cells [9]. Glyphosate
was able to induce proliferation in these cells in
concentrations of parts per trillion,2 and it did so through
binding affinity to the oestrogen receptor and inducing
activation of the oestrogen response element (ERE). The
fact that an oestrogen antagonist, ICI 182780, could inhibit
glyphosate’s action demonstrated rather conclusively that it
was mediated through oestrogen mimicry.
Traditional concepts in toxicology are centred on
Paracelsus’ dictum that “the dose makes the poison”,
meaning that one should expect an increasing risk of
toxicity as the level of exposure is increased. However,
the generality of this concept has been challenged due to
the realization that endocrine-disrupting chemicals
(EDCs) often show a greater potential to cause cancer at
very low doses than at higher doses; i.e., the relationship
between dose and response is nonmonotonic, with higher
doses producing a lower toxic effect than lower doses. In
fact, levels of exposure well below the lowest level used
in standard toxicology studies can be carcinogenic, as
discussed by Vandenberg et al. [10]. These authors
concluded their abstract as follows: “We illustrate that
nonmonotonic responses and low-dose effects are
remarkably common in studies of natural hormones and
EDCs. Whether low doses of EDCs influence certain
human disorders is no longer conjecture, because
epidemiological studies show that environmental
exposures to EDCs are associated with human diseases
and disabilities. We conclude that when nonmonotonic
dose-response curves occur, the effects of low doses
cannot be predicted by the effects observed at high doses.
Thus, fundamental changes in chemical testing and safety
determination are needed to protect human health.”
Glyphosate is toxic to many microbes as well as to
most plants, and one likely effect of chronic low-dose
oral exposure to glyphosate is a disruption of the balance
among gut microbes towards an over-representation of
pathogens [11]. This leads to a chronic inflammatory
state in the gut, as well as an impaired gut barrier and
many other sequelae. It has become increasingly
apparent that chronic inflammation increases cancer risk
and, in fact, many inflammatory conditions, such as
Crohn’s disease, hepatitis, schistosomiasis, thyroiditis,
prostatitis and inflammatory bowel disease are known
cancer risk factors [12].
In this paper, we review the research literature on
glyphosate, with particular emphasis on evidence of
carcinogenic potential, which includes glyphosate’s
induction of metabolic disorders, oxidative stress and
DNA damage, known precursors to cancer development.
We b eg in wi th a section t ha t s um ma ri ze s o ur own f in di ng s
following perusal of large numbers of documents that
were provided to one of us (Samsel) by the US Environ-
mental Protection Agency (EPA), according to the
Freedom of Information Act, which provided detailed
information on Monsanto’s own early experimental animal
studies on glyphosate.
This section motivates and inspires subsequent
sections where we seek to explain the likely mechanisms
by which glyphosate might cause the tumours observed in
Monsanto’s studies as well as explaining the strong
statistical correlations with human cancers. Following a
section that provides direct evidence of DNA damage,
the next four sections discuss metabolic disorders linked
to glyphosate that are known to increase cancer risk,
including succinate dehydrogenase inhibition, glycation
damage, N-nitrosylation, and disrupted glycine homeostasis.
The subsequent eight sections successively address
cancer of the colon, liver, pancreas and kidney,
melanoma, thyroid cancer, breast cancer, and lymphoma.
In each section we provide evidence of a link to
glyphosate from the research literature and propose
plausible explanations for a causal link. We finally
conclude with a summary of our findings.
2U.S. trillion, i.e. 1012.

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JBPC Vol. 15 (2015)
4. MONSANTO’S EARLY STUDIES
One of us (Samsel) petitioned the EPA for copies of
documents originating from Monsanto, dating from the
1970s through the 1980s, which described experiments
conducted by Monsanto to evaluate whether glyphosate
is safe for human consumption. In this section, we
provide a summary of our findings related to those
documents, especially with respect to indications of
kidney damage, tumorigenicity, bioaccumulation, and
glyphosate metabolites.
4.1 Kidney damage
Classification of types of kidney damage, which are
indicative of kidney disease, are noted below, based on
information contained in Monsanto’s glyphosate studies
on rats and mice [13–18]. In [13], changes in the kidneys
associated with chronic progressive neuropathy were
noted mostly in males, but also in some female animals of
both control and treated groups. There was also
mineralization and mineralized debris found in the pelvic
epithelium of the kidney, most often in females.
Following submission of the study, the EPA
subsequently asked Monsanto for a histological re-
examination of the low- and mid-dose male animals,
which resulted in establishing a no observable effect level
(NOEL). In response, Monsanto submitted an addendum
[14] to the pathology report. The results of the addendum
summarized the examination of the kidneys and found
minimal tubular dilatation accompanied by interstitial
fibrosis in all test groups. Statistically significant
increases in tubular dilatation of the kidney were noted. A
50% increase in changes to the kidney of the low-dose
group and, in the high-dose group, a fourfold increase in
incidence was found compared to the control.
Interstitial renal fibrosis begins with an accumulation
of extracellular matrix proteins, which is the result of
inflammation and injury to the cells, which is found in
every type of chronic kidney disease (CKD). Interstitial
fibrosis is a progressive pathogenesis leading to end-stage
renal failure [19].
The results of the 1981 study [17] further found:
1. Focal tubular hyperplasia, a hyperplasia of the tubular
epithelium of the kidney caused by repeated tubular
damage. It is characterized by an abnormal increase in
the number of cells, which causes enlargement. Tubular
epithelial hyperplasia precedes the pathogenesis of
tubular dilatation in acute tubular necrosis [20].
2. Focal tubular dilation, a swelling or flattening of the
renal tubule, seen as a result of an ischaemic or toxic
event as in pharmaceutical, antibiotic or chemical
poisoning. This leads to acute tubular necrosis, a cause
of acute kidney injury and kidney failure.
3. Focal tubular nephrosis, a degenerative disease of the
renal tubules of the kidney. This nephrosis is a noninflam-
matory nephropathy that features damage of the renal
tubules [21].
4. Interstitial mononuclear cell infiltrate characteristic of
inflammatory lesions, which consist of white blood
cells that clear debris from an injury site.
Mineral deposits can be indicative of kidney stones,
which may be calcium oxalate deposits inside the kidney,
as we shall discuss more fully later in this paper.
A 1983 chronic feeding study in mice [16] found a
carcinogenic response to glyphosate in both male and
female mice. There was also an increased incidence of
chronic interstitial nephritis in male animals. The study,
lasting 18 months, involved feeding glyphosate by diet using
concentrations of 1000, 5000 and 30
000 ppm. The
incidence of kidney tumours in the control animals was
0/49, as was also noted in the lowest dose group. However,
the mid-dose and high-dose groups produced incidences of
neoplasms at 1/50 and 3/50 respectively, which caused the
EPA Oncogenicity Peer Review Committee to temporarily
classify glyphosate as a Class C carcinogen.
Monsanto, dissatisfied with the action, consulted
another pathologist who, upon further examination, found
a small tumour in the control. This was followed by the
EPA using a number of pathologists to re-examine
additional kidney sections from the mice to check the
validity of the findings. However, their re-examination did
not find any additional tumours nor confirm the tumour in
the control animal. There were no tumours present in any
additional sections. EPA asked for the decision to be
externally refereed by the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA) Scientific Advisory Panel,
who found the results were statistically significant even
after comparing the data to historical controls. However,
the committee agreed to downgrade glyphosate to a Class
D compound, arguing inadequate evidence of oncogenicity,
and further sealed the study as a trade secret of Monsanto.
Non-neoplastic changes included:
1. Renal tubular neoplasms (in male mice; none found in
females);
2. Chronic interstitial nephritis (in males);
3. Renal tubular epithelial basophilia and hyperplasias
(decreased in males, but a dose-related increase
found in females);
4. Proximal tubule epithelial cell basophilia and
hypertrophy (females).
4.2 Tumorigenicity
A 26-month long-term study in rats conducted by Bio/
dynamics revealed multitudes of tumours in glands and
organs [13]. They occurred (from highest to lowest

124 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
incidence) in the following organs: pituitary, thyroid,
thymus, mammary glands, testes, kid ney, p anc reas , li ver
and lungs. Pituitary, thyroid and thymus glands control
body and immune function, and disruption can induce
disease, including cancer. These glands produce many
necessary hormones that control numerous biological
processes. Tumorigenic growth also disrupts functionality
of the glands and organs where the growth occurs. A
Monsanto trade secret document [13] revealed that there
were statistically significant lymphocytic hyperplasias of
the thymus as well as significant C-cell thyroid tumours.
Thymus lymphoid hyperplasia occurs in Graves disease
and thymus hyperplasia is commonly observed with
computed tomography (CT) scans of thyroid cancer
patients [22], and is also associated with autoimmune
disorders such as myasthenia gravis, lupus erythematosis,
scleroderma and rheumatoid arthritis [23].
It should be noted that significant incidence of
tumours was found during these investigations. However,
to create doubt and obscure the statistical significance of
inconvenient findings, which may have prevented
product registration, Monsanto used experimental noise
from 3, 5, 7 and even 11 unrelated study controls to
effectively eliminate results, as needed. In some instances
the experiments’ own control showed 0% incidence of
tumours, while the results for the glyphosate-treated
groups were statistically significant. However, through
the dishonest magic of comparing the findings to data
from unrelated historical controls, they were explained
away as a mystery and deemed not to be related to
administration of the glyphosate.
Using these deviations effectively neutralized the
inconvenient results and thus allowed the product to be
brought to market. Had they not engaged in this
deception, glyphosate may never have been registered for
use. EPA documents show that unanimity of opinion for
product registration was not reached. Not all members of
the EPA glyphosate review committee approved the
registration of glyphosate. There were those who
dissented and signed “DO NOT CONCUR.”3
The EC GLP document [24] notes: “Misdosing and/
or cross-contamination of the test item is always a risk in
animal studies. These problems are usually detected by
the presence of the test item and /or its metabolites in
plasma or other biological samples from control animals.
It is recognized that dietary and topical studies might lead
to a higher level and incidence of contamination of test item
in control animals. However, contamination of biological
samples from control animals has been observed also in
studies using other routes of administration, e.g. gavage,
intravenous, intraperitoneal, subcutaneous or inhalation.
Exposure of the control animals to the test item may
compromise or invalidate the study from a scientific point
of view.”
Thus, these unrelated historical controls were most
likely corrupted studies, whether by technician error,
contaminated water and /or feed, or other mistakes. This
explains Monsanto’s collusion with the EPA and the
subsequent hiding of the data from purview.
Data tables are presented in Tables 2 through 7,
without the use of experimental noise from historical
controls. Only the data results of the experiment are shown.
Gl
yp
hosate dose /m
g
k
g
–
1
da
y
–
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%) 1/5 0 (2%) 6/ 50 (12%)
Glyphosate dose /mg kg
–
1
da
y
–
1
0 3 10 30
FTD unilateral 2/10 (20%) 3/10 (30%) 2/9 (22%) 7/10 (70%)
FTD bilatera l 0/10 (0%) 2/10 (2 0%) 1/9 (11%) 1/10 (10%)
FTN unilateral 1/10 (10%) 2/10 (20%) 1/9 (11%) 0/10 (0%)
FTN bilatera l 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%)
Tab le 2. 198 1 Bio/dynamics 26-month glyphosate feeding study [17]: interstitial cell tumours of the testes in Sprague
Dawley rats.
Tab le 3 . 19 81 Bio /dy nam ics 26- mon th g lyp hos ate f eedin g st udy [17 ]. I nci den ce o f kidn ey f oca l tu bul ar d ila tat ion (F TD) and
focal tubuler nephrosis (FTN) in Sprague Dawley rats.
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.

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 125
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JBPC Vol. 15 (2015)
Glyphosate
d
ose /mg kg
–
1
da
y
–
1
0 3 10 30
Adenomas 0/50 (0%) 5/4 9 ( 10%) 2 /5 0 ( 4%) 2/50 (4%)
Carcinomas 0/50 (0%) 0/49 (0%) 0/5 0 (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%)
Glyphosate dose (ppm) 0 2000 8000 20
000
Adenomas 1/43 (2%) 8/45 (1 8%) 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 (1 8%) 5/49 ( 10%) 7/48 (15%)
P 0.241 0.052 0.275 0.108
Hyperplasi a 2/43 (5%) 0/4 5 (0%) 3/49 (6%) 2/48 (4%)
P 0.323 0.236 0.526 0.649
Table 4. 1981 Bio/dynamics 26-month glyphosate feeding study [17]: incidence of pancreatic
islet cell tumours in male Sprague Dawley rats.
Glyphosate dose (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 0.09 9
Carc inomas 0/54 (0% ) 2/55 (4%) 0/58 (0%) 1/ 58 (2 %)
P 0. 452 0.252 1. 000 0.51 8
Adenomas and carcinomas 2/54 (4%) 6/55 (11%) 8/58(14%) 8/58 (14%)
P 0. 077 0.141 0. 060 0.06 0
Hyperplasia 4/54 (7%) 1/55 (2%) 5/58 (9%) 4/58 (7%)
P 0.312 0.176 0.546 0.601
Glyphosate dose (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 0.12 4
Carc inomas 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
Table 5. 1990 Stout & Rueker 24 month glyphosate feeding study [15]: incidence of pancreatic islet cell tumours in male
Sprague Dawley rats.
Tab le 6 . 199 0 Stout & Ru eke r 24 mont h gl yph osa te fe edi ng s tud y [15 ]: i nci den ce of thy roid C-cell tumours in male Sprague
Dawley rats.
Table 7. 1990 Stout and Rueker 24 month glyphosate feeding study [15]: incidence of thyroid C-cell tumours in female
Sprague Dawley rats.
In a long-term study conducted by Monsanto between
1987 and 1989 [15], glyphosate was found to induce a
statistically significant (P < 0.0 5) cat ar act ou s le ns for matio n,
highest in male rats. Considerably higher doses of glyphosate,
i.e., 2000, 8000 and 20
000 ppm, were administered to
low-, mid- and high-dose animals respectively, as compared
to long-term studies conducted on mice and rats in the
early 1980s. Over the course of the study, cataract lens
changes were seen in low-, mid- and high-dosed groups
of both male and female rats. A second pathology

126 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
examination also found statistically significant changes
(see Table 8). The pathologist concluded that there was a
glyphosate-treatment related response for lens changes
to the eyes. Monsanto documents also revealed an
increased incidence of basophilic degeneration of the
posterior subcapsular lens (fibroses) in highly dosed males.
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,
further incidence of degenerative lens changes was
revealed, as shown in Table 8. The ophthalmic examination
yielded no noticeable changes to the control animals (0/15
or 0.0%); however, highly dosed males were significantly
Table 8. Incidence and occurrence of ophthalmic degenerative lens changes by glyphosate [15].
impacted as 5/20 (25%), as shown in Table 9. The study
again noted that “the occurrence of degenerative lens
changes in high dose male rats appears to have been
exacerbated by (glyphosate) treatment” [15]. Unrelated
historical controls were used to negate all findings.
Tab le 9. Data on un ilat eral and b ilat eral cata rac ts (a ll ty pes) and Y-s utu re op acit ies, excl udin g “pr omin ent
Y suture”, following glyphosate exposure to rats. From Stout & Rueker (1990) [15].
Se x Gr oup No. Exami ned No. Affe cted % A ffe cted
Male N 1 5 0 0
1 22 1 5
2 183 17
3 205 25
Female N 2 3 0 0
1 24 0 0
2 17 1 6
3 192 11
Stout & Ruecker [15] noted in a two year study with
chronic feeding of glyphosate in rats: “Histopathological
examination revealed an increase in the number of mid-dose
females displaying inflammation of the stomach squamous
mucosa. This was the only statistically significant occur-
rence of non-neoplastic lesions.” Incidence of lesions of the
squamous mucosa are shown in Table 10. Again, Monsanto
used unrelated historical controls to negate these findings.
Controls Low Mid High
Glyphosate (ppm) 0 2000 8000 20
000
Mal es 2/58 (3.44 %) 3/5 8 ( 5.17 %) 5/59 (8.47% ) 7 /59 (1 1.86%)
Females 0/58 (0.00%) 3/60 (5.00%) 9/60 (15.00%) 6/59 (1 0.16%)
Tab le 10 . Les ions of the stom ach s quam ous m ucos a in ra ts ch roni call y exp osed to gl ypho sate at thr ee di ffe rent
levels (adapted from Stout and Ruecker [15].
4.3 Bioaccumulation
Ridley and Mirly [25] found bioaccumulation of 14C-
radiolabelled glyphosate in Sprague Dawley rat tissues.
Residues were present in bone, marrow, blood and glands
including the thyroid, testes and ovaries, as well as major
organs, including the heart, liver, lungs, kidneys, spleen
and stomach. Further details are shown in Table 11. A
low-dose, oral absorption (10 mg/kg body weight) of the
radiolabelled xenohormone indicated highest bioaccumula-
tions. The 1988 Monsanto study disclosed: “A significantly
greater percentage of the dose remained in the organs
and tissues and residual carcasses for the males than for
the females. Overall recoveries for group 5 animals were
92.8% and 94.2% for males and females respectively.”
The study examined seven test groups of 3 to 5 animals
per sex/group that were administered a single radiolabelled
dose of glyphosate. Blood, expired air, faeces and urine
were collected and analysed by liquid scintillation counting

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 127
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JBPC Vol. 15 (2015)
(LSC), and glyphosate with its metabolites analysed by two
methods of high pressure liquid chromatography (HPLC).
Three animals were used in groups sacrificed at the end of
24 hours, and 5 animals were used for all other groups, which
were sacrificed at the end of the seven day study. Groups 3
and 7 received a 10 mg/kg intravenous dose, while group 4 a
high oral dose (1 g/kg). Groups 1, 2, 5 and 6 each received a
single oral 10 mg/kg radiolabelled dose. Group 6 animals
received multiple low doses of 10 mg/kg of nonradiolabelled
glyphosate for 14 days prior to administration of a single
10 mg/kg radiolabelled dose.
Oral absorption of glyphosate was 30% and 35%,
with a radiological β half-life of 7.5 and 14 days in male
and female animals, respectively. Bioaccumulation of
glyphosate found in bone was 0.748 ppm for males and
0.462 ppm for females for group 6 animals. Group 5
animals retained 0.552 ppm and 0.313 ppm for males and
females, respectively. Males also had higher levels of
glyphosate in their blood. Approximately 0.27% of the
orally administered dose was found in expired CO2 of t he
group 1 rats sacrificed after 24 hours. Table 11 shows
the mean average and percentage distribution of
radioactivity in ppm that were found in tissues and organs
of groups 4, 5 and 6 of the orally dosed animals.

Glyphosate mean (ppm)
Group 4
Group 5
Group 6
Male / Female
Male / Female M ale / Fem ale
BLOOD
Blood
p
lasma
0.129 / 0.127
0.00158 / 0.00114 0.00178 / 0.00152
Red
b
lood cells
0.517 / 0.275
0.00845 / 0.00424 0.00763 / 0.00474
Whole
b
loo
d
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. 024 5 / 0 .0 23 1
GLANDS
Thyroi
d
1.50 / 1.2 4
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. 01 44 / 0. 01 10
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
Kidn ey
1.94 / 1.3 5
0.0216 / 0.0132 0. 032 7 / 0. 01 96
Liver
1.91 / 1.3 7
0.0298 / 0.0135 0. 040 7 / 0. 02 57
Lung
1.54 / 1.1 3
0.0148 / 0.0120 0. 021 1 / 0. 01 67
Splee
n
2.61 / 2.9 8
0.0119 / 0.00727
0. 015 5 / 0 .0 13 0
Uterus – / 0.618 – / 0 .00517 – / 0.00185
DIGESTIVE SYS TEM
Stomach
2.38 / 2.36
0. 007 95 / 0. 0 0367
0. 037 7 / 0 .0 23 9
Small
i
ntestine
1.90 / 1.55
0.216 / 0.0183
0. 044 1 / 0 .0 25 7
Colo
n
11.0 / 9.20
0.0342 / 0.0159 0. 04 29 / 0. 02 98
FAT/MUSCLE
Abdo minal fat
0.418 / 0.457 0. 00 364 / 0 .0 03 24
0.00557 / 0.00576
Testicular/ovarian fat
0.442 / 0.037 0. 00 495 / 0 .0 03 47
0.00721 / 0.00563
Abdo minal
m
uscle
0.262 / 0.214 0. 00 232 / 0 .0 01 60
0.00278 / 0.00216
Shoulder muscle
0.419 / 0.423 0. 00 388 / 0 .0 06 67
0.00783 / 0.00590
N
asal mucosa
1.71 / 1.79
0.00485 / 0.0226
0. 031 6 / 0 .0 12 5
Residual carcass
8.78 / 7.74
0.106 / 0.0870
0.157 / 0 .101
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).

128 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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4.4 Glyphosate metabolites
Howe, Chott & McClanahan [26] identified, characterized
and quantified glyphosate and its metabolites after
intravenous and oral administration of the radiolabelled
compound. They employed several analytical tools, including
LSC, strong anion exchange (SAX), cation exchange
(CX) and ion pair chromatography (IPC). CX and IPC
methods of HPLC were used primarily for the identification
of glyphosate and its metabolites contained in urine and
faeces. Metabolites of glyphosate found during analysis
include the nonbasic compounds aminomethylphosphonic
acid (AMPA), methylaminomethylphosphonic acid
(MAMPA), N-formylglyphosate, N-acetylglyphosate, N-
nitrosoglyphosate and an unknown compound tagged as
“Compound #11”. Metabolites found in the dosing solutions
administered to rats of these experiments would be
expected in all glyphosate-based products. CX analysis
was used to identify AMPA and MAMPA and IPC was
used to identify all other nonbasic glyphosate metabolites.
Results are presented in Table 12. Metabolites were also
found in the urine and faeces of both male and female
rats, as shown in Table 13 for orally dosed groups 4, 5 and 6.

Dose group
Glyphosate AMPA MAMPA
N-acetyl-
glyphosate
N-formyl-
glyp hosate
N-nitroso -
glyphosate
Compound
#11
1: Ora
l
98.21 0.63 0.26 <0.04 0.49 <0.05 <0.06
10 mg/kg
3: Intraveno us
99.14 0.36 0.00 <0.02 0.36 <0.01 0.03
10 mg/
k
g
4: Ora
l
98.88 0.57 0.31 <0.03 0.14 <0.02 0.04
1000 mg/kg
5: Ora
l
99.41 0.17 0.00 <0.03 0.18 <0.03 0.03
10 mg/kg
6: Preconditione
d
99.36 0.19 0.07 <0.03 0.21 <0.02 <0.02
Oral 1 0 mg/kg

Dose gro up
Glyphosate
AMPA
(A)
MAMPA
(M)
N-Acetyl-
glyphosate
N-Formyl-
glyphosate
N-Nitroso-
glyphosate
Compound
#11
4
Dos e so lu ti on
98.88 0.570.31 <0.03 0.14 <0.02 0.04
Mal e u rin e 9 7.7 6 1. 25 A+M 0.1 0 0 .20 0 .09 0. 46
Mal e fae ces
98.64 0.82 A+M <0.03 <0.04 0.13 0.16
Fe mal e u ri ne
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
Dos e so lu ti on
99.41 0.170.00 <0.03 0.18 <0.03 0.03
Mal e u rin e 9 9.0 5 0. 32 A+M <0 .05 0 .12 0.1 1 0. 31
Mal e fae ces
98.78 0.56 A+M < 0.06 <0.10 0.21 0.16
Fe mal e u ri ne
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
Dos e so lu ti on
99.36 0.190.07 <0.03 0.21 <0.02 <0.02
Mal e u rin e 9 9.2 4 0. 29 A+M <0 .05 < 0.1 1 0. 08 0. 18
Mal e fae ces
98.31 0.90 A+M <0.06 <0.10 0.24 0.17
Fe mal e u ri ne
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
Table 12. Glyphosate and its metabolites: Analysis of dose solutions expressed as % of total. Table adapted from
Howe et al. [26].
Tab le 1 3. G lyp hos ate a nd i ts m eta bol ite s: An aly sis of fa ece s an d ur ine fro m ma le a nd f emal e ra ts e xpr ess ed a s % o f to tal .
Tab le a dapte d fr om H owe et a l. [ 26] .
In vivo metabolization of glyphosate to AMPA was
found in the excreta in quantities ≤ 0.4%. The bone was
the site of highest bioaccumulation and it retained 0.02 to
0.05% of the oral dose and 1% of the intravenous dose.
Repetitive dosing of group 6 animals did not significantly
change the metabolization or excretion of glyphosate. Of
all of the nonbasic compounds found during analysis of
excreta, AMPA followed by N-nitrosoglyphosate were
most prevalent. Total N-nitrosoglyphosate levels found in
the animals ranged between 0.06–0.20% of the given
dose. Faecal samples contained 0.10–0.32% and urine
0.06–0.15% of N-nitrosoglyphosate. Stability studies

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revealed that the majority of the N-nitrosoglyphosate
found in the faeces was not completely due to presence
of the compound as a contaminant of glyphosate, nor was
it due to animal metabolism, but rather was due to the
chemical reaction of glyphosate with nitrites contained in the
excreta. Glyphosate readily reacts with oxides of nitrogen
(e.g., NO2) to form the metabolite N-nitrosoglyphosate.
This engenders concern because N-nitroso compounds
are carcinogens. Nitrous acid occurring in sweat excreta
of the skin could be problematic in the presence of
glyphosate and may be responsible for the rise of some
skin cancers. N-nitrosoglyphosate, the product of chemical
reaction between glyphosate residues and nitrites in the
colon, may in fact be a causal agent in the alarming increase
in colorectal cancer. We discuss N-nitrosoglyphosate in §8.
Colvin, Moran & Miller [27] evaluated the metabolism
of 14C-AMPA in male Wistar rats. A 6.7 mg/kg dose of
radiolabelled AMPA was administered orally, of which 20%
was found unchanged in the urine of the animals and 74% in
the faeces. Recovery from excreta totalled 94% of the
dose. In another study, Sutherland [28] fed Sprague Dawley
rats a single radiolabelled dose of N-nitrosglyphosate and
successfully quantified the metabolite in the urine and
faeces. Male and female animals received 3.6 mg/kg and
4.7 mg/kg, excreting 2.8% (faeces) 88.7% (urine) and
10.7% (faeces), 80.8% (urine) respectively. Both male and
female rats retained 8.5% of the N-nitrosoglyphosate dose,
while 90.5% was eliminated in excreta.
5. THE ISSUE OF CONTROL RATS’ DIET
“Historical control data” show that 13–71% of the lab
animals used to conduct toxicity tests on various chemicals
would spontaneously present with mammary tumours, and
26– 93% develop pituitary tumours. Their kidney function
is also frequently impaired. A recent study by Mesnage et
al. [29] sought to evaluate whether toxic chemicals present
in the feed that is standard fare for these animals might be
causative for this surprisingly high background rate of
disease. Nine out of 13 samples of commonly used
laboratory rat feeds tested positive for glyphosate. Thus,
these “spontaneous” disease manifestations may well be
due to the toxic chemicals in the feed in the control animals
rather than to some underlying genetic defects, and this
fact raises serious questions about the validity of any
studies based on such exposed animals as a control group.
A 1995 paper by Dixon et al. describes a thorough
analysis of the frequencies of various organ pathologies
related to cancer and other diseases in “control” animals
not subjected to any explicit administration of the toxic
chemical under investigation [30]. The paper gave no
information on the rats’ feed or supplements, which
would have been important as a possible confounding
factor in the observed pathologies, one of which was
acinar cell atrophy, present in the pancreas of 6.9% of the
males and 5.0% of the female rats. The authors noted a
decrease in size and number of acini and increased
amounts of interstitial tissue, suggesting fibrosis, along
with increased infiltration of lymphocytes and
macrophages. Since this is quite similar to the pathology
observed with glyphosate exposure to rats, a possibility is
that glyphosate contamination in their feed or water
supply contributed to the pathology, perhaps in part by
chelating manganese; this transition metal is known to
stimulate protein synthesis in acini isolated from both
diabetic and normal rats and, in the case of diabetic rats,
the effect was shown to be specific to manganese
(cobalt, nickel, barium, strontium and magnesium failed to
exert the effect) [31].
To test for the hypothesis of glyphosate
contamination in rat feed, we used HPLC to test for
glyphosate and AMPA levels in three distinct rat chow
products, containing corn, soy and wheat middlings, and
found significant levels of both chemicals in all products
examined. We also tested for choline and folic acid. As
shown in Table 14, our laboratory analysis of standard
rodent diets found no detectable folic acid. Folic acid
(folate) is supplied not only through diet but also,
particularly, by commensal bacteria via the shikimate
pathway [32]. Therefore, glyphosate evidently disrupts
folic acid production both in exposed plant food sources
and in the human gut, leading to deficiencies. Folate is a
cofactor in many important biologic processes, including
remethylation of methionine and single carbon unit donors
during DNA biosynthesis. This impacts gene regulation,
transcription and genomic repair. Folate deficiency
enhances colorectal carcinogenesis, in part through
impaired DNA methylation [33]. Folate deficiency has
also been implicated in the development of several
cancers, including cancer of the colorectum, breast,
ovary, pancreas, brain, lung and cervix [34]. Folate
deficiency during gestation is linked to neural tube defects
such as anencephaly and spina bifida.
A synthetic form of choline, choline chloride, has been
added to formulated lab chow diets for decades, as
indicated from historical references available from
manufacturers such as Purina. A 2010 European patent
application describes the addition of choline chloride to
glyphosate formulations to act as a bioactivator and to
enhance penetration of glyphosate into the cells of the target
weed [35]. A study of 47,
896 male health professionals in
the US found that high choline intake was associated with
an increased risk of lethal prostate cancer [36]. Our
samples all tested positive for choline (see Table 14).

130 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
The American Veterinary Medical Foundation notes
that “Cancer is the leading cause of death in older pets,
accounting for almost half of the deaths of pets over 10
years of age.” According to the Morris Animal Foundation,
established in 1948, one in four dogs will die of cancer
and over 22
000 cats will be diagnosed with aggressive
sarcomas. Oral cancer squamous cell carcinomas are

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
Tab le 14. Evide nce o f glyp hosa te con tami natio n, an d l eve ls of f olat e a nd c holin e, in Pu rin a rat c how pr oduc ts
as determined from authors’ own analyses.
now found in cats and lead to the destruction of the
jawbone. Mammary tumours, a common cancer found in
dogs and cats, are also on the rise. We suspect that
glyphosate may be a causal agent related to the rise of pet
cancers, and used HPLC to analyse 9 popular brands of
dog and cat food. We found significant levels of both
glyphosate and AMPA in all pet foods tested (Table 15).

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
Table 15. Glyphosate and AMPA residues found in various dog food and cat food products, as measured
from samples tested by the authors.
Clearly, it is imperative that future studies on the
potential toxicity of any environmental chemical address
the issue of the possible toxicity of chemicals contaminat-
ing the diet of the control animals, and/or the potential
impact of nutritional imbalances. Feeding the control
animals an unhealthy diet leads to an increased risk of
cancer in the control group making it much harder to see
a signal in the experimental group. Furthermore, since
oestrogenic chemicals are often more toxic at extremely
low doses than at mid-range doses, it is easy to see why the
control group may manifest a significant incidence of cancer.
6. EVIDENCE OF DNA DAMAGE FROM THE RESEARCH
LITERATURE
According to the IARC’s report [2], while there exists
only limited direct evidence of carcinogenicity of
glyphosate in humans, strong evidence exists to show that
glyphosate can operate through two key features of
carcinogens: induction of chromosomal damage and
induction of oxidative stress. In this section, we review
the evidence that glyphosate can damage DNA, a crucial
first step leading to cancer. We examine evidence based
on sea urchins, children in Malaysia, in mouse models,
both in vitro and in vivo, in human lymphocytes, and in
fish. We conclude with a paragraph on folate deficiency,
its probable link to glyphosate exposure, and folate’s
essential rôle in DNA maintenance.
Cell cycle disruption is a hallmark of tumour cells and
human cancers. A study on sea urchins investigated
several different glyphosate-based pesticide formulations,
and found that all of them disrupted the cell cycle. The
sprays used to disseminate pesticides can expose people
in the vicinity to 500 to 4000 times higher doses than those
needed to induce cell cycle disruption [37].
A study on children living near rice paddy farms in
Malaysia revealed DNA strand breaks and chromosome
breakage associated with reduced blood cholinesterase
levels [38], which were attributed to exposure to
organophosphate insecticides. The study did not specify
exactly to which pesticides the children were exposed,
but glyphosate is a general-purpose herbicide whose use
in rice paddies in Sri Lanka led to widespread kidney

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JBPC Vol. 15 (2015)
failure among young agricultural workers there, ultimately
resulting in a ban on glyphosate usage in Sri Lanka [4, 5].
While glyphosate is technically an organophosphonate
rather than an organophosphate, a study on the fish
Prochilodus lineatus has demonstrated that it suppresses
cholinesterase in both muscle and brain [39].
Bolognesi et al. [40] studied the genotoxic potential
of both glyphosate in isolation and Roundup, in both
mouse in vivo studies and in vitro studies of human
lymphocytes. In the mouse studies they found evidence
of DNA strand breaks and alkali-labile sites in liver but
especially in kidney, as well as in bone marrow. Roundup
was found to be more toxic than glyphosate, with damage
occuring at lower concentrations. They also demonstrated
dose-dependent sister chromatid exchanges in human
lymphocytes exposed to glyphosate and to Roundup.
A recent study on a 96-hour Roundup exposure to
the economically important tropical fish tambaqui found
disturbed gill morphology, inhibited cholinesterase activity
in the brain and DNA damage in erythrocytes [41]. They
found a sixfold increase in a genetic damage indicator
(GDI) in erythrocytes, using the “comet” assay method.
Similarly, the comet assay applied to goldfish erythrocytes
revealed DNA damage following exposure to glyphosate
[42], and studies on exposure of eels to realistic
concentrations of Roundup and the principal individual
components, glyphosate and the surfactant polyethoxylated
amine (POEA) in isolation, confirmed DNA damage in
erythrocytes [43, 44].
Folate deficiency mimics radiation in damaging
DNA through single- and double-strand breaks as well as
oxidative lesions [45]. It is estimated that 10% of the US
population is at risk from folate deficiency-induced DNA
damage. Cancer of the colorectum in particular is linked
to folate deficiency [45, 34], which causes reduced
bioavailability of cytosine methylation capacity in DNA,
inappropriately activating proto-oncogenes and inducing
malignant transformation. Folate is also itself crucial for
DNA synthesis and repair. Folate deficiency can also
lead to uracil misincorporation into DNA and subsequent
chromosome breaks [34]. Folate is an essential B vitamin,
but it can be synthesized by gut microbes, particularly
Lactobacillus and Bifidobacterium [46]. Glyphosate is
a patented antimicrobial agent, and these two species
are more vulnerable than others to growth inhibition by
glyphosate [47]. Furthermore, folate is derived from
chorismate, a product of the shikimate pathway that
glyphosate disrupts [48].
7. SUCCINATE DEHYDROGENASE INHIBITION
A study on Escherichia coli revealed that glyphosate
suppressed three different components of the succinate
dehydrogenase (SDH) enzyme, cytochrome b556, the
avoprotein subunit and the hydrophobic subunit, reducing
their activity three- to fourfold [48]. Roundup cytotoxicity
in human cells is mediated in part through inhibition of
SDH, a key enzyme in mitochondrial complex II [49–51].
A theoretical study of the mechanism of inhibition
suggests that glyphosate binds at the succinate binding
site with a higher binding energy than succinate, thus
blocking substrate bioavailability [52]. Roundup has also
been shown to depress complexes II and III [53].
Both SDH (complex II) and fumarate hydratase (FH)
(complex III) are tumour suppressors. Their suppressive
mechanism can be understood through the effects of
enhanced glycolysis following their inhibition [54].
Mutations in SDH lead to the development of
paraganglioma (tumours originating in the ganglia of the
sympathetic nervous system), and phaeochromocytoma
(neuroendocrine tumours of the adrenal glands), and
mutations in FH cause renal cell carcinoma. Neuroblastoma
is the most common extracranial solid tumour in infants
and young children [55]. An increase in growth rate and
invasiveness in neuroblastomas is linked to impaired
succinate dehydrogenase function [56].
Succinate and fumarate will accumulate in
mitochondria when SDH and/or FH are suppressed, and
they leak out into the cytosol. Two newly recognized
signalling pathways result in enhanced glycolysis in a
“pseudohypoxic response”, as well as resistance to
apoptotic signals [54]. A characteristic feature of tumour
cells is their increased use of glycolysis as a source of
energy, even in the presence of available oxygen, a
phenomenon referred to as the Warburg effect [57, 58].
Malignant, rapidly growing tumour cells typically have
glycolytic rates up to 200 times higher than those of their
normal tissues of origin, even when oxygen is plentiful.
8. GLYOXAL, METHYLGLYOXAL AND GLYOXYLATE
In this section, we discuss the potent toxicity of multiple
metabolites of fructose that are plausibly present in foods
derived from glyphosate-resistant crops, or as a contaminant
in glyphosate-based products, or as a breakdown product
generated endogenously following glyphosate exposure.
These include glyoxylate, glyoxal and methylglyoxal. We
show that these molecules are genotoxic and can induce
cancer. We surmise that their toxicity is enhanced by
glyphosate exposure diminishing bioavailability of vitamin E,
an antioxidant.
Vitamin E, a tocophe rol, is der ived from the shikimate
pathway, which glyphosate disrupts [59]. One of the best
characterized functions of tocopherols is to protect biological
membranes against oxidative stress. Superoxide dismutase
(SOD) catalyses the conversion of superoxide anion

132 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
(
–
2
O), a reactive oxygen species (ROS), to hydrogen
peroxide (H2O2) and molecular oxygen (O2). Nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase can
also produce ROS, which leads to proteinuria and
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
acids, peptides and proteins to form advanced glycation
end products (AGEs), and they cause carbonyl stress in
the presence of oxidizing agents such as
–
2
O and H2O2
[66]. A study linking AGEs to cancer showed that
methylglyoxal–bovine serum albumin (methylglyoxal-
BSA) induced significant DNA damage [67]. Cancer
incidence is increased in association with chronic renal
failure, and this is likely due to the binding of AGEs to
receptors for advanced glycation end products (RAGE),
leading to increased intracellular formation of ROS [67].
Extremely high levels of methylglyoxal are found in
commercial carbonated beverages sweetened with high
fructose corn syrup (HFCS), but not in those that are
sweetened with artificial sweeteners [68]. Since HFCS is
derived from glyphosate-resistant corn, it is conceivable
that the methylglyoxal was produced in the plant in
response to glyphosate exposure. There is a plausible
biological mechanism for this, caused by the accumulation
of excessive amounts of phosphoenolpyruvate (PEP) as a
consequence of the disruption of the enzyme, 5-
enolpyruvyl-shikimate-3-phosphate (EPSP) synthase,
that uses PEP as substrate for the first step in the
shikimate pathway [69]. PEP suppresses glycolysis by
binding to the active site in the enzyme, triose phosphate
isomerase (TPI) [70], outcompeting the natural substrates.
Furthermore, PEP reacts with fructose to initiate its
conversion to triose phosphate, also known as
glyceraldehyde 3-phosphate (glyceraldehyde 3-p), as
illustrated in Fig. 1 [71]. Glyceraldehyde 3-p is highly
unstable and it spontaneously breaks down to
methylglyoxal [72]. Severe impairment of TPI due to
genetic defects leads to sharp increases in methylglyoxal
and protein glycation, as well as oxidation and nitrosation
damage [73]. Inhibition of glycolysis will increase the
residence time of glyceraldehyde 3-p and increase its
chances to spontaneously degrade to methylglyoxal. It
can be expected that similar problems will occur in gut
microbes exposed to glyphosate, as well as human cells,
and this may explain the increased levels of methylglyoxal
observed in association with diabetes [74].
Figure 1. Possible pathways of fructose metabolism in E. coli.
Genes are pgi, phosphoglucose isomerase; pc, fructose B-
phosphate kinase; fdp, fructose diphosphatase; and fda,
fructose diphosphate aldolase. PEP, phosphoenolpyruvate.
Adapted from Fraenkel, 1968 [71].
A study comparing rats fed a high-fructose
compared to a high-glucose diet revealed that those rats
fed fructose experienced a significant increase in body
weight, liver mass and fat mass compared to the glucose-
fed rats [75]. This was accompanied by a reduction in
physical activity, although the total number of calories
consumed remained equivalent. We suspect that this
phenomenon may be largely due to the presence of
glyphosate and methylglyoxal contamination in the fructose
(which was likely derived from the GMO Roundup-
Ready HFCS). A study exposing male Sprague Dawley
rats to a high-fructose diet during an interval over a period
of four months showed elevated serum levels of
methylglyoxal, along with several indicators of diabetes
and metabolic syndrome, including expression of RAGE,
NF-kB, mediators of the renin angiotensin system and
elevated blood pressure [76]. At physiological concentra-
tions, methylglyoxal can modify plasmid DNA and cause
mutations and abnormal gene expression [77].
Glyphosate formulations are trade secrets, but a 2006
Monsanto patent proposed using oxalic acid (oxalate) as an
additive to increase the toxicity of glyphosate to weeds
[78]. Oxalate inhibits pyruvate kinase and this leads to an
elevation in PEP along with a reduction in production of
lactate and pyruvate. The synthesis of PEP in rat livers
exposed to 0.1 mM oxalate more than doubled [79], which
likely induces excess exposure to methylglyoxal as
discussed above, causing liver stress. The effects of
oxalate would be synergistic with the effects of glyphosate
inhibition of the shikimate pathway in gut microbes, which
can be expected to also increase PEP levels, since PEP is
substrate for the enzyme that glyphosate disrupts.

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JBPC Vol. 15 (2015)
Several anaerobic bacteria, including Oxalobacter
formigenes, Eubacterium lentum, Enterococcus
faecalis and Lactobacillus acidophilus can metabolize
oxalate in the gut [80]. However, both oxalate
decarboxylase and oxalate oxidase, enzymes involved in
oxalate metabolism, depend on manganese as a cofactor
[81], and manganese is chelated by glyphosate, making it
unavailable to gut microbes [82, 83].
Elevated serum glyoxylate has been found to be an
early marker for diabetes risk [84]. The conversion of
glyoxylate to oxalate by the enzyme lactate dehydroge-
nase is inhibited by oxalate [85, 86]. Hence glyoxylate,
derived from glyphosate breakdown, can be expected to
accumulate in the presence of excess oxalate. Glyoxylate
can be derived from glyoxal, and both glyoxal and
glyoxylate have been proposed as key reactants in the
production of glyphosate, as described in multiple patents
from the mid-1980s [87, 88]. Furthermore, glyphosate
can itself be metabolized to AMPA and glyoxylate by
microbial action along two distinct pathways, via glycine
oxidase or via glyphosate oxidoreductase [89]. In vitro
exposure of hepatocytes to glyoxal showed hepatotoxicity
induced by lipid peroxidation, ROS, and collapsed
mitochondrial membrane potential [90, 91].
LDH is also known to be involved in tumour
metabolism. A Monsanto study conducted by Johnson on
rabbits found that extremely high doses of glyphosate
(5000 mg/kg) severely downregulated production of
LDH, reducing values in both male and female animals,
whereas a fivefold lower dose (1000 mg/kg) upregulated
LDH similarly in both males and females compared to the
experimental control [92]. Glyphosate was administered
by dermal absorption to three groups, each of 5 male and
5 female rabbits. Doses of 100, 1000 and 5000 mg/kg
were held in place by occlusion for 6 hours/day, five
days/week for 21 days. A control group of the same
numbers of animals and sex did not receive the
compound. Results for the control, low-, mid- and high-
dose groups were 250, 169, 291 and 76 for male animals
and 189, 149, 258 and 28 for female animals, respectively.
Not understanding glyphosate’s nonmonotonic dose-
response relationship caused Johnson to dismiss this
haematological finding. A similar pattern of LDH
regulation was recorded by Stout & Ruecker in 1990 in
experiments with albino rats [15].
A Monsanto patent application from 1985 describes
the invention as follows: “glyphosate and various glyphosate
derivatives can be produced with very high selectivity by
the reductive alkylation of aminomethylphosphonic acid,
its salts or its esters, in an aqueous medium with a carbonyl
compound, such as, for example, glyoxal, glyoxylic acid, a
glyoxylate salt, or a glyoxylate polyacetal salt or ester”
[88]. An earlier US patent application disclosed a similar
process whereby aminomethylphosphonic acid is reacted
in an aqueous medium with glyoxal in the presence of
sulfur dioxide to produce glyphosate. Methylglyoxal is
cytotoxic, and it has been shown to arrest growth and
react with nucleotides, increasing the incidence of sister
chromatid exchanges, a step towards tumorigenesis [93].
Methylglyoxal also decreases protein thiols, especially
glutathione, an essential antioxidant. In in vitro studies,
glyphosate has also been shown to reduce glutathione
levels in mammalian cells, possibly mediated through
methylglyoxal [94]. Methylglyoxal induces DNA
mutations mainly at G:C base pairs, and it severely
inhibits DNA replication by inducing cross-links between
DNA and DNA polymerase [95]. The mutagenicity of
methylglyoxal is suppressed by sulfur-containing molecules,
such as sulfite, cysteine and glutathione [96]. Glyphosate
has been shown to deplete methionine levels by 50% to
65% in a glyphosate-sensitive carrot plant line [97].
Methionine is an essential sulfur-containing amino acid
crucial for maintaining levels of cysteine, glutathione and
sulfate. Most bacteria possess biosynthetic pathways for
methionine [98], and it is possible that glyphosate disrupts
their ability to supply this critical nutrient to the host.
Glyoxalase is a key enzyme in the pathway that
detoxifies methylglyoxal. Mouse studies have demonstrated
that its overexpression can reduce AGE production and
oxidative damage associated with hyperglycaemia [99],
thus demonstrating a direct link between methylglyoxal
and these pathologies. Glyoxalase is upregulated in
association with rapid cell proliferation [100] and also in
association with some cancers, including gastric cancer
[101] and prostate cancer [102] (gastric cancer is the
second highest cause of cancer-related mortality worldwide
[103]). Overexpression of glyoxalase I is associated with
increased gastric wall invasion and lymph node metastasis
[101]. Glyphosate exposure has been shown experimentally
to induce increased expression of glyoxalase activity in
Arachis hypogaea (groundnut), which was engineered
to be glyphosate-tolerant [100]. In addition, the observed
upregulation of redox-regulated kinases, phosphatases
and transcription factors shows the importance of redox
couples to reorganize growth and metabolic needs under
stress conditions, such as exposure to glyphosate.
Mitogen-activated protein kinase (MAPK) phosphatases
(MKPs) play an important rôle in the development of
cancer in humans [104].
9. N-NITROSOGLYPHOSATE AND N-NITROSOSARCOSINE
As was shown by Monsanto’s own studies [26],
glyphosate readily reacts with nitrogen oxides to form N-
nitrosoglyphosate (NNG), which is of great concern due

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to its toxicity [105]. N-nitroso compounds (NOCs) can
induce cancer in multiple organs in at least 40 different
animal species, including higher primates [106–108]. In in
vitro studies on human liver slices, the mechanism of
action was shown to be nucleic acid alkylation [109].
Schmahl and Habs commented: “N-nitroso compounds
can act carcinogenically in a large number of animal
species; there is no rational reason why human beings
should be an exception, all the less so since in vitro
experiments have shown N-nitroso compounds are
metabolized in the same way by human livers as by the
livers of experimental animals” [108, p. 240]. Several
different nitrosylated compounds have been targeted as
potential carcinogenic agents, although it is conceded that
the long lag time between exposure and tumour
development makes it difficult to recognize the links
[110]. Dietary N-nitrosyl compounds especially are
thought to increase the risk of colon cancer and rectal
carcinoma [111, 112].
The Food and Agricultural Organization of the
United Nations (FAO) has set a strict upper limit of 1
ppm NNG [113]. The accepted methodology for measuring
contamination levels, proposed by Monsanto in 1986
[114], has complicated instrumentation and operation
conditions and is relatively insensitive [105]. New
advanced methodologies offer safer and more reliable
testing methods [115, 105].
One of the pathways by which some bacteria break
down glyphosate is by first using carbon-phosphorus
lyase (C-P lyase) to produce sarcosine as an immediate
breakdown product [89, 116]. Nitrosylated sarcosine is well
recognized as a carcinogenic agent. Injection of 225 mg/kg
of nitrososarcosine into mice at days 1, 4 and 7 of life led
to the development of metastasizing liver carcinomas in
later life in 8 out of 14 exposed animals [117].
Elevated levels of sarcosine are also linked to
prostate cancer, particularly metastatic prostate cancer
[118]. An unbiased metabolomic survey of prostate
cancer patients identified elevated levels of serum or
urinary sarcosine as a marker of aggressive disease
[119] (prostate cancer is the most commonly diagnosed
cancer in men in the USA, and it afflicts one in nine men
over the age of 65 [120]). In both in vitro and in vivo
prostate cancer models, exposure to sarcosine, but not
glycine or alanine, induced invasion and intravasation [119].
10. IMPAIRED GLYCINE SYNTHESIS
Perhaps surprisingly, a recent study has proposed that
glyphosate might serve a useful rôle in cancer treatment
due to its ability to inhibit glycine synthesis [121]. Glycine
is essential for the synthesis of DNA and, therefore, for
cell proliferation. In vitro studies on 8 different cancer
cell lines (including prostate, ovarian, cervical and lung
cancer) demonstrated that glyphosate at doses ranging
from 15 to 50 mM was cytotoxic to tumour cells, and that
cytotoxicity to normal cell lines required higher doses
(e.g., 100 mM). It was hypothesized that the mechanism
of action involved impaired glycine synthesis due to
glyphosate acting as a glycine mimetic.
In direct contradiction, however, glycine has been
shown to prevent tumorigenesis [122] and it is a potent
anti-angiogenic nutrient that suppresses tumour growth,
possibly through activation of a glycine-gated chloride
channel [123]. Impaired glycine synthesis likely has other
adverse effects as well, such as the possibility that
glyphosate interferes with glycine conjugation of benzene-
based compounds. In particular, this is a mechanism used
by gut microbes, particularly Bifidobacteria, to detoxify
phenolic compounds, producing hippurate (benzoylglycine),
a glycine conjugate of benzoic acid, as a mechanism for
detoxification [124]. Glycine has been shown to be a
limiting factor for hippurate production [125]. We stated
earlier that glyphosate preferentially harms Bifidobacteria
[46], and studies have shown reduced counts of
Bifidobacteria in obese rats along with reduced excretion
of hippurate [126]. Obese humans have also been shown
to have reduced urinary hippurate [127]. Furthermore,
lower urinary hippurate is linked to ulcerative colitis,
particularly Crohn’s disease [128]. A Swedish study of
over 21
000 Crohn’s disease patients identified increased
risk of a broad range of cancers, including liver, pancreatic,
lung, prostate, testicular, kidney, squamous cell skin
cancer, nonthyroid endocrine tumours and leukaemia
[129]. Crohn’s and inflammatory bowel disease have
been increasing in incidence in the USA in step with the
increase in glyphosate usage on corn and soy crops (R =
0.938, P ≤ 7.1 × 10–8) [1].
11. COL ON AN D LI VER CAN CER
As shown in Table 1, the incidence of liver cancer in the
USA has increased substantially in the past two decades,
pari passu with the increase in glyphosate usage on corn
and soy crops (P ≤ 4.6) × 10–8.
Nonalcoholic steatohepatitis (NASH) is a fatty liver
disease that has been linked to excess dietary fructose
[130]. We hypothesize that it is due primarily to the
disruption in gut metabolism of fructose due to glyphosate
blocking the shikimate pathway, as discussed previously.
Fructose, which should have been processed in the gut
leading to production of aromatic amino acids, instead is
delivered to the liver, which converts it into fat for either
local storage or distribution within low-density lipid
particles (LDL). NASH affects a large proportion of the
US population and is increasing in prevalence worldwide

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with adoption of a “Western diet” [131]. NASH causes
cirrhosis and increases risk of liver cancer [131, 132].
Hepatocellular carcinoma (HCC) is the most common
cause of obesity-related cancer deaths among middle-aged
men in America. The consumption of refined carbohydrates
in soft drinks has been postulated to be a key factor in the
development of NASH [130]. As we have seen, soft
drinks containing HFCS are very high in methylglyoxal.
A study from 1988 on children with severe chronic
liver disease revealed that those children with low vitamin
E levels were susceptible to H2O2-induced haemolytic
anaemia [133]. We earlier discussed the rôle of glyphosate
in depleting vitamin E. Haemolysis leads to haemochroma-
tosis (release of free iron from haem). The endocrine
glands, heart, liver, testes and pancreas are all affected
by haemochromatosis. Damage to pancreatic islet β-cells
from iron deposition can lead to cellular death and
functional impairment associated with diabetes [134].
Other effects of haemochromatosis include bone and joint
pain, arthritis, cardiomyopathy and testicular problems.
The liver synthesizes substantial amounts of haem,
which is needed primarily for the cytochrome P450
(CYP) enzymes, which perform many important rôles,
including bile acid synthesis, hormone activation and
breakdown, and detoxifying many carcinogenic agents,
including phenolic and other organic xenobiotics as well
as drugs and bilirubin. Glyphosate likely contributes to the
destruction of CYP enzymes both through H2O2 atta ck at
their haem centre as well as through direct interference
via nitrosylation at the active site by glyphosate [11].
CYP-mediated drug metabolism is impaired in patients
with liver disease, particularly CYP1A, CYP2C19, and
CYP3A [135], and this makes these individuals even
more susceptible to liver damage.
Inflammation and metabolic disorders are intimately
linked, and both are characteristic features of diabetes
and obesity [136]. Diabetes and obesity are linked to
dramatically higher risk of cancer, particularly of the liver
and gastrointestinal tract [137]. This is directly linked to
bile acid dysregulation and dysbiosis of the gut
microbiome. Elevated levels of cytotoxic secondary bile
acids and inflammation induced by an immune response to
gut pathogens induce heightened oxidative DNA damage,
increased cell proliferation and enterohepatic carcinogenesis
[137]. Temporal patterns of glyphosate use on corn and
soy crops strongly correlate with the increase in both
diabetes and liver cancer observed over the same time
interval [1].
Gut dysbiosis, due in part to glyphosate’s antimicrobial
effects, leads to gut inflammation and impairment of the
gut barrier function. This means that pathogens will
escape the gut and infiltrate the liver. Exposure to
endotoxin produced by gut microbes, such as lipopolysac-
charides (LPS) leads to inflammation in the liver along
with hepatic fibrosis [138]. Several types of chronic liver
disease are associated with increased levels of bacterial
LPS in the portal and/or systemic circulation [139].
Acute hepatic porphyrias are disorders caused by
enzyme defects in haem biosynthesis [140], and they are
risk factors for liver cancer [141–143]. Glyphosate has
been shown to disrupt haem synthesis, by suppressing the
enzyme that activates the first step, combining glycine
with succinyl coenzyme A to form δ-aminolevulinic acid
[144]. An often-overlooked component of glyphosate’s
toxicity to plants is inhibition of chlorophyll synthesis
[145], as δ-aminolevulinic acid is also a precursor to
chlorophyll as well as haem.
γ-glutamyl transferase (GGT) is a membrane-bound
enzyme that decomposes glutathione into cysteinyl
glycine and glutamate; it is highly expressed in the liver.
Excess serum GGT has been linked to both oxidative
stress [146] and increased cancer risk [147] as well as
many other diseases [148]. In a study on 283
438 people
who were divided into five subgroups based on GGT
level, a hazard ratio of 18.5 for risk of hepatic carcinoma
was ascertained for the highest level compared to the
lowest [149]. Another study based in Korea found an
increased risk of multiple cancers in association with
elevated GGT: most especially liver cancer, but also
cancer of the esophagus, larynx, stomach, bile ducts,
lungs and colon [150]. GGT induces generation of
reactive oxygen species through interactions of cysteinyl
glycine with free iron [151, 152].
Exposure to Roundup at low doses increased GGT
expression in rat testis and Sertoli cells [94]. A
comparison between goats fed GM Roundup-Ready
solvent-extracted soybean vs goats fed a conventional
soy equivalent revealed that the male kids born to the
goats fed the GM soy had elevated expression of GGT in
both liver and kidney (P < 0.0 1) [1 53] . A study has s how n
that 70% of GM Roundup-ready soy samples had
significant levels of glyphosate, whereas the conventional
soy did not [154].
Exposure of Wistar rats to the herbicide Glyphosate-
Biocarb over a period of 75 days resulted in liver damage,
including elevated serum alanine aminotransferase (ALT)
and aspartate aminotransferase (AST), suggesting
irreversible hepatocyte damage, as well as large deposition
of reticulin fibres containing collagen type III [155],
suggesting liver fibrosis [156], which is a major risk factor
for hepatocarcinogenesis.
Excessive retinoic acid signalling in the liver is
expected due to the interference of glyphosate with liver
CYP enzymes [11, 157, 158], because the CYP2C gene

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family is needed to metabolize retinoic acid in the liver
[159]. The action of retinoic acid is likely mediated
through sonic hedgehog signalling [160]. Studies on mice
have revealed that hedgehog signalling induces fibrosis
and hepatocellular carcinoma [161]. Studies on tadpoles
have demonstrated that glyphosate produces teratogenic
effects characteristic of excessive retinoic acid signalling,
and these effects were reversed by a retinoic acid
antagonist [162].
12. PANCREATIC CANCER
Pancreatic cancer is one of the cancers whose incidence
is going up in step with the increase in glyphosate usage
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
deficient in manganese showed significantly lower
concentrations of manganese in liver, kidney, heart and
pancreas compared to controls [165]. Pancreatic insulin
content was reduced by 63%, and insulin output was
correspondingly reduced, suggesting that manganese
deficiency may play a direct rôle in insulin-deficient
diabetes and islet cell stress.
Acinar cell carcinoma is the second most common
type of pancreatic cancer, characterized histologically by
zymogen-like granules as well as fibrillary internal
structures in the tumour cells [166]. A comparison
between mice fed GM soy and wild soy demonstrated
alterations in pancreatic acinar cells including smaller
zymogen granules and less zymogen content in one
month-old mice, along with reduced production of α-
amylase [167]. The authors did not consider possible
effects of glyphosate contamination, even though another
study has shown significant glyphosate residues in GM
soy as compared to conventional soy treated with
glyphosate [154]. Pancreatic atrophy of the acinar cells
along with degranulation and intracellular fibrillation is a
fundamental aspect of the childhood wasting disease
kwashiorkor [168], which is linked to disrupted gut
microbes [169], and may also be in part attributable to
glyphosate poisoning.
A two-year study of glyphosate toxicity to rats
reported by the EPA in 1991 showed several signs of
tumours, which were ultimately dismissed partly because
of a lack of a dose–response relationship, and in part
because it was argued that historical controls (but not the
controls in the study) demonstrated tumours at comparable
rates, but under very different and uncontrolled dietary
and lifestyle practices [170]. The most frequently
observed tumours were pancreatic islet cell adenomas in
males, thyroid C-cell adenomas and/or carcinomas in
males and females, and hepatocellular adenomas and
carcinomas in males. Both low-dose and high-dose, but
not mid-dose, males had a statistically significant
increased incidence of pancreatic islet cell adenomas.
Figure 2. Incidence of nephritis and kidney failure reports in the
US CDC’s hospital discharge data from 1998 to 2010 normalized
to counts per million population each year. This includes all
reports of ICD-9 codes from 580 to 589.
13. KIDNEY CANCER
Chronic kidney disease (CKD) and cancer are closely
linked in reciprocal fashion: cancer or its treatment can
cause CKD and patients with CKD have increased risk
of cancer. Dialysis patients have an increased risk
ranging from 10% to 80%; kidney transplant recipients
have a 3- to 4-fold increased risk of cancer [6]. The
number of patients with kidney failure treated by dialysis
and transplantation increased dramatically in the USA
from 209
000 in 1991 to 472
000 in 2004 [171]. There
have been concurrent increases in earlier stages of
chronic kidney disease such as albuminuria and impaired
glomerular filtration [172]. Since 2004, this trend has
worsened. Figure 2 shows the trend over time in the US
Centers for Disease Control (CDC)’s hospital discharge
data4 for ICD-9 codes 580-589, including acute and
chronic glomerulonephritis, nephritis and nephropathy,
acute and chronic renal failure, renal sclerosis, and
disorders resulting from impaired renal function. There
has been an alarming rise in the frequency of these
conditions, especially since 2006.
4ftp://ftp.cdc.gov/pub/Health Statistics/NCHS/Datasets/NHDS

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JBPC Vol. 15 (2015)
Studies on rats show that CYP 2B1 plays a pivotal
rôle as an important site for ROS production through
cytotoxicity in the glomeruli [173]. The breakdown of the
CYP haem protein through attack by H2O2 leads to the
release of catalytic iron, which, in turn, generates more
potent tissue-damaging oxidants such as the hydroxyl
radical. Glyphosate’s induction of excess H2O2 as discu ssed
earlier would cause an increase in the bioavailability of
catalytic free iron to work synergistically with H2O2 to
cause toxicity.
Methylglyoxal and other glycating agents may be a
significant factor in the development of kidney disease.
Twe lve w eeks of ad mini str atio n thr ough drin king wate r of
methylglyoxal to Dahl salt-sensitive rats led to an increase
in systolic blood pressure and significantly increased
urinary albumin excretion, glomerular sclerosis, tubular
injury, myocardial collagen content and cardiac perivascular
fibrosis [174]. Renal markers of AGE production,
oxidative stress and inflammation were all elevated.
Acquired cystic kidney disease (ACKD) can lead to
renal tumours, and the tumours often accumulate calcium
oxalate crystals [175]. These tumours are often
associated with distinctive morphological features, where
the tumour cells have ill-defined cell membranes,
abundant granular eosinophilic cytoplasm, large nuclei
and prominent nucleoli. In another study identifying
intratumoral calcium oxalate crystal deposition in two
cases of high-grade renal carcinomas, the authors
suggested a relationship between tumour growth and
oxalate crystal deposition [176]. This suggests a rôle for
oxalic acid added to glyphosate-based formulations.
An in vitro study on rat testis and Sertoli cells
demonstrated that Roundup triggers calcium-mediated
cell death associated with reductions in levels of the
antioxidant glutathione, along with thiobarbituric acid
reactive species (TBARS) and protein carbonyls indicative
of protein oxidation and glycation damage [94]. Adminis-
tration of L-buthionine(S,R)-sulfoximine (BSO), a specific
inhibitor of glutathione synthesis, to rats caused reduced
glutathione levels in the kidneys and a marked increase in
pathologies linked to polycystic kidney disease [177].
14. CATARACTS AND MELANOMA
As we showed previously, Monsanto’s own studies
revealed increased risk of cataracts following exposure to
Roundup. Early-onset cataracts are associated with
insufficient antioxidative activity and, therefore, are a
potential risk of cancer, as verified in a recent nationwide
study based in Taiwan [178].
Methylglyoxal is implicated in cataract development
[179, 180]. Methylglyoxal induces endoplasmic reticulum
stress in human lens epithelial cells, and activates an
unfolded protein response leading to overproduction of
ROS. Overexpression of Keap1 protein causes proteasomal
degradation of Nrf2, thus suppressing Nrf2-dependent
stress protection. As a consequence, the cellular redox
balance is altered toward lens oxidation and cataract
formation [179].
There is a link between cholestasis and cataracts via
poor absorption of nutrients that protect the lens from
UV damage. Studies on short-term exposure of catfish to
sublethal levels of Roundup revealed toxicity to the gills,
liver and kidneys [181]. The observed elevated levels of
unconjugated bilirubin and alanine aminotransferase
(ALT) are indicative of cholestasis, likely in part a
consequence of impaired CYP enzyme function.
Cholestasis impairs the absorption of fat-soluble vitamins
and previtamins such as the carotenoids [182]. Lutein
and zeaxanthin are carotenoids that play an important rôle
in the lens and macular region of the retina to protect
from oxidative damage due to sunlight exposure [183,
184]. They are highly lipophilic and, therefore, like the
fat-soluble vitamins, depend on adequate bile flow for
gastrointestinal absorption. Cholestatic patients have
greatly reduced serum levels of these nutrients [182].
Tryptophan is a product of the shikimate pathway
that glyphosate suppresses. A tryptophan-free diet
induces cataracts in young Wistar rats, along with a
significant decrease in lens weight and water-soluble lens
protein [185]. Kynurenine is a breakdown product of
tryptophan, and it has been suggested that kynurenine
and its glycoside derivatives in the ocular lens protect the
retina from UV light by absorbing UV radiation [186].
Kynurenine is present in excessive concentrations in
cataracts [186].
Melanoma is one of the types of cancer that have
been linked to glyphosate exposure in agriculture. An
age-adjusted analysis revealed an 80% increased risk of
melanoma associated with glyphosate use in a study on
pesticide applicators in Iowa and North Carolina [187]. It
is possible that impaired supply of the aromatic amino
acids, tryptophan and tyrosine due to disruption of the
shikimate pathway in gut microbes plays a rôle in
increased risk to melanoma.
In vitro, exposure to 0.1 mM glyphosate induced
hyperproliferation in human skin keratinocytes (HaCaT)
cells, suggesting carcinogenic potential [188]. The
mechanism involves increased ROS expression and the
emptying of intracellular calcium stores, which facilitates
basal cell or squamous cell carcinomas. Cells accumulated
in S-phase of the cell cycle, while mitochondrial apoptotic
signalling pathways were downregulated.
Melanin plays an important protective rôle in the skin
against UV exposure, and dark-skinned races have

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significantly reduced risk of skin melanoma because of
their naturally higher levels of melanin [189].
Melanosomes are tissue-specific organelles in pigment
cells that resemble lysosomes, in which melanin is
synthesized and stored [190]. L-tyrosine is the precursor
to melanin synthesis, and the pathway involves the
intermediary, L-dopa. Both L-tyrosine and L-dopa, when
supplied to cells with melanogenic potential, increase not
only the synthesis of melanin but also the formation of
melanosomes within the cells [191].
While blacks have protection against skin cancer
due to the high concentration of melanin in their skin, dark
skin also appears to be a risk factor for autism. A study
based in Los Angeles showed that children born to black
foreign-born women had a substantially increased risk for
low-functioning autism [192]. A similar observation has
been made in Sweden [193] and the UK [194]. One
possibility is that increased demand for melanin in the skin
depletes the supply of tyrosine for dopamine synthesis.
Genetic mutations in dopamine transport proteins have
been linked to autism [195, 196]. The defect features a
persistent reverse transport of dopamine (substrate efflux
from the synapse), which reduces the amount of time
extracellular dopamine is available for signalling effects
[195]. Other genes of the dopaminergic network are also
linked to autism, including syntaxin [197] and enzymes
involved in dopamine metabolism [198]. Hence, we
hypothesize that reduced bioavailability of tyrosine (due
to disruption of the shikimate pathway in gut microbes)
for either dopamine synthesis or melanin synthesis leads
to different outcomes (autism vs melanoma) depending
on race-related skin colour.
Tryptophan is an essential amino acid for lymphocyte
activation and proliferation, which promotes surveillance
and elimination of tumour cells [199, 200]. Tryptophan is
also produced by gut microbes via the shikimate pathway
that glyphosate disrupts, suggesting that glyphosate exposure
to gut microbes could impair tryptophan bioavailability to the
human host. The enzyme indoleamine 2,3-dioxygenase
(IDO) catalyses the degradation of tryptophan to
kynurenines. Tumours of the lung [201], colon [202],
liver [203], breast [204] and uvea [205], as well as skin
melanoma [206], overexpress IDO, and it is believed that
this leads to an ability to evade immune surveillance by T-
cells via depletion of tryptophan bioavailability in the
surrounding milieu [205]. It is interesting that IDO offers
significant protection from UV damage by producing
tryptophan-based filters that protect the cornea, lens and
retina from UV-induced photo-oxidation [207, 208]. It
may well be that tumours exploit IDO for this purpose as
well. Clearly, decreased bioavailability of tryptophan due
to glyphosate’s effects on gut microbes would enhance
the tumour’s ability to deplete tryptophan and avoid
immune surveillance, but might also lead to accelerated
DNA damage within the tumour and increased risk of
metastasis [209].
15. THYROID CANCER
The incidence of thyroid cancer in the United States has
increased dramatically in the past two decades, in step
with the increase in glyphosate usage on corn and soy
crops (R = 0.988, P ≤ 7.6 × 10–9) [1]. It is not clear how
glyphosate might increase risk of thyroid cancer beyond
the general factors already described previously in this
paper, but it is possible that impaired selenium
incorporation into selenoproteins plays a rôle.
Selenium is an important trace element involved in
the protection of cells from oxidative stress, and it is
particularly important for the thyroid. Low serum levels
of selenium are associated with increased risk of thyroid
cancer, and probably play a rôle in carcinogenesis. All
three of the deiodinases that convert thyroxine (T4) into
triiodothyronine (T3) contain selenocysteine, as do
glutathione peroxidase and thioredoxin reductase, which
are important antioxidant enzymes essential for
protecting thyrocytes from oxidative damage [210].
The microbiome plays an important rôle in
incorporating free selenium into selenoproteins, especially
selenocysteine. Lactobacillus reuteri is a p opu lar s pec ies
in probiotics, shown to be effective against diarrhoea in
children [211], and to inhibit the prooxidant cytokine TNF-α
in humans [212]. This species has been found to be
especially effective in its ability to produce selenocysteine,
and has been proposed to have therapeutic benefit in
cases of selenium deficiency [213]. Lactobacillus is
especially vulnerable to glyphosate due to its crucial and
unusual need for manganese as an antioxidant [214, 215],
so it is plausible that diminished Lactobacillus re pr esen ta tio n
in the gut could lead to an impaired supply of selenocysteine
for the thyroid.
16. BREAST CANCER
Breast cancer accounts for one third of cancer diagnoses
and 15% of cancer deaths in women in the United States.
As mentioned previously, an in vitro stu dy ha s co nfir med
that glyphosate stimulates proliferation of human breast
cancer cells when present in concentrations of parts per
trillion [9].1 Thi s ef fect is sp eci fic t o ho rmo ne-d epen den t
cell lines, and is mediated by the ability of glyphosate to
act as an oestrogenic agent.
One can obtain an estimate of the time trends in
breast cancer by looking at the CDC’s hospital discharge
data. The results show a steady decrease in breast cancer

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 139
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JBPC Vol. 15 (2015)
diagnoses up to 2006, followed by an increase from 2006 to
2010 (the last year for which data are available). The
decrease can logically be explained by a growing
awareness of the increased risk of breast cancer
associated with hormone replacement therapy (HRT). A
Women’s Health Initiative (WHI) study, published in
2003, showed a 24% increase in invasive breast cancer
risk associated with oestrogen/progestin therapy [216].
In direct response to this alarming report, HRT
prescriptions in the United States decreased by 38% in
2003. A large study on 1
642
824 women published in 2013,
based on the Breast Cancer Surveillance Consortium,
revealed that HRT (commonly used to treat symptoms of
menopause) increased the risk of breast cancer by 20%
in whites, Asians and hispanics, but not in blacks [217].
By forming separate records from the hospital
discharge data for black and white women, it can be
confirmed that the breast cancer rates among blacks
remained flat up to 2006, supporting the observation that
black women are not subject to increased risk from HRT.
This suggests that one can build a model to correct for the
influence of reduced use of HRT among white women in
order to arrive at a time trend that might more closely
capture any effects of glyphosate. A simple decaying
exponential model matches well for the Caucasian data
from 1998 to 2006, and this model can be extended into
the time interval from 2006 to 2010, and then subtracted
from the original plot, to yield a plot of the residual trends
for breast cancer. The resulting plot is shown in Fig. 3
alongside rates of glyphosate usage on corn and soy crops.
The correlation coefficient is 0.9375 (P-value ≤ 0.0001132).
A study on rats conducted by Séralini et al. [7]
divided the rats into four groups: (1) control, (2) GM maize
without Roundup, (3) GM maize with Roundup, and (4)
Roundup alone. The major tumours detected in the
female rats were mammary fibroadenomas and adenocarci-
nomas. These authors summaraized their findings as:
“The Roundup treatment groups showed the greatest
rates of tumour incidence, with 80% of animals affected
with up to 3 tumours for one female, in each group.” For
the group that received Roundup in their drinking water,
all but one of the females presented with mammary
hypertrophies and hyperplasias. The one exception suffered
from a metastatic ovarian carcinoma.
Glyphosate may also indirectly increase risk of
breast cancer by impairing metabolism of toxic phenolic
compounds such as nonylphenols, diethylstilbestrol
(DES), and Bisphenol A (BPA), all widely recognized to
possess oestrogenic activity. Nonylphenols, also known
as alkylphenols, are a family of organic compounds used
extensively as additives in laundry detergents, lubricating
oils, paints, pesticides, personal care products and plastics,
which are known to be xenoestrogenic [218]. DES is an
oestrogenic compound linked to vaginal tumours in
women exposed in utero to this compound when it was
mistakenly believed to be of therapeutic benefit. BPA,
commonly used in plastics production, is now widely
recognized as an endocrine disruptor. PCBs were widely
used as coolants and insulating fluids for transformers
and capacitors until their ban in 1979 by the US
government due to recognition of their toxicity due to
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.
High dietary iron enhances the incidence of carcinogen-
induced mammary cancer in rats and oestrogen-induced
kidney tumours in hamsters [222]. Oestrogen facilitates
iron uptake by cells in culture. Elevated body iron storage
increases the risk of several cancers, including breast
cancer in humans. Although it might be argued that
Figure 3. Incidence of breast cancer in US hospital discharge data
from 1998 to 2010 normalized to counts per 1,000
,
000 population
each year, after subtraction of an exponential model accounting
for the decline in the years up to 2006 in the Caucasian
subpopulation [see text]. This includes all reports of ICD-9 codes
174 and 175. The red line shows trends in glyphosate usage on
corn and soy crops over the same time period.

140 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
glyphosate’s chelating effects may protect from iron
overload, glyphosate could increase the bioavailability of
free iron due to its damaging effects on red blood cells
[42, 223] working synergistically with its interference in
haem synthesis [144], and by acting as an oestrogen
mimetic to enhance iron uptake. Haem degradation by
reactive oxygen species [224] will lead to the release of
free iron, and we have previously discussed how
glyphosate would induce oxidative stress. In fact, recent
evidence strongly suggests that GGT induces lipid
peroxidation of red blood cell membranes leading to
haemolysis and the release of free iron from chelating
agents [225]. This also results in impaired deformability
which impedes their passage through narrow capillaries.
GGT was found to be enhanced up to 5.4-fold in the liver
in Séralini et al.’s long-term study of rats exposed to
GMO’s plus Roundup [7].
17. NON-HODGKIN’S LYMPHOMA
Striking increases in the incidence of non-Hodgkin
lymphoma (NHL) cancer have occurred over the past
three decades, both in Europe [226] and America [227].
Agricultural workers have a higher risk of NHL than the
general population, but it is difficult to tease out the
effects of glyphosate compared to the myriad other toxic
chaemicals they are exposed to, which also confer
increased risk [228]. However, some studies have been
able to directly link glyphosate to NHL. A threefold
increased risk of NHL in association with glyphosate
exposure was found in a 2002 study from Sweden [229]. A
later Swedish study in 2008 of over 900 cancer cases also
found a significant increased risk of NHL (OR 2.02)
[230]. A Canadian study demonstrated a correlation
between the number of days per year of glyphosate
exposure and the risk of NHL [231].
Increased exposure to superoxide is implicated as a
causal agent in oncogenesis [232], and manganese SOD
(Mn-SOD) is an important antioxidant defence agent in
mitochondria [233]. Mice engineered to be defective in
Mn-SOD had increased DNA damage and higher cancer
incidence [234]. We mentioned earlier that Mn-SOD is
protective against pancreatic cancer. Mn-SOD expression
was also found to be anomalously low in erythrocytes of
patients suffering from NHL [235]. In vitro studies have
shown that an Mn-SOD mimetic had an anti-proliferation
effect on human NHL Raji cells [236]. Glyphosate’s chelating
effects on manganese can be expected to interfere with
Mn-SOD function [82]. Increased Mn-SOD expression
potentiates apoptosis of tumour cells exposed to
dexamethasone [237]. Cationic manganese porphyrins,
probably by acting as Mn-SOD mimetics, have also been
found to play a protective rôle in treating NHL [238, 239].
Bone marrow involvement is common in NHL and,
particularly for those of T-cell origin, it portends a poor
prognosis [240]. An unpublished study by Monsanto in
1983 confirmed that glyphosate administered by
intraperitoneal injection to rats reaches the bone marrow
within 30 minutes [241]. In an experiment to assess
potential toxicity to bone marrow cells [242], a single
intraperitoneal dose of glyphosate at concentrations of 25
and 50 mg/kg was administered to Swiss albino mice.
Chromosal aberrations and micronuclei, analysed 24, 48,
and 72 hours later, were shown to be significantly
increased compared to vehicle control (P < 0.0 5). M itos is
rates were also decreased, indicating cytotoxic effects.
Multiple myeloma is the second most common
haematological malignancy in the USA after non-Hodgkin
lymphoma; it constitutes 1% of all cancers [243]. In a
prospective cohort study of 57
311 licensed pesticide
applicators in Iowa and North Carolina, a greater than
twofold increased risk of multiple myeloma was associated
with ever-use of glyphosate [187].
Coeliac disease, along with the more general
condition, gluten intolerance, has recently reached
epidemic levels in the United States, and it has been
hypothesized that this heightened wheat sensitivity is a
direct consequence of glyphosate contamination of the
wheat, due to the increasingly common practice of wheat
desiccation with glyphosate just before harvest [158].
Coeliac disease patients are at increased risk of cancer,
particularly non-Hodgkin lymphoma, and they have
statistically a shortened lifespan mainly due to this
increased cancer risk.
For coeliac disease patients, serum prolactin (PRL)
levels are high in association with an unrestricted gluten-
containing diet, and PRL has been proposed as a useful
marker for coeliac disease [244]. PRL is an important
regulatory hormone released by the pituitary gland, which
is best known for inducing lactation. Bisphenol A, a well-
established oestrogenic agent, has been shown to lead to
hyperprolactinaemia and growth of prolactin-producing
pituitary cells [245]. Prolonged exposure to Bisphenol A
during childhood may contribute to the growth of a
prolactinoma, the most common form of cancer of the
pituitary. Oestrogen treatment of ovariectomized rats
induced a marked elevation of serum PRL levels [246],
and this was found to be due to oestrogen’s ability to
reduce the capacity of PRL cells to incorporate dopamine
into their secretory granules. Since glyphosate has been
confirmed to be oestrogenic, it is plausible that glyphosate
contamination in wheat is the true source of the observed
elevation of PRL in association with gluten ingestion
among coeliac patients.

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 141
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JBPC Vol. 15 (2015)
18. CONCLUSION
In this paper, we have reviewed the research literature on
glyphosate and on the biological processes associated
with cancer, and we have provided strong evidence that
glyphosate is likely contributing to the increased prevalence
of multiple types of cancer in humans. Monsanto’s own
early studies revealed some trends in animal models that
should not have been ignored. Forty years of glyphosate
exposure have provided a living laboratory where humans
are the guinea pigs and the outcomes are alarmingly
apparent.
We have shown that glyphosate transforms exposed
cells into a tumour-provoking state by suppressing crucial
enzymes in the electron transport chain, such as succinate
dehydrogenase and fumarate hydratase. Glyphosate
chelates manganese, reducing its bioavailability, and
manganese is an important catalyst for Mn-SOD, which
protects mitochondria from oxidative damage, which can
cause mutations in DNA. Glyphosate also causes impaired
metabolism of fructose, due to the accumulation of PEP
following blockage of the shikimate pathway. This leads
to the synthesis of multiple short-chain sugars that are
known to be highly potent glycating agents, such as
methylglyoxal and glyoxalate. Glyphosate is readily
nitrosylated, and nitrosyl glyphosate is known to be
extremely toxic and carcinogenic. Microbial pathways
convert glyphosate into sarcosine, a known marker for
prostate cancer, likely due to its nitrosylated form.
An often overlooked aspect of glyphosate’s toxicity
is its interference with enzymes that have glycine as
substrate, due to mimicry. Phenolic compounds are
detoxified by gut microbes through glycine conjugation to
produce products such as hippurate. Bifidobacteria are
important for the rôle they play in protecting from these
xenobiotics through such conjugation. Reduced hippurate
is linked to Crohn’s diseases and inflammatory bowel
disease, which show epidemiological trends that match
the increased use of glyphosate on core crops, and which
are linked to increased risk of a broad range of cancers,
most especially non-Hodgkin lymphoma. Lymphoma has
also been linked to glyphosate through studies of
environmental exposure in agricultural settings.
Multiple studies, both in vitro and in vivo, have shown
that glyphosate damages DNA, a direct step towards
tumorigenicity. These studies have been conducted on
sea urchins, fish, mice and various human cell types in
vitro. Children in Malaysia living near rice paddies have
evidence of DNA damage.
Epidemiological studies strongly support links
between glyphosate and multiple cancers, with extremely
well matched upward trends in multiple forms of cancer
in step with the increased use of glyphosate on corn and
soy crops. While these strong correlations cannot prove
causality, the biological evidence is strong to support
mechanisms that are likely in play, which can explain the
observed correlations through plausible scientific arguments.
Glyphosate’s links to specific cancer types can often
be explained through specific pathologies. For example,
succinate dehydrogenase deficiency is linked to adrenal
cancer [17]. Selenoprotein deficiency is likely contributory
towards thyroid cancer. Glyphosate’s action as an
oestrogen mimetic explains increased breast cancer risk.
Prostate cancer is linked to sarcosine, a by-product of
glyphosate breakdown by gut microbes. Impaired
fructose metabolism links to fatty liver disease, which is a
risk factor for hepatic tumorigenesis. Impaired melanin
synthesis by melanocytes due to deficiencies in the
precursor, tyrosine, a product of the shikimate pathway,
can explain increased incidence of skin melanoma. This
is compounded by tryptophan deficiency, as tryptophan is
also protective against UV exposure.
Manganese deficiency stresses the pancreas and
impairs insulin synthesis, and this could explain the recent
epidemic in pancreatic cancer. Increased oxalate, due in
part to the proprietary formulations, stresses the kidney
and contributes to risk of renal tumours. Glyphosate’s
accumulation in bone marrow can be expected to disrupt
the maturation process of lymphocytes from stem cell
precursors. Glycine forms conjugates with organic benzene-
derived carcinogenic agents, and glyphosate likely
interferes with this process. Glyphosate’s interference
with CYP enzyme function impairs detoxification of
multiple other carcinogenic agents, increasing their
carcinogenic potential. Overall, the evidence of the carcino-
genicity of glyphosate is compelling and multifactorial.
APPENDIX: NEOPLASTIC INCIDENCE DATA FROM
MONSANTO
Two-Year Animal Studies
In this section we present selected tables tabulating
tumours and malignancies, separately for male and female
rats, in the long-term study conducted by Lankas & Hogan
and reported on in an unpublished document in 1981 [17].
The rats were exposed to three different doses of
glyphosate added to their feed (3, 10, and 30 mg kg–1 d ay–1)
and compared with unexposed controls.
Similarly, we present tables tabulating all of the
tumours and malignancies that were found, separately for
male and female mice, in the long-term study conducted
by Knezevich & Hogan and reported on in an
unpublished document in 1983 [18]. The mice were
exposed to three different doses of glyphosate added to
their feed (1000, 5000 and 30
000 ppm) and compared
with unexposed controls.

142 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)

Gl
yp
hosate /m
g
k
g
–
1
da
y
–
1
0 3 10 30
PITUITARY
Adenoma 16/48
(33%)
19/49 (3 8%) 20/48 (40%) 18 /47 (36 %)
Carcinoma 3/48(6%) 2/49(4%) 3/48 (6%) 1/47 (2%)
BRAIN
Glio ma 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%)
LUN G
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 Malignan t mixed tumou
r
0/50(0%) 1/50(2%) 0/50(0%) 0/50(0%)
MANDI BUL AR SALIVARY GL AND
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 tumo
u
r 0/50 (0%) 3/50(6%) 1/50(2%) 6/50 (12%)
Tab le A1 . In cide nce of n eop last ic f ind ing s in m ale rat s wi th gl yph osa te a dmin ist ere d by diet . Pa rt I . Da ta ex tra cte d
from Lankas & Hogan (1981) [17].
aMS = metastatic.

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 143
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JBPC Vol. 15 (2015)

Gl
yp
hosate /m
g
k
g
–
1
da
y
–
1
0
3
10 30
PROSTATE
Reticulum cell sarcoma 0/50 (0%) 0/47 (0%) 1/49 (2%) 0/4
9
(0%)
URINARY BLADDER
Papilloma 0/46 (0%) 1/45 (2%) 0/43 (0%) 0/4
6
(0%)
THYROID
C-cell carcinoma 0/47
(
0%
)
0/49
(
0%
)
1/49
(
2%
)
0/4
9
(
0%
)
Follicular adenoma 1/47 (2%) 2/49 (4%) 4/49 (8%) 4/4
9
(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%) 0/5
0
(0%)
Pheochromo-cytoma 8/50 (16%) 8/50 (16%) 5/5
0
(10%) 11/5
0
(22%)
Cortical adenoma 2/50 (4%) 4/50 (8%) 1/50 (2%) 1/5
0
(2%)
SKIN
Basosquamous cell
t
umo
u
r
0/49 (0%) 0/48 (0%) 0/49 (0%)1/4
9
(2%)
Sebaceous gland adenoma
0/49 (0%) 0/48 (0%) 0/49 (0%)1/4
9
(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%) 2/1
0
(20%) 3/7 (43%)
Fibroma 0/10 (0%) 3/12 (24%) 1/1
0
(10%) 2/7 (29%)
N
euro 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%)
Osteogeni c sarcoma 0/10 (0%) 0/ 12 (0%) 1/1
0
(10%) 0/7 (0%)
Mal ignant
m
ixed tumou
r
0/10 (0%) 1/12 (8%) 0/10 (0%) 0/7 (0%)
MEDIASTINAL TI SSUE
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
MSa Islet cell carcinoma 0/0 (0%) 0/0 (0 %) 0/
0
(0%) 1/1 (100%)
SACRAL LYMPH NOD
E
Reticulum cell sarcoma 0/1 (0%) 1/3 (33%) 0/3(0%) 0/3 (0%)
Tab le A2. I ncid ence of ne opla stic findi ngs i n mal e rat s wit h glyp hosa te ad mini ster ed by diet . Part II.
Data extracted from Lankas & Hogan (1981) [17].
aMS = metastatic.

144 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
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JBPC Vol. 15 (2015)
Tab le A3. I nci denc e of n eopl asti c fin ding s in f emal e rat s wit h gl ypho sate admi nist ered by di et. P art I.
Data extracted from Lankas & Hogan (1981) [17]. 
Glyphosate /mg kg
–
1
d ay
–
1
0 3 10 30
PITUITARY
Carcin oma 8/48 (17 %) 7 /48 (15%) 5/50 (1 0%) 12/49 (24%)
BRAIN
Invasi ve pitu itary carcinoma 0 /50 (0%) 0/4 9 ( 0%) 1 /50 (2%) 1/50 (2%)
Mali gnant lymphoma 0/5 0 (0 %) 0/4 9 ( 0% ) 0/50 (0%) 1/50 (2%)
Glioma 0/50 (0%) 0/49 ( 0%) 0/50 (0%) 1/50 (2%)
CERV ICAL SP INAL CORD
Mali gnant lymphoma 0/5 0 (0 %) 0/5 0 ( 0% ) 0/50 (0%) 1 /5 0 (2% )
HEART
Mali gnant lymphoma 0/5 0 (0 %) 0/5 0 ( 0% ) 0/50 (0%) 1/50 (2%)
LUNG
Reti cu lum cell sarco ma 2/49 (4 %) 2/5 0 (4%) 1/49 (2 %) 3 /50 (6%)
Mali gnant lymphoma 0/4 9 (0 %) 1/5 0 ( 2% ) 0/49 (0%) 1/50 (2%)
Adenocarcinoma 0 /49 (0%) 0/50 (0%) 0/49 (0%) 1/50 (2%)
Carcin oma 0 /4 9 (0%) 0/50 ( 0%) 1/49 (2 %) 0/5 0 (0%)
LIVER
Reti cu lum cell sarco ma 2/50 (4 %) 2/5 0 (4%) 1/50 (2 %) 2 /50 (4%)
Mali gnant lymphoma 0/5 0 (0 %) 0/5 0 ( 0% ) 1/50 (2%) 2/50 (4%)
Hepatocellul ar carcinoma 1/50 (2%) 0/50 ( 0%) 0/50 (0%) 2 /50 (4%)
MESENTERIC LYMPH NODE
Mali gnant lymphoma 0/4 2 (0 %) 0/3 9 ( 0% ) 0/48 (0%) 1/47 (2%)
Reti cu lum cell sarco ma 0/42 (0 %) 0/3 9 (0%) 0/48 (0 %) 2 /47 (4%)
PANCREAS
Islet cel l carcinoma 0/50 (0%) 1/5 0 ( 2%) 1 /50 (2%) 1 /4 9 (2%)
MANDIBULAR SALIVARY GLAND
Metastatic fib rosarc oma 0 /48 (0 %) 0/50 ( 0%) 1/49 (2%) 0 /49 (0%)
THYMUS
Mali gnant lymphoma 0/2 5 (0 %) 0/3 2 ( 0% ) 1/37 (3%) 1/34 (3%)
Th ymom a 0/25 (0 %) 0/32 ( 0%) 1/37 (3 %) 0 /3 4 (0% )
MEDIASTINAL LYMPH NO DE
Reti cu lum cell sarco ma 0/33 (0 %) 1/2 9 (3%) 0/37 (0 %) 0 /30 (0%)
Mali gnant lymphoma 0/3 3 (0 %) 0/2 9 ( 0% ) 1/37 (3%) 2/30 (7%)
SPLEEN
Mali gnant lymphoma 0/5 0 (0 %) 0/5 0 ( 0% ) 1/50 (2%) 2/50 (4%)
Reti cu lum cell sarco ma 2/50 (4 %) 2/5 0 (4%) 1/50 (2 %) 5/50 (10 %)
STOMACH
Mali gnant lymphoma 0/5 0 (0 %) 0/5 0 ( 0% ) 0/50 (0%) 1/50 (2%)
JEJUNUM
Leiomyos arc oma 0/5 0 (0 %) 1/4 8 ( 2%) 0 /49 (0 %) 0 /4 9 (0% )
ILEUM
Reti cu lum cell sarco ma 0/47 (0 %) 0/4 9 (0%) 0/49 (0 %) 1 /48 (2%)
COLON
Reti cu lum cell sarco ma 0/50 (0 %) 0/5 0 (0%) 0/49 (0 %) 1 /48 (2%)
URINARY BLADDER
Tr ans itio nal c ell tumo ur 0/50 (0 %) 0/48 ( 0% ) 0 /48 (0%) 1/4 4 (2%)

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 145
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
Gl
yp
hosate /m
g
k
g
–
1
da
y
–
1
0
3
10
30
OVARY
Granu losa cell
t
umo
u
r 8/4
9
(16%) 8/50 (16%) 6/48 (13%) 6/45 (13%)
Theca-granulosa cell tumou
r
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%) 3/4
9
(6%)
6/50 (12%) 3/47 (6%)
C-cell carcinoma 1/47 (2%) 0/4
9
(0%)
2/50 (4%) 6/47 ( 12%)
Met ast atic fibrosarcoma 0/ 47 (0%) 0/4
9
(0%)
1/50 (2%) 0/47 (0%)
PARATHYROID
Aden oma 0/23 (0%) 0 /25
(0%)
0/25 (0%) 1/23 (4%)
ADRENAL
Reticulum cell sarcoma 1/50 (2%) 1/5
0
(2%)
1/50 (2%) 3/49 (6%)
Pheochromo-cytoma 1/50 (2%) 2/5
0
(4%)
2/50 (4%) 2/49 (4%)
Cortical adenoma 5/5
0
(10%) 10/5
0
(20%)
6/50 (12%) 4/49 (8%)
Mal ignant
l
ymph oma 0/ 50 (0%) 0/5
0
(0%)
0/50 (0%) 1/49 (2%)
MAMMARY GLAND (L&R)
Aden oma (L) 4(47) (8%)
7(46) (15%) 10(48) (20%) 5(44) (11 %)
Aden oma (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
Mal ignant
l
ymph oma 0/ 47 (0%) 0/4 5
(0%)
0/47 (0%) 1/44 (2 %)
Invasive fibrosarcoma 0/47 (0%) 0/45
(0%)
1/47 (2%) 0 /44 (0 %
BONE MARRO
W
Mal ignant
l
ymph oma 0/ 46 (0%) 0/4
4
(0%)
1/46 (2%) 1/45 (2 %)
Reticulum cell sarcoma 1/46 (2%) 0/4
4
(0%)
1/46 (2%) 3/45 (6%)
SUBCUTANEOUS TISSUE
Li
p
oma 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%)
MEDI ASTINAL TI SSUE
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%)
MANDIB ULAR LYMPH NOD E
Mal ignant
l
ymph oma 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%)
Tab le A4. In ciden ce of n eopla stic f indin gs in f emale rats w ith gl yphos ate ad mini stere d by di et. Pa rt II.
Data extracted from Lankas & Hogan (1981) [17].

146 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
______________________________________________________________________________________________________
JBPC Vol. 15 (2015)

Glyphosate (
p
pm) 0 Low (1000) Mid (5000) High (30
000)
BRAI N
MS Lymp hoblastic lympho sarcoma 0/49 (0%) 0/ 50 (0%) 1/ 50 ( 2%) 0/50 ( 0%)
with leuk aemic manifest atio ns
HEART
MS Lymp hoblastic lympho sarcoma 0/47 (0%) 1/ 49 (2%) 2/ 49 ( 4%) 1/50 ( 2%)
with leuk aemic manifest atio ns
LUNG S
BN Bronchiolar-alveolar adenoma 5/48 (10%) 9/50 (18%) 9/50 (18%) 9/50 (18%)
MG Bronchi olar-alve ola
r
4/48 (8%) 3/50 (6%)2/50 (4%) 1/50 (2%)
adeno-carcinoma
MS Lymp hoblastic lympho sarcoma 1/48 (2%) 4/ 50 (8%) 3/ 50 ( 6%) 1/50 ( 2%)
with leuk aemic manifest atio ns
MS Lymp hoblastic lympho sarcoma 0/48 (0%) 1/ 50 (2%) 0/ 50 ( 0%) 0/50 ( 0%)
LIVER
MG Hepatoc ell ular ad en ocarcin oma 5/4 9 (10% ) 6 /5 0 (12% ) 6 /50 (1 2%) 4 /50 ( 8%)
BN Hepatocellular adenoma 0/49 (0%) 0/50 (0%) 1/50 (2%) 0/50 (0%)
MG Hepatocell ular carc ino ma 0/49 (0%) 0/ 50 (0%) 0/ 50 (0%) 2/50 ( 4%)
MS Hist iocyti c sarcoma 0/49 ( 0%) 1/50 (2%) 0/50 (0%) 0/5 0 ( 0%)
MS Lipo sarcoma 0/49 (0%) 0/50 (0%) 1/50 (2%) 1/5 0 (2%)
MS Lymp hoblastic lympho sarcoma 1/49 (2%) 4/ 50 (8%) 2/ 50 ( 4%) 2/50 ( 4%)
with leuk aemic manifest atio ns
MESE NTERI C L YMP H NODES
MG Hist iocyti c S arcoma 0/40 (0%) 1/50 (2%) 0/46 (0%) 0/4 9 (0%)
with leuk aemic manifest atio ns
MG Lymphoblastic lympho sarcoma 1/40 (2%) 2/50 (4%) 1/46 (2%) 0/4 9 (0%)
with leuk aemic
m
an ifes tat ions
MS Lymp hoblastic lympho sarcoma 0/40 (0%) 0/ 50 (0%) 1/ 46 ( 2%) 2/49 ( 4%)
with leuk aemic manifest atio ns
MG Lymphoblastic lympho sarcoma 0/40 (0%) 1/50 (2%) 0/46 (0%) 0/4 9 (0%)
MEDIASTINAL LYMPH NODES
MS Hist iocyti c sarcoma 0/45 ( 0%) 1/49 (2%) 0/41 (0%) 0/4 9 ( 0%)
MS Lymp hoblastic lympho sarcoma 1/45 (2%) 2/ 49 (4%) 1/ 41 ( 2%) 2/49 ( 4%)
with leuk aemic manifest atio ns
MG Lymphoblastic lympho sarcoma 0/45 (0%) 0/49 (0%) 2/41 (5%) 0/4 9 (0%)
with leuk aemic manifest atio ns
Tab le A 5. I nci denc e of n eop last ic f indi ngs in ma le m ice w ith glyp hos ate a dmi nist ered by d iet. Par t I. F rom Knez evi ch
& Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 147
______________________________________________________________________________________________________
JBPC Vol. 15 (2015)

Glyphosate (
p
pm) 0 Low (1000) Mid (5000) High (30
000)
SPLEEN
MG Heman gio-endot helioma 0/ 48 (0% ) 0/49 (0%) 1/50 (2%) 0/49 (0%)
MS H istiocytic sarcoma 0/48 (0%) 1/49 (2%) 0 /50 (0 %) 0/49 (0%)
MS Lymphoblastic l ymphosarco ma 1/48 (2%) 2 /49 (4 %) 2 /50 (4 %) 0/49 (0%)
MG Lymph oblastic lymphosarcoma 0/48 (0%) 2/49 (4%) 0 /50 (0 %) 1/49 (2%)
with leu
k
aemic manifestations
PANCREAS
MS H istiocytic Sarc oma 0/48 (0%) 1/48 (2%) 0 /50 (0 %) 0/ 49 (0% )
MS Lymphoblastic l ymphosarco ma 0/48 (0%) 0 /48 (0 %) 1 /49 (2 %) 0/50 (0%)
with leu
k
aemic manifestations
KIDNEYS
BN Renal t ubul e ade noma 0/ 49 (0%) 0/49 (0 %) 1/50 (2%) 3/50 (6%)
MS H istiocytic sarcoma 0/49 (0%) 1/49 (2%) 0 /50 (0 %) 0/50 (0%)
MS C ompo site lymphosarc oma 1/ 49 (2%) 0/49 (0%) 0/50 (0%) 0/50 (0%)
MS Lymphoblastic l ymphosarco ma 1/49 (2%) 3 /49 (6 %) 2 /50 (4 %) 2/50 (4%)
with leu
k
aemic manifestations
ADRENAL GLANDS
BN Corti cal adeno ma 1/ 48 (2%) 2/49 (4%) 0 /50 (0%) 1/ 48 (2%)
MS Lymphoblastic l ymphosarco ma 0/48 (0%) 1 /49 (2 %) 0 /50 (0 %) 0/48 (0%)
with leu
k
aemic manifestations
BN Lymphoblasti c ly mpho sarcoma 0/ 48 (0%) 0/49 (0 %) 1/49 (2%) 0/48 (0%)
with leu
k
aemic 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 MARRO
W
MS Lymphoblastic l ymphosarco ma 1/40 (2%) 2 /45 (4 %) 1 /47 (2 %) 1/49 (2%)
with leu
k
aemic manifestations
LYMPH NODE
MS H istiocytic sa rcoma 0/0 (0%) 1/3 (33%) 0/2 (0%) 0/2 (0%)
MS Compo site lymph osarcoma 0/ 0 (0% ) 0 /3 (0%) 1/2 (50%) 0/2 (0%)
MS Lymphoblastic l ymphosarco ma 0/0 (0%) 1/3 (33%) 1 /2 (50 %) 0/2 (0%)
with leu
k
aemic manifestations
MG Lymph oblastic lymphosarcoma 0/0 (0%) 0/3 (0%) 0/2 (0% ) 1/2 (50%)
with leu
k
aemic manifestations
TESTES
BN Inter sti tial cell t umor 1/49 (2%) 0 /48 (0%) 2 /50 (4 %) 0/50 (0% )
MS Lymphoblastic l ymphosarco ma 0/49 (0%) 1 /48 (2 %) 0 /50 (0 %) 0/50 (0%)
with leu
k
aemic manifestations
BN Lymphoblasti c ly mpho sarcoma 0/ 49 (0%) 0/48 (0 %) 1/50 (2%) 0/50 (0%)
with leu
k
aemic manifestations
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.

148 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
______________________________________________________________________________________________________
JBPC Vol. 15 (2015)
Tab le A7 . In cide nce of n eop last ic f ind ing s in f ema le m ice wit h gly pho sat e ad mini ste red by d iet. Par t I. Fro m Kn ezev ich
& Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.

Controls
Low
Mid Hi
g
h
Glyphosate (
p
pm) 0 Low (1000) Mid (5000) High (30 000)
BRAIN
MS L
y
m
p
hobl astic l
y
m
p
hosarcoma 0/50
(
0%
)
0/49
(
0%
)
1/50
(
2%
)
0/50
(
0%
)
with leukaemic manife stations
HEART
MS Lymphoblastic lymphosarcoma 0/50 (0%) 0/50 (0%) 2/50(4%) 0/49(0%)
with leukaemic manife stations
LUNGS
BN Bronchiola
r
-alveolar adenoma 10/49 (20%) 9 /50 ( 18%) 10/49 (20%) 1/50 (2%)
MG Bronchiola
r
-alveolar adenocarcinoma 1/49 (2%) 3/50 (6%) 4/49 (8%) 4/50 (8%)
BN Granulosa cell tumou
r
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 leu
k
aemic manifestations
MS L
y
m
p
hobl astic l
y
m
p
hosarcoma 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 leu
k
aemia 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 L
y
m
p
hobl astic l
y
m
p
hosarcoma 1/49
(
2%
)
4/50
(
8%
)
4/49
(
8%
)
1/49
(
2%
)
with leukaemic manife stations
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 leu
k
aemia 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 manife stations
MS Lymphoblastic lymphosarcoma 1/49 (2%) 1/49 (2%) 3/48(6%) 0/48 (0%)
with leukaemic manife stations
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%)

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 149
______________________________________________________________________________________________________
JBPC Vol. 15 (2015)
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.

Cont rol
s
Low Mi d H i
g
h
Glyphosate (
p
pm) 0 Low (1000 ) Mid (5000) High (30
000)
MEDI ASTIN AL LY MPH NODES
MS Leimyosarcoma 0/ 42 (0%) 1 /48 (2 %) 0/39 (0% ) 0/ 47 (0%)
MS Granulocyt ic leukaemia 0/42 (0%) 1 /48 (2%) 0/ 39 (0%) 0/ 47 (0%)
MS
L
iposarcoma 1/42 (2%) 0/48 (0%) 0/39 (0%) 0/47 (0%)
MS Co mp osite lymphos arcoma 1/ 42 (2% ) 1 /48 (2 %) 0/39 (0% ) 2/ 47 (4%)
MS Ly mpho blast ic ly mphosarc oma 0/ 42 (0%) 1 /48 (2 %) 3/39 (8% ) 0/ 47 (0%)
with leuk aemic manifestatio ns
MG Ly mp hobl astic l ymphosarc oma 1/ 42 (2%) 1 /48 (2 %) 2/39 (5% ) 0/ 47 (0%)
with leuk aemic manifestatio ns
MS
L
ymphoblastic lymphosarcoma 0/42 (0%) 1/48 (2%) 0/39 (0%) 1/47 (2%)
SALIVARY GLAND
MS Leiomyosar coma 0/50 (0%) 0 /50 (0 %) 1/50 (2% ) 0/ 47 (0%)
SPLEEN
MG Hemang io-end othe lioma 1/ 50 (2%) 0 /48 (0%) 2/ 49 (4%) 1/49 (2%)
MG Granuloc ytic leukemi a 0/50 (0%) 3 /48 (6%) 0/49 (0%) 0/ 49 ( 0%)
MS Hema ngio- en diot helio ma 0/50 (0%) 0 /48 (0 %) 0/49 (0% ) 1/ 49 (2%)
MS Ly mpho blast ic ly mphosarc oma 1/ 50 (2%) 2 /48 (4 %) 2/49 (4% ) 0/ 49 (0%)
with leuk aemic manifestatio ns
MG
L
ymphoblastic lymphosarcoma 0/50 (0%) 0/48 (0%) 2/49 (4%) 0/49 (0%)
with leuk aemic manifestatio ns
MG Composit e ly mpho sarcoma 1/ 50 (2%) 1/48 (2%) 1/49 (2%) 5/49 10% )
MS Ly mpho blast ic ly mphosarc oma 0/ 50 (0%) 0 /48 (0 %) 0/49 (0% ) 1/ 49 (2%)
STOMACH
MG Le iomyosa rcoma 0/48 (0%) 0 /49 (0 %) 1/50 (2% ) 0/ 50 (0%)
MG Gastri c ade nos arco ma 0/ 48 (0%) 0 /49 (0%) 1/ 50 (2%) 0/50 (0%)
PANCREAS
MS Granulocyt ic leukaemia 0/47 (0%) 1 /47 (2%) 0/ 49 (0%) 0/ 50 (0%)
MS Co mp osite lymphos arcoma 2/ 47 (4% ) 1 /47 (2 %) 0/49 (0% ) 1/ 50 (2%)
MS Ly mpho blast ic ly mphosarc oma 1/ 47 (2%) 1 /47 (2 %) 1/49 (2% ) 0/ 50 (0%)
with leuk aemic manifestatio ns
KIDNEYS
MS Leiomyosar coma 0/50 (0%) 1 /50 (2 %) 0/50 (0% ) 0/ 50 (0%)
MS Granulocyt ic leukaemia 0/50 (0%) 1 /50 (2%) 0/ 50 (0%) 0/ 50 (0%)
MS Co mp osite lymphos arcoma 2/ 50 (4% ) 1 /50 (2 %) 1/50 (2% ) 2/ 50 (4%)
MS Ly mpho blast ic ly mphosarc oma 1/ 50 (2%) 2 /50 (4 %) 3/50 (6% ) 1/ 50 (2%)
with leuk aemic manifestatio ns
MS Ly mpho blast ic ly mphosarc oma 0/ 50 (0%) 0 /50 (0 %) 0/50 (0% ) 1/ 50 (2%)

150 A. Samsel and S. Seneff Glyphosate, pathways to modern diseases IV
______________________________________________________________________________________________________
JBPC Vol. 15 (2015)
Tab le A9. In cide nce of neop last ic fin ding s in fe male mice with g lyph osat e admi nist ered by die t. Pa rt III . Fro m
Knezevich & Hogan,1983 [18]. BN = Benign, MG = Malignant, MS = Metastatic.

Controls
Low
Mid High
Glyph osate (pp
m
)
0
Low (1000) Mid (5000) High (30
000)
URINARY BLADDER
MS Gra nul ocytic leukaemia 0/47 (0%) 1/ 43 (2% ) 0 /49 (0 %) 0 /48 (0 %)
MS Composite ly mpho sarcoma 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 leuk aemic manifestations
OVARIES
MG Tera to ma 0/47 (0%) 1/47 (2%) 0/50 (0%) 0/47 (0%)
MG Granulosa cell tumo
u
r
0/47 (0%)1/47 (2%) 0/50 (0%) 0/47 (0%)
MS Lei omyosarc oma 0/47 (0 %) 1/47 (2%) 0 /50 (0 %) 0/47 (0 %)
MS L
y
m
p
hoblastic l
y
m
p
hosarcoma
0/47
(
0%
)
1/47
(
2%
)
0/50
(
0%
)
0/47
(
0%
)
with leuk aemic manifestations
MS/BN Lymphoblastic lympho sar- 1 /47 (2 %) 0/47 (0%) 2 /50 (4 %) 0/47 (0 %)
coma with leukaemic manifestations
UTERUS
MS Lei omyoma 2 /49 (4 %) 1/48 ( 2%) 1/4 9 (2%) 1 /50 (2 %)
MG Lei omyosarcoma 2 /49 (4 %) 3/48 ( 6%) 2/4 9 (4%) 3 /50 (6 %)
MG Endo metrial st ro mal ce ll car cinoma 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 Haemangi o-endiothel io ma 0 /49 (0 %) 0/48 ( 0%) 0/4 9 (0%) 1 /50 (0 %)
MS L
y
m
p
hoblastic l
y
m
p
hosarcoma
0/49
(
0%
)
3/48
(
6%
)
1/49
(
2%
)
0/50
(
0%
)
with leuk aemic manifestations
CERVIX
MG Lei omyosarcoma 0/0 (0 %) 2 /2 (10 0%) 0/0 (0%) 0/1 (0%)
THYROID
MS Fol licula r adenoma 0/43 (0%) 0/ 37 ( 0%) 1/49 (2 %) 0 /48 (0%)
SKIN
MG Fib rosarc oma 0 /45 (0 %) 1/45 (2%) 1/4 9 (2%) 0 /48 (0 %)
MAMMARY
MG Ductal adenoc arc inoma 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 leuk aemic manifestations
BONE MARROW
MS Lymphoblastic lymphosarcoma
0/46 (0%) 1/49 (2%) 3/47 (6%) 1/49 (2%)
with
l
eukaemic manifestations
MS Lymphoblastic lymphosarcoma
0/46 (0%) 0/49 (0%) 0/47 (0%) 2/49 (4%)
MS Composite ly mpho sarcoma 0/46 (0%) 0/ 49 ( 0%) 0/47 (0 %) 1/49 (2%)

Glyphosate, pathways to modern diseases IV A. Samsel and S. Seneff 151
______________________________________________________________________________________________________
JBPC Vol. 15 (2015)
ACKNOWLEDGMENTS
This work benefited from discussions with Yi-Wan Chen,
Nancy Swanson, Bob Davidson, James Beecham and
Gerry Koenig. This work was funded in part by Quanta
Computers, Taipei, Taiwan, under the auspices of the
Qmulus Project.
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