Glifosat
Glifosat
Glifosat
1. Exposure Data
O
H
1.1.1 Nomenclature
Chem. Abstr. Serv. Reg. No.: 1071-83-6 (acid);
also relevant:
38641-94-0 (glyphosate-isopropylamine salt)
40465-66-5 (monoammonium salt)
69254-40-6 (diammonium salt)
34494-03-6 (glyphosate-sodium)
81591-81-3 (glyphosate-trimesium)
Chem. Abstr. Serv. Name: N-(phosphono
methyl)glycine
Preferred IUPAC Name: N-(phosphono
methyl)glycine
Synonyms: Gliphosate; glyphosate; glyphosate hydrochloride; glyphosate [calcium,
copper (2+), dilithium, disodium, magnesium, monoammonium, monopotassium,
monosodium, sodium, or zinc] salt
Trade names: Glyphosate products have been
sold worldwide under numerous trade names,
including: Abundit Extra; Credit; Xtreme;
Glifonox; Glyphogan; Ground-Up; Rodeo;
Roundup; Touchdown; Tragli; Wipe Out;
Yerbimat (Farm Chemicals International,
2015).
OH
P
H2C
OH
CH 2
HO
C
O
Manufacturing processes
Glyphosate
facilitate uptake by plants (Szkcs & Darvas,
2012). Formulations might contain other active
ingredients, such as simasine, 2,4-dichlorophen
oxyacetic acid (2,4-D), or 4-chloro-2-methylphenoxyacetic acid (IPCS, 1996), with herbicide
resistance driving demand for new herbicide
formulations containing multiple active ingredients (Freedonia, 2012).
(b)
Production volume
1.2.2 Uses
Glyphosate is a broad-spectrum, post-emergent,
non-selective, systemic herbicide, which effectively
kills or suppresses all plant types, including grasses,
perennials, vines, shrubs, and trees. When applied
at lower rates, glyphosate is a plant-growth regulator
and desiccant. It has agricultural and non-agricultural uses throughout the world.
(a) Agriculture
Glyphosate is effective against more than 100
annual broadleaf weed and grass species, and
more than 60 perennial weed species (Dill et al.,
2010). Application rates are about 1.52 kg/ha
for pre-harvest, post-planting, and pre-emergence use; about 4.3kg/ha as a directed spray in
vines, orchards, pastures, forestry, and industrial
weed control; and about 2 kg/ha as an aquatic
herbicide (Tomlin, 2000). Common application
methods include broadcast, aerial, spot, and
directed spray applications (EPA, 1993a).
Due to its broad-spectrum activity, the
use of glyphosate in agriculture was formerly
limited to post-harvest treatments and weed
control between established rows of tree, nut,
and vine crops. Widespread adoption of no-till
and conservation-till practices (which require
chemical weed control while reducing soil
erosion and labour and fuel costs) and the introduction of transgenic crop varieties engineered
to be resistant to glyphosate have transformed
glyphosate to a post-emergent, selective herbicide for use on annual crops (Duke & Powles,
2009; Dill et al. 2010). Glyphosate-resistant
transgenic varieties have been widely adopted
for the production of corn, cotton, canola, and
soybean (Duke & Powles, 2009). Production
of such crops accounted for 45% of worldwide
demand for glyphosate in 2012 (Transparency
Market Research, 2014). However, in Europe,
3
Residential use
Other uses
Glyphosate
Assay procedure
Limit of detection
Reference
Water
0.08 g/L
0.05 g/L
0.02 g/L
6.0 g/L
Abraxis (2005)
Hidalgo et al. (2004)
EPA (1992)
1.1 g/L
0.02 mg/kg
0.0007 mg/kg
0.01 ng/m3
1.2 g/kg
0.0070.12 mg/kg
0.3 mg/kg
Soil
Dust
Air
Fruits and vegetables
Field crops
(rice, maize and soybean)
Plant vegetation
Serum
Urine
0.03 g/mL
Yoshioka et al. (2011)
0.02 g/mL
(aminomethylphosphonic acid)
0.01 g/mL
(3-methylphosphinicopropionic acid)
1 g/L
Acquavella et al. (2004)
Curwin et al. (2007)
0.9 g/L
ELISA, enzyme-linked immunosorbent assay; ESI-MS/MS, electrospray tandem mass spectrometry; FD, fluorescence detection; GC-MSMID, gas chromatography-mass spectrometry in multiple ion detection mode; HILIC/WAX, hydrophilic interaction/weak anion-exchange
liquid chromatography; HPLC/MS, high-performance liquid chromatography with mass spectrometry; HPLC, high-performance liquid
chromatography; LC-ESIMS/MS, liquid chromatography-electrospraytandem mass spectrometry; LCLC, coupled-column liquid
chromatography; LCMS/MS, liquid chromatographytandem mass spectrometry
1.4.1 Exposure
(a)
(b)
Community exposure
6
Median, 16 mg/m3 in 85% of 21 personal
air samples for workers spraying with
mechanized all-terrain vehicle
Median, 0.12 mg/m3 in 33% of 12
personal air samples collected from
workers with backpack with lance
applications
Municipal weed
control workers
(n = 18)
Weed control
United Kingdom,
year NR
USA, year NR
Results
Workers performing
silvicultural clearing
(n = 5)
Mixer
Overseer
Operator
Signaller
Job/process
Finland, year NR
Forestry
Canada, 1986
Industry,
country, year
Centre de Toxicologie
du Qubec (1988)
Reference
Comments/additional data
Occupational and
para-occupational
exposure of 24
farm families (24
fathers, 24 mothers
and 65 children).
Comparison group:
25 non-farm families
(23 fathers, 24
mothers and 51
children)
Occupational and
para-occupational
exposures of 48
farmers, their
spouses, and 79
children
Job/process
Results
USA, year NR
Farming
USA, 2001
Industry,
country, year
Comments/additional data
Reference
Glyphosate
Biological markers
Glyphosate concentrations in urine were
analysed in urban populations in Europe, and
in a rural population living near areas sprayed
for drug eradication in Colombia (MLHB, 2013;
Varona et al., 2009). Glyphosate concentrations
in Colombia were considerably higher than in
Europe, with means of 7.6ng/L and 0.02g/L,
respectively (Table 1.5). In a study in Canada,
glyphosate concentrations in serum ranged from
undetectable to 93.6 ng/mL in non-pregnant
women (n=39), and were undetectable in serum
of pregnant women (n=30) and fetal cord serum
(Aris & Leblanc, 2011).
51 streams/agricultural areas
(154 samples)
USA, 2002
USA, 2002
Denmark, 20102012
Maximum concentration,
30.1g/L (minimum and mean,
NR)
Range, <0.131.0 g/L
Maximum glyphosate
concentration, 5.1 g/L
Maximum AMPA concentration,
3.67 g/L
Results
AMPA, aminomethylphosphonic acid; MDL, method detection limit; NR, data not reported
Colombia, year NR
Canada, 2002
Number of samples/setting
Country, year of
sampling
Comments/additional data
Reference
Glyphosate
10
Cereals
27 European Union
member states, Norway
and Iceland, 2007
Australia, 2006
Results
Comments/additional data
30 pregnant women
and 39 non-pregnant
women
Results
AMPA, aminomethylphosphonic acid; LOD, limit of detection; ND, not detected; NR, not reported
Serum
Canada, NR
162 individuals
Urine
18 European countries, 2013
Colombia, 20052006
Subjects
Country, period
Comments/additional data
Table 1.5 Concentrations of glyphosate and AMPA in urine and serum in the general population
Type of food
Country, year
MLHB (2013)
Reference
EFSA (2009)
Reference
Glyphosate
2. Cancer in Humans
2.0 General discussion of
epidemiological studies
A general discussion of the epidemiological
studies on agents considered in Volume 112 of
the IARC Monographs is presented in Section 2.0
of the Monograph on Malathion.
12
Reference,
study location,
enrolment
period/followup, study-design
De Roos et al.
(2005a)
Iowa and North
Carolina, USA
19932001
NHL
Multiple
myeloma
Melanoma
Lung
Organ site
(ICD code)
Exposed
cases/
deaths
Ever use
147
Cumulative
exposure
days:
120
40
2156
26
572678
26
Trend-test P value: 0.21
Ever use
75
120
23
2156
20
572678
14
Trend-test P value: 0.77
Ever use
32
Ever use
32
120
8
2156
5
Trend-test P value: 0.27
Ever use
92
120
29
2156
15
572678
17
Trend-test P value: 0.73
Exposure
category or
level
1.1 (0.71.9)
1 (ref.)
0.7 (0.41.4)
0.9 (0.51.6)
1.1 (0.52.4)
2.6 (0.79.4)
1 (ref.)
1.1 (0.43.5)
1.6 (0.83)
1 (ref.)
1.2 (0.72.3)
0.9 (0.51.8)
1 (ref.)
0.9 (0.51.5)
0.7 (0.41.2)
0.9 (0.61.3)
Age only
(results in this
row only)
Age, smoking,
other
pesticides,
alcohol
consumption,
family history
of cancer,
education
AHS
Cancer sites
investigated: lung,
melanoma, multiple
myeloma and NHL
(results tabulated) as
well as oral cavity,
colon, rectum, pancreas,
kidney, bladder, prostate
and leukaemia (results
not tabulated)
[Strengths: large cohort;
specific assessment
of glyphosate;
semiquantitative
exposure assessment.
Limitations: risk
estimates based on
self-reported exposure;
limited to licensed
applicators; potential
exposure to multiple
pesticides]
Comments
Flower et al.
(2004)
Iowa and North
Carolina, USA
Enrolment,
19931997;
follow-up,
19751998
Engel et al.
(2005)
Iowa and North
Carolina, USA
Enrolment,
19931997
follow-up to
2000
Reference,
study location,
enrolment
period/followup, study-design
Rectum
Colon
Colorectum
Breast
Childhood
cancer
Organ site
(ICD code)
Exposed to
glyphosate
Exposed to
glyphosate
Exposed to
glyphosate
Direct
exposure to
glyphosate
Husbands
use of
glyphosate
Maternal
use of
glyphosate
(ever)
Paternal
use of
glyphosate
(prenatal)
Exposure
category or
level
74
151
1.2 (0.91.6)
1.3 (0.81.9)
109
225
0.9 (0.71.1)
0.84
(0.352.34)
82
0.61
(0.321.16)
Age, smoking,
state, total
days of any
pesticide
application
Childs age at
enrolment
13
Exposed
cases/
deaths
AHS
Glyphosate results relate
to the Iowa participants
only
[Strengths: Large cohort;
specific assessment of
glyphosate. Limitations:
based on self-reported
exposure; potential
exposure to multiple
pesticides; limited
power for glyphosate
exposure]
AHS
[Strengths: large cohort;
specific assessment of
glyphosate. Limitations:
based on self-reported
exposure; limited to
licensed applicators;
potential exposure to
multiple pesticides]
AHS
[Strengths: large cohort.
Limitations: based on
self-reported exposure,
limited to licensed
applicators, potential
Comments
Glyphosate
13
14
Andreotti et al.
(2009)
Iowa and North
Carolina, USA
Enrolment,
19931997;
follow-up to
2004
Nested case
control study
Pancreas
(C25.0
C25.9)
Organ site
(ICD code)
AHS, Agricultural Health Study; NHL, non-Hodgkin lymphoma; NR, not reported
Reference,
study location,
enrolment
period/followup, study-design
Age, smoking,
diabetes
Ever
55
1.1 (0.61.7)
exposure to
glyphosate
Low
29
(<185 days)
High
19
(185 days)
Trend-test P value: 0.85
Exposure
category or
level
AHS
[Strengths: large cohort.
Limitations: based on
self-reported exposure;
limited to licensed
applicators; potential
exposure to multiple
pesticides]
Comments
Glyphosate
(De Roos et al., 2005b). [The study had limited
power for the analysis of multiple myeloma; there
were missing data on covariates when multiple
adjustments were done, limiting the interpretation of the findings.] A re-analysis of these data
conducted by Sorahan (2015) confirmed that the
excess risk of multiple myeloma was present only
in the subset with no missing information (of 22
cases in the restricted data set). In a subsequent
cross-sectional analysis of 678 male participants
from the same cohort, Landgren et al. (2009)
did not find an association between exposure to
glyphosate and risk of monoclonal gammopathy
of undetermined significance (MGUS), a premalignant plasma disorder that often precedes
multiple myeloma (odds ratio, OR, 0.5; 95% CI,
0.21.0; 27 exposed cases).
Flower et al. (2004) reported the results of the
analyses of risk of childhood cancer associated
with pesticide application by parents in the AHS.
The analyses for glyphosate were conducted
among 17357 children of Iowa pesticide applicators from the AHS. Parents provided data
via questionnaires (19931997) and the cancer
follow-up (retrospectively and prospectively)
was done through the state cancer registries.
Fifty incident childhood cancers were identified (19751998; age, 019 years). For all the
children of the pesticide applicators, risk was
increased for all childhood cancers combined,
for all lymphomas combined, and for Hodgkin
lymphoma, compared with the general population. The odds ratio for use of glyphosate and risk
of childhood cancer was 0.61 (95% CI, 0.321.16;
13 exposed cases) for maternal use and 0.84 (95%
CI, 0.352.34; 6 exposed cases) for paternal use.
[The Working Group noted that this analysis
had limited power to study a rare disease such as
childhood cancer.]
Engel et al. (2005) reported on incidence of
cancer of the breast among farmers wives in the
AHS cohort, which included 30454 women with
no history of cancer of the breast before enrolment in 19931997. Information on pesticide use
Cantor et al.
(1992)
Iowa and
Minnesota, USA
19801982
USA
Brown et al.
(1990)
Iowa and
Minnesota, USA
19811983
Reference,
location,
enrolment
period
Organ site
(ICD code)
Ever handled
glyphosate
Any
glyphosate
Exposure
category or
level
26
15
1.1 (0.71.9)
0.9 (0.51.6)
Table 2.2 Casecontrol studies of leukaemia and lymphoma and exposure to glyphosate
Age, vital
status, state,
smoking status,
family history
lymphopoietic
cancer, high-risk
occupations,
high-risk
exposures
Covariates
controlled
Data subsequentially
pooled in De Roos
et al. (2003); white
men only
[Strengths: large
population-based
study in farming
areas.
Limitations: not
controlled for
exposure to other
pesticides. Limited
power for glyphosate
exposure]
[Strengths: large
population based
study in a farming
area.
Limitations: not
controlled for
exposure to other
pesticides. Limited
power for glyphosate
exposure]
Comments
Glyphosate
17
18
De Roos et al.
(2003)
Nebraska, Iowa,
Minnesota,
Kansas, USA
19791986
Brown et al.
(1993)
Iowa, USA
19811984
Organ site
(ICD code)
Reference,
location,
enrolment
period
Any
glyphosate
exposure
Any
glyphosate
Exposure
category or
level
36
11
2.1 (1.14)
1.7 (0.83.6)
Covariates
controlled
Both logistic
regression and
hierarchical regression
were used in data
analysis, the latter
providing more
conservative estimates
[Strengths: increased
power when compared
with other studies,
population-based, and
conducted in farming
areas. Advanced
analytical methods to
account for multiple
exposures]
Included participants
from Cantor et al.
(1992), Zahm et al.
(1990), Hoar et al.
(1986), and Brown et
al. (1990)
[Strengths:
population-based
study. Areas with high
prevalence of farming.
Limitations: limited
power for glyphosate
exposure]
Comments
Canada
McDuffie et al.
(2001)
Canada
19911994
Reference,
location,
enrolment
period
NHL
NHL
Organ site
(ICD code)
1.2 (0.43.3)
1
1.0 (0.631.57)
2.12 (1.23.73)
51
464
28
23
Unexposed
>0 and 2
days
>2 days
1.2 (0.831.74)
1.4 (0.982.1)
53
Exposed to
glyphosate
Exposed to
glyphosate
nonasthmatics
Exposed to
glyphosate
asthmatics
Exposure
category or
level
Age, province of
residence
Covariates
controlled
Cross-Canada study
[Strengths: large
population based
study. Limitations:
no quantitative
exposure data.
Exposure assessment
by questionnaire.
Relatively low
participation]
177 participants
(45 NHL cases, 132
controls) reported
having been told by
their doctor that they
had asthma
Comments
Glyphosate
19
20
Reference,
location,
enrolment
period
Karunanayake
et al. (2012)
Six provinces
in Canada
(Quebec, Ontario,
Manitoba,
Saskatchewan,
Alberta, and
British Columbia)
19911994
HL (ICDO2
included
nodular
sclerosis
(M9656/3;
M9663/3;
M9664/3;
M9665/3;
M9666/3;
M9667/3),
lymphocytic
predominance
(M9651/3;
M9657/3;
M9658/3;
M9659/3),
mixed
cellularity
(M9652/3),
lymphocytic
depletion
(M9653/3;
M9654/3),
miscellaneous
(other
M9650-M9669
codes for HL)
Organ site
(ICD code)
Glyphosatebased
formulation
Glyphosatebased
formulation
Exposure
category or
level
38
38
Covariates
controlled
Age group,
province of
residence
0.99 (0.621.56) Age group,
province of
residence, medical
history
1.14 (0.741.76)
Comments
Kachuri et al.
(2013)
Six Canadian
provinces (British
Columbia,
Alberta,
Saskatchewan,
Manitoba,
Ontario and
Quebec)
19911994
Sweden
Nordstrm et al.
(1998)
Sweden
19871992
Reference,
location,
enrolment
period
HCL
Multiple
myeloma
Organ site
(ICD code)
Exposed to
glyphosate
Glyphosate
use
Use of
glyphosate
(>0 and
2days per
year)
Use of
glyphosate
(>2days per
year)
Exposure
category or
level
3.1 (0.812)
Age
2.04 (0.984.23)
12
15
Covariates
controlled
32
Cross-Canada study
[Strengths:
population-based
casecontrol study.
Limitations: relatively
low response rates]
Comments
Glyphosate
21
22
Hardell &
Eriksson (1999)
Northern and
middle Sweden
19871990
Hardell et al.
(2002)
Sweden; four
Northern
counties and
three counties in
mid Sweden
19871992
Reference,
location,
enrolment
period
NHL (ICD-9
200 and 202)
Organ site
(ICD code)
Ever
glyphosate
exposure
(univariate)
Ever
glyphosate
exposure
(multivariate)
Ever
glyphosate
univariate
Ever
glyphosate
multivariate
Exposure
category or
level
3.04 (1.088.5)
1.85 (0.556.2)
5.8 (0.654)
NR
2.3 (0.413)
Not specified in
the multivariable
analysis
Covariates
controlled
Overlaps with
Nordstrm et al.
(1998) and Hardell &
Eriksson (1999),
[Strengths: large
population-based
study. Limitations:
limited power for
glyphosate exposure]
Comments
Reference,
location,
enrolment
period
Eriksson et al.
(2008)
Sweden. Four
health service
areas (Lund,
Linkoping,
Orebro and
Umea)
19992002
B-cell
lymphoma
Lymphocytic
lymphoma/BCLL
Diffuse
large B-cell
lymphoma
Follicular,
grade IIII
Other
specified B-cell
lymphoma
Unspecified
B-cell
lymphoma
T-cell
lymphoma
Unspecified
NHL
NHL
NHL
Organ site
(ICD code)
2.29 (0.5110.4)
5.63 (1.4422)
NR
NR
Exposure to
glyphosate
Exposure to
glyphosate
1.47 (0.336.61)
NR
1.63 (0.534.96)
NR
Exposure to
glyphosate
1.89 (0.625.79)
NR
Exposure to
glyphosate
Exposure to
glyphosate
1.22 (0.443.35)
3.35 (1.427.89)
NR
NR
1.11 (0.245.08)
2.26 (1.164.4)
1.87 (0.9983.51)
2.36 (1.045.37)
17
NR
NR
NR
1.69 (0.74.07)
1.51 (0.772.94)
29
12
2.02 (1.13.71)
29
Exposure to
glyphosate
10 days per
year use
>10 days per
year use
110 yrs
>10 yrs
Exposure to
glyphosate
Exposure to
glyphosate
Any
glyphosate
Any
glyphosate*
Exposure
category or
level
Age, sex, year of
enrolment
Covariates
controlled
[Strengths:
population-based
case-control.
Limitations: limited
power for glyphosate]
* Exposure to other
pesticides (e.g. MPCA)
controlled in the
analysis
Comments
Glyphosate
23
24
Reference,
location,
enrolment
period
LPS/HCL
LPS/CLL
NHL, diffuse
large cell
lymphoma
NHL, follicular
lymphoma
All lymphoid
neoplasms
MM
LPS
HL
NHL
Organ site
(ICD code)
Occupational
use of
glyphosate
Occupational
exposure to
glyphosate
Occupational
exposure to
glyphosate
Occupational
exposure to
glyphosate
Any
glyphosate
exposure
Any exposure
to glyphosate
Any exposure
to glyphosate
Any exposure
to glyphosate
Any exposure
to glyphosate
Exposure
category or
level
1.8 (0.39.3)
0.4 (0.11.8)
1.4 (0.45.2)
3
2
1.0 (0.32.7)
1.2 (0.62.1)
2.4 (0.87.3)
0.6 (0.22.1)
1.7 (0.65)
1.0 (0.52.2)
27
12
Age, centre,
socioeconomic
category (blue/
white collar)
Covariates
controlled
[Limitations: limited
power for glyphosate]
Comments
Cocco et al.
(2013)
Czech Republic,
France, Germany,
Italy, Ireland and
Spain
19982004
B-cell
lymphoma
Organ site
(ICD code)
Occupational
exposure to
glyphosate
Exposure
category or
level
4
3.1 (0.617.1)
Covariates
controlled
Comments
ALL, acute lymphocytic leukaemia; B-CLL, chronic lymphocytic leukaemia; CLL, chronic lymphocytic leukaemia; HCL, hairy cell leukaemia; HL, Hodgkin lymphoma; LPS,
lymphoproliferative syndrome; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; NR, not reported; ref., reference; STS, soft tissue
sarcoma
Reference,
location,
enrolment
period
Glyphosate
25
McDuffie et al. (2001) studied the associations between exposure to specific pesticides and
NHL in a multicentre population-based study
with 517 cases and 1506 controls among men of
six Canadian provinces (see the Monograph on
Malathion, Section 2.0, for a detailed description of this study). Odds ratios of 1.26 (95%
CI, 0.871.80; 51 exposed cases; adjusted for
age and province) and 1.20 (95% CI, 0.831.74,
adjusted for age, province, high-risk exposures)
were observed for exposure to glyphosate. In an
analysis by frequency of exposure to glyphosate,
participants with > 2 days of exposure per year
had an odds ratio of 2.12 (95% CI, 1.203.73, 23
26
Glyphosate
controls (matched by age, sex, county, and vital
status). Increased risks of NHL were found for
subjects exposed to herbicides and fungicides.
The odds ratio for ever-use of glyphosate was 2.3
(95% CI, 0.413; 4 exposed cases) in a univariate
analysis, and 5.8 (95% CI, 0.654) in a multivariable analysis. [The exposure frequency was low
for glyphosate, and the study had limited power
to detect an effect. The variables included in the
multivariate analysis were not specified. This
study may have overlapped partially with those
of Hardell et al. (2002).]
Hardell et al. (2002) conducted a pooled analysis of two casecontrol studies, one on NHL
(already reported in Hardell & Eriksson, 1999)
and another on hairy cell leukaemia, a subtype
of NHL (already reported by Nordstrm et al.,
1998). The pooled analysis of NHL and hairy
cell leukaemia was based on 515 cases and 1141
controls. Increased risk was found for exposure
to glyphosate (OR, 3.04; 95% CI, 1.088.52; 8
exposed cases) in the univariate analysis, but the
odds ratio decreased to 1.85 (95% CI, 0.556.20)
when study, study area, and vital status were
considered in a multivariate analysis. [The exposure frequency was low for glyphosate and the
study had limited power. This study partially
overlapped with those of Hardell & Eriksson
(1999) and Nordstrm et al. (1998).]
Eriksson et al. (2008) reported the results of
a population based casecontrol study of exposure to pesticides as a risk factor for NHL. Men
and women aged 1874 years living in Sweden
were included from 1 December 1999 to 30
April 2002. Incident cases of NHL were enrolled
from university hospitals in Lund, Linkping,
rebro, and Ume. Controls (matched by age
and sex) were selected from the national population registry. Exposure to different agents was
assessed by questionnaire. In total, 910 (91%)
cases and 1016 (92%) controls participated.
Multivariable models included agents with
statistically significant increased odds ratios
(MCPA, 2-methyl-4-chlorophenoxyacetic acid),
Glyphosate
30
2.4. Meta-analyses
Schinasi & Leon (2014) conducted a systematic review and meta-analysis of NHL and occupational exposure to agricultural pesticides,
including glyphosate. The meta-analysis for
glyphosate included six studies (McDuffie et al.,
2001; Hardell et al., 2002; De Roos et al., 2003;
2005a; Eriksson et al., 2008; Orsi et al., 2009) and
yielded a meta risk-ratio of 1.5 (95% CI, 1.12.0).
[The Working Group noted that the most fully
adjusted risk estimates from the articles by
Hardell et al. (2002) and Eriksson et al. (2008)
were not used in this analysis. After considering
the adjusted estimates of the two Swedish studies
in the meta-analysis, the Working Group estimated a meta risk-ratio of 1.3 (95% CI, 1.031.65),
I2=0%, P for heterogeneity 0.589.]
Males
Haemangiosarcoma: 0/50, 0/50,
0/50, 4/50 (8%)
Histiocytic sarcoma in the
lymphoreticular/haemopoietic
tissue: 0/50, 2/50 (4%), 0/50, 2/50
(4%)
Females
Haemangiosarcoma: 0/50, 2/50
(4%), 0/50, 1/50 (2%)
Histiocytic sarcoma in the
lymphoreticular/haemopoietic
tissue: 0/50, 3/50 (6%), 3/50 (6%),
1/50 (2%)
P for trend=0.016;
see Comments
Males
Renal tubule adenoma: 0/49, 0/49,
1/50 (2%), 3/50 (6%)
Females
No data provided on the kidney
Comments
NS
NS
[P<0.001; Cochran
Armitage trend test]
NS
Significance
Glyphosate
31
32
*P<0.05 vs group VI
*P<0.05 vs groups
VI and VII
Significance
Comments
bw, body weight; DMBA, 7,12-dimethylbenz[a]anthracene; EPA, United States Environmental Protection Agency; F, female; M, male; mo, month; NR, not reported; NS, not significant;
POEA, polyethoxylated tallowamine; PWG, pathology working group; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; vs, versus; wk, week; yr, year
Group V: 0/20
Group I: 0/20
Group I: 0/20
Group II: 0/20
Initiationpromotion study
Skin application of glyphosate-based
formulation (glyphosate, 41%; POEA,
~15%) (referred to as glyphosate)
dissolved in 50% ethanol; DMBA
dissolved in 50% ethanol, and TPA
dissolved in 50% acetone, used in the
groups described below
20 M/group
Group I: untreated control (no treatment)
Group II: glyphosate only: 25 mg/kg bw
topically, 3/wk, for 32 wk
Group III: single topical application of
DMBA, 52g/mouse, followed 1wk later
by TPA, 5g/mouse, 3/wk, for 32 wk
Group IV: single topical application of
glyphosate, 25mg/kg bw, followed 1wk
later by TPA, 5g/mouse, 3/wk, for 32
wk
Group V: 3/wk topical application
of glyphosate, 25 mg/kg bw, for 3 wk,
followed 1 wk later by TPA, 5 g/mouse,
3/wk, for 32 wk
Group VI: single topical application of
DMBA, 52 g/mouse
Group VII: topical application of TPA,
5 g/mouse, 3/wk, for 32 wk
Group VIII: single topical application of
DMBA, 52g/mouse, followed 1 wk later
by topical treatment with glyphosate,
25mg/kg bw, 3/wk, for 32 wk
Glyphosate
were provided for female mice. No other tumour
sites were identified (EPA, 1985a). Subsequent to
its initial report (EPA, 1985a), the United States
Environmental Protection Agency (EPA) recommended that additional renal sections be cut and
evaluated from all male mice in the control and
treated groups. The pathology report for these
additional sections (EPA, 1985b) indicated the
same incidence of renal tubule adenoma as originally reported, with no significant increase in
incidence between the control group and treated
groups by pairwise comparison. However, as
already reported above, the test for linear trend
in proportions resulted in a significance of
P=0.016. The EPA (1986) also requested that a
pathology working group (PWG) be convened
to evaluate the tumours of the kidney observed
in male mice treated with glyphosate, including
the additional renal sections. In this second evaluation, the PWG reported that the incidence of
adenoma of the renal tubule was 1/49 (2%), 0/49,
0/50, 1/50 (2%) [not statistically significant]; the
incidence of carcinoma of the renal tubule was
0/49, 0/49, 1/50 (2%), 2/50 (4%) [P=0.037, trend
test for carcinoma]; and the incidence of adenoma
or carcinoma (combined) of the renal tubule was
1/49 (2%), 0/49, 1/50 (2%), 3/50 (6%) [P=0.034,
trend test for combined]. [The Working Group
considered that this second evaluation indicated
a significant increase in the incidence of rare
tumours, with a dose-related trend, which could
be attributed to glyphosate. Chandra & Frith
(1994) reported that only 1 out of 725 [0.14%]
CD-1 male mice in their historical database had
developed renal cell tumours (one carcinoma).]
[The Working Group noted the differences
in histopathological diagnosis between pathologists. Proliferative lesions of the renal tubules
are typically categorized according to published
criteria as hyperplasia, adenoma, or carcinoma.
The difference is not trivial, because focal hyperplasia, a potentially preneoplastic lesion, should
be carefully differentiated from the regenerative
changes of the tubular epithelium. There is a
33
3.1.2 Initiationpromotion
Groups of 20 male Swiss mice [age at start
not reported; body weight, 1215 g] were given a
glyphosate-based formulation (glyphosate, 41%;
polyethoxylated tallowamine, ~15%) (referred to
as glyphosate in the article) that was dissolved in
50% ethanol and applied onto the shaved back
skin (George et al., 2010). Treatment groups were
identified as follows:
Group I untreated control;
Group II glyphosate only (25 mg/kg bw),
applied topically three times per week for 32
weeks;
Group III single topical application of
dimethylbenz[a]anthracene (DMBA; in ethanol;
52 g/mouse), followed 1 week later by
12-O-tetradecanoylphorbol-13-acetate (TPA;
in acetone; 5 g/mouse), applied topically three
times per week for 32 weeks;
Group IV single topical application of
glyphosate (25 mg/kg bw) followed 1 week
later by TPA (in acetone; 5 g/mouse), applied
topically three times per week for 32 weeks;
Group V glyphosate (25 mg/kg bw) applied
topically three times per week for 3 weeks
(total of nine applications), followed 1 week
later by TPA (in acetone; 5g/mouse), applied
topically three times per week for 32 weeks;
Group VI single topical application of
DMBA (in ethanol; 52g/mouse);
Group VII TPA (in acetone; 5 g/mouse),
applied topically three times per week for 32
weeks; and
Group VIII single topical application of
DMBA (in ethanol; 52 g/mouse), followed
1 week later by glyphosate (25 mg/kg bw),
applied topically three times per week for 32
weeks.
All mice were killed at 32 weeks. Skin
tumours were observed only in group III (positive control, DMBA + TPA, 20/20) and group
34
Glyphosate
mice [age at start not reported] were given diets
containing glyphosate (purity, 9496%) at a
concentration of 0, 1600, 8000, or 40 000 ppm
for 18 months. The increase in the incidence of
bronchiolo-alveolar adenoma and carcinoma,
and of lymphoma, was reported to be not statistically significant in males and females receiving
glyphosate. [The Working Group was unable to
evaluate this study because of the limited experimental data provided in the review article and
supplemental information.]
In the second study (identified as Study 13,
2001), groups of 50 male and 50 female Swiss
albino mice [age at start not reported] were
given diets containing glyphosate (purity, >95%)
at a concentration of 0 (control), 100, 1000, or
10000ppm for 18 months. The authors reported
a statistically significant increase in the incidence
of malignant lymphoma (not otherwise specified,
NOS) in males at the highest dose: 10/50 (20%),
15/50 (30%), 16/50 (32%), 19/50 (38%; P < 0.05;
pairwise test); and in females at the highest dose:
18/50 (36%), 20/50 (40%), 19/50 (38%), 25/50
(50%; P < 0.05; pairwise test). [The Working
Group was unable to evaluate this study because
of the limited experimental data provided in the
review article and supplemental information.]
In the third study (identified as Study 14,
2009a), groups of 51 male and 51 female CD-1
mice [age at start not reported] were given diets
containing glyphosate (purity, 94.697.6%) at a
concentration of 0, 500, 1500, or 5000ppm for
18 months. Incidences for bronchiolo-alveolar
adenoma and carcinoma, malignant lymphoma
(NOS), and hepatocellular adenoma and carcinoma in males, and for bronchiolo-alveolar
adenoma and carcinoma, malignant lymphoma
(NOS) and pituitary adenoma in females, were
included in the article. In males, the authors
reported that there was a significant positive trend
[statistical test not specified] in the incidence of
bronchiolo-alveolar carcinoma (5/51, 5/51, 7/51,
11/51) and of malignant lymphoma (0/51, 1/51,
2/51, 5/51). [The Working Group was unable to
evaluate this study because of the limited experimental data provided in the review article and
supplemental information.]
3.2 Rat
See Table3.2
3.2.1 Drinking-water
Groups of 10 male and 10 female SpragueDawley rats (age, 5 weeks) were given drinkingwater containing a glyphosate-based formulation
at a dose of 0 (control), 1.1108% (5.0105 mg/L),
0.09% (400mg/L) or 0.5% (2.25103 mg/L), ad
libitum, for 24 months (Sralini et al., 2014). [The
study reported is a life-long toxicology study on
a glyphosate-based formulation and on genetically modified NK603 maize, which the authors
stated was designed as a full study of long-term
toxicity and not a study of carcinogenicity. No
information was provided on the identity or
concentration of other chemicals contained in
this formulation.] Survival was similar in treated
and control rats. [No data on body weight were
provided.] In female rats, there was an almost
twofold increase in the incidence of tumours
of the mammary gland (mainly fibroadenoma
and adenocarcinoma) in animals exposed to
the glyphosate-based formulation only versus
control animals: control, 5/10 (50%); lowest dose,
9/10 (90%); intermediate dose, 10/10 (100%)
[P < 0.05; Fisher exact test]; highest dose, 9/10
(90%). [The Working Group concluded that this
study conducted on a glyphosate-based formulation was inadequate for evaluation because
the number of animals per group was small, the
histopathological description of tumours was
poor, and incidences of tumours for individual
animals were not provided.]
In another study with drinking-water,
Chruscielska et al. (2000) gave groups of 55
male and 55 female Wistar rats (age, 67 weeks)
drinking-water containing an ammonium salt
35
groups of 52 male and 52 female WistarAlpk:APfSD rats [age at start not reported] were
given diets containing glyphosate (purity, 97.6%)
at a concentration of 0, 2000, 6000, or 20000ppm,
ad libitum, for 24 months (JMPR, 2006). There
was a treatment-related decrease in body-weight
gain in males and females at the highest dose, and
a corresponding significant increase in survival
in males. No significant increase in tumour incidence was observed in any of the treated groups.
The EPA (1991a, b, c, d) provided information
on a long-term study in which groups of 60 male
and 60 female Sprague-Dawley rats (age, 8 weeks)
were given diets containing glyphosate (technical
grade; purity, 96.5%) at a concentration of 0ppm,
2000ppm, 8000ppm, or 20000ppm, ad libitum,
for 24 months. Ten animals per group were killed
after 12 months. There was no compound-related
effect on survival, and no statistically significant
decreases in body-weight gain in male rats. In
females at the highest dose, body-weight gain
was significantly decreased, starting on day 51. In
males at the lowest dose, there was a statistically
significant increase in the incidence of pancreatic islet cell adenoma compared with controls:
8/57 (14%) versus 1/58 (2%), P0.05 (Fisher exact
test). Additional analyses by the EPA (1991a)
(using the CochranArmitage trend test and
Fisher exact test, and excluding rats that died or
were killed before week 55) revealed a statistically
significant higher incidence of pancreatic islet
cell adenoma in males at the lowest and highest
doses compared with controls: lowest dose, 8/45
(18%; P=0.018; pairwise test); intermediate dose,
5/49 (10%); highest dose, 7/48 (15%; P = 0.042;
pairwise test) versus controls, 1/43 (2%). The
range for historical controls for pancreatic islet
cell adenoma reported in males at this laboratory was 1.88.5%. [The Working Group noted
that there was no statistically significant positive
trend in the incidence of these tumours, and
no apparent progression to carcinoma.] There
was also a statistically significant positive trend
in the incidence of hepatocellular adenoma in
Rat, Sprague-Dawley
(M,F)
24 mo
Sralini et al. (2014)
Dosing regimen,
Animals/group at start
NS
NS
NS
No significant increase in
tumour incidence observed in
any groups of treated animals
No significant increase in
tumour incidence observed in
any groups of treated animals
NS
[NS]
*[P<0.05]
NS
Significance
No significant increase in
tumour incidence observed in
any groups of treated animals
Males
No significant increase in
tumour incidence observed in
any of the treated groups
Females
Mammary tumours
(mainly fibroadenomas and
adenocarcinomas): 5/10
(50%), 9/10 (90%), 10/10
(100%)*, 9/10 (90%)
Pituitary lesions
(hypertrophy, hyperplasia,
and adenoma): 6/10 (60%),
8/10 (80%), 7/10 (70%), 7/10
(70%)
No significant increase in
tumour incidence observed in
any of the treated groups
Comments
Glyphosate
37
38
Dosing regimen,
Animals/group at start
Rat Sprague-Dawley
(M,F)
24 mo
EPA (1991a, b, c, d)
Males
Pancreas (islet cell):
Adenoma: 1/58 (2%), 8/57
(14%)*, 5/60 (8%), 7/59 (12%)
Carcinoma: 1/58 (2%), 0/57,
0/60, 0/59
Adenoma or carcinoma
(combined): 2/58 (3%), 8/57
(14%), 5/60 (8%), 7/59 (12%)
Liver:
Hepatocellular adenoma: 2/60
(3%), 2/60 (3%), 3/60 (6%),
7/60 (12%)
Hepatocellular carcinoma:
3/60 (5%), 2/60 (3%), 1/60
(2%), 2/60 (3%)
Females
Pancreas (islet cell):
Adenoma: 5/60 (8%), 1/60
(2%), 4/60 (7%), 0/59
Carcinoma: 0/60, 0/60, 0/60,
0/59
Adenoma or carcinoma
(combined): 5/60 (8%), 1/60
(2%), 4/60 (7%), 0/59
Thyroid:
C-cell adenoma: 2/60 (3%),
2/60 (3%), 6/60 (10%), 6/60
(10%)
C-cell carcinoma: 0/60, 0/60,
1/60, 0/60
Adenoma,
P for trend
= 0.031; see
comments
NS
Adenoma,
P for trend
= 0.016; see
comments
Adenoma,
* P0.05
(Fisher exact
test with
Bonferroni
inequality);
see
comments
Significance
Comments
Rat Sprague-Dawley
(M,F)
Lifetime (up to 26
mo)
EPA (1991a, b, c, d)
Carcinoma: 0/50 (0%), 0/49
(0%), 0/50 (0%), 1/50 (2%)
Adenoma or carcinoma
(combined): 0/50 (0%), 5/49
(10%), 2/50 (4%), 3/50 (6%)
Females
Pancreas (islet cell):
Adenoma: 2/50 (4%), 1/50
(2%), 1/50 (2%), 0/50 (0%)
Carcinoma: 0/50 (0%), 1/50
(2%), 1/50 (2%), 1/50 (2%)
Adenoma or carcinoma
(combined): 2/50 (10%), 2/50
(2%), 2/50 (74%), 1/50 (2%)
Males
Pancreas (islet cell):
Adenoma: 0/50 (0%), 5/49*
(10%), 2/50 (4%), 2/50 (4%)
NS
Adenoma,
*[P<0.05;
Fisher exact
test]
Significance
bw, body weight; d, day; F, female; M, male; mo, month; NR, not reported; NS, not significant; wk, week; yr, year
Dosing regimen,
Animals/group at start
Comments
Glyphosate
39
Glyphosate
study because of the limited experimental data
provided in the review article and supplemental
information.]
In another study in male and female Wistar
rats (identified as Study 8, 2009b), groups of
51 male and 51 female rats [age at start not
reported] were fed diets containing glyphosate
(purity, 95.7%) at a concentration of 0, 1500,
5000, or 15000 ppm, ad libitum, for 24 months.
The highest dose was progressively increased
to reach 24000ppm by week 40. A non-significant increase in tumour incidence was noted
for adenocarcinoma of the mammary gland in
females at the highest dose (6/51) compared with
controls (2/51). [The Working Group was unable
to evaluate this study because of the limited
experimental data provided in the review article
and supplemental information. The Working
Group noted that tumours of the mammary
gland had been observed in other studies in rats
reviewed for the present Monograph.]
4.1.2 Absorption
(a) Humans
Data on the absorption of glyphosate via
intake of food and water in humans were not
available to the Working Group. Inhalation of
glyphosate is considered to be a minor route
of exposure in humans, because glyphosate is
usually formulated as an isopropylamine salt
with a very low vapour pressure (Tomlin, 2000).
In the Farm Family Exposure Study, 60% of
farmers had detectable levels of glyphosate in
24-hour composite urine samples taken on the
day they had applied a glyphosate-based formulation (Acquavella et al., 2004). Farmers who
did not use rubber gloves had higher urinary
concentrations of glyphosate than those who did
use gloves [indicating that dermal absorption is
a relevant route of exposure]. In a separate study,
detectable levels of glyphosate were found in
urine samples from farm families and non-farm
families (Curwin et al., 2007).
In accidental and deliberate intoxication cases
involving ingestion of glyphosate-based formulations, glyphosate was readily detectable in the
blood (Zouaoui et al., 2013). After deliberate
or accidental ingestion, one glyphosate-based
formulation was found to be more lethal to
humans than another (Srensen & Gregersen,
1999). [Greater lethality was attributed to the
presence of trimethylsulfonium counterion,
which might facilitate greater absorption after
oral exposure.]
Small amounts of glyphosate can be absorbed
after dermal exposures in humans in vitro.
For example, when an aqueous solution of 1%
glyphosate was applied in an in-vitro human
skin model, only 1.4% of the applied dose was
absorbed through the skin. Glyphosate is typically formulated as an isopropylamine salt, and
is dissolved in a water-based vehicle, while the
41
Experimental systems
Three studies have been conducted to investigate the absorption of a single oral dose of
glyphosate in rats (Brewster et al., 1991; Chan &
Mahler, 1992; EPA, 1993b).
In male Sprague-Dawley rats given
[14C]-labelled glyphosate (10 mg/kg bw), the
majority of the radiolabel was associated with
the gastrointestinal contents and small intestinal
tissue 2 hours after administration (Brewster
et al., 1991). Approximately 3540% of the administered dose was found to be absorbed from the
gastrointestinal tract. Urinary and faecal routes
of elimination were equally important. [The
Working Group concluded that glyphosate is
incompletely absorbed from the gastrointestinal
tract after oral exposure in rats.]
In a study by the United States National
Toxicology Programme (NTP) in Fisher 344 rats,
30% of the administered oral dose (5.6 mg/kg bw)
was absorbed, as determined by urinary excretion data (Chan & Mahler, 1992). This finding
was in accordance with the previously described
study of oral exposure in rats (Brewster et al.,
1991).
42
In a study reviewed by the EPA, SpragueDawley rats were given an oral dose of glyphosate
(10 mg/kg bw); 30% and 36% of the administered
dose was absorbed in males and females, respectively (EPA, 1993b). At a dose that was ~10-fold
higher (1000 mg/kg bw), oral absorption of
glyphosate by the rats was slightly reduced.
In a 14-day feeding study in Wistar rats given
glyphosate at dietary concentrations of up to 100
ppm, only ~15% of the administered dose was
found to be absorbed (JMPR, 2006). In New
Zealand White rabbits or lactating goats given
glyphosate as single oral doses (69 mg/kg bw),
a large percentage of the administered dose was
recovered in the faeces [suggesting very poor
gastrointestinal absorption of glyphosate in
these animal models] (JMPR, 2006).
In monkeys given glyphosate by dermal application, percutaneous absorption was estimated
to be between 1% and 2% of the administered
dose (Wester et al., 1991). Most of the administered dose was removed by surface washes of the
exposed skin.
4.1.3 Distribution
(a) Humans
No data in humans on the distribution of
glyphosate in systemic tissues other than blood
were available to the Working Group. In cases
of accidental or deliberate intoxication involving
ingestion of glyphosate-based formulations,
glyphosate was measured in blood. Mean blood
concentrations of glyphosate were 61mg/L and
4146mg/L in mild-to-moderate cases of intoxication and in fatal cases, respectively (Zouaoui
et al., 2013).
One report, using optical spectroscopy and
molecular modelling, indicated that glyphosate
could bind to human serum albumin, mainly
by hydrogen bonding; however, the fraction of
glyphosate that might bind to serum proteins
in blood was not actually measured (Yue et al.,
2008).
Glyphosate
Fig.4.1 Microbial metabolism of glyphosate to AMPA
O
HO
H
N
P
OH
microbes
H2N
OH
glyphosate
P
OH
OH
CO 2
(b)
Experimental systems
(i) Humans
In human hepatic cell lines, treatment with
one of four glyphosate-based formulations
produced by the same company was shown to
enhance CYP3A4 and CYP1A2 levels, while
glutathione transferase levels were reduced
(Gasnier et al., 2010). [The Working Group noted
that it was not clear whether the effects were
caused by glyphosate alone or by the adjuvants
contained in the formulation.]
(ii)
Experimental systems
Exposure of Wistar rats to a glyphosate-based
formulation significantly altered some hepatic
xenobiotic enzyme activities (Larsen et al.,
2014). Liver microsomes obtained from male
and female rats treated with the formulation
exhibited ~50% reductions in cytochrome
P450 (CYP450) content compared with control
(untreated) rats. However, opposing effects were
observed when assessing 7-ethoxycoumarin
O-deethylase activity (7-ECOD, a non-specific
CYP450 substrate). Female rats treated with the
glyphosate-based formulation exhibited a 57%
increase in hepatic microsomal 7-ECOD activity
compared with controls, while male rats treated
with the formulation exhibited a 58% decrease in
this activity (Larsen et al., 2014). [The Working
Group noted that it was not clear whether the
effects were caused by glyphosate alone or by
adjuvants contained in the formulation.]
44
4.1.5 Excretion
(a) Humans
Excretion of glyphosate in humans was documented in several biomonitoring studies. For
example, as part of the Farm Family Exposure
Study, urinary concentrations of glyphosate were
evaluated immediately before, during, and after
glyphosate application in 48 farmers and their
spouses and children (Acquavella et al., 2004).
Dermal contact with glyphosate during mixing,
loading, and application was considered to be the
main route of exposure in the study. On the day
the herbicide was applied, 60% of the farmers
had detectable levels of glyphosate in 24-hour
composite urine samples, as did 4% of their
spouses and 12% of children. For farmers, the
geometric mean concentration was 3 g/L, the
maximum value was 233 g/L, and the highest
estimated systemic dose was 0.004 mg/kg bw
(Acquavella et al., 2004). In a separate study,
detectable levels of glyphosate were excreted
in the urine of members of farm families and
of non-farm families, with geometric means
ranging from 1.2 to 2.7g/L (Curwin et al., 2007).
In a study of a rural population living near
areas sprayed for drug eradication in Colombia
(see Section 1.4.1, Table 1.5), mean urinary
glyphosate concentrations were 7.6g/L (range,
undetectable to 130g/L) (Varona et al., 2009).
AMPA was detected in 4% of urine samples
(arithmetic mean, 1.6 g/L; range, undetectable
to 56g/L).
(b)
Experimental systems
Glyphosate
1993b). By either route, most (98%) of the administered dose was excreted as unchanged parent
compound. AMPA was the only metabolite found
in the urine (0.20.3% of the administered dose)
and faeces (0.20.4% of the administered dose).
[The large amount of glyphosate excreted in the
faeces is consistent with its poor oral absorption.]
Less than 0.3% of the administered dose was
expired as carbon dioxide.
In rhesus monkeys given glyphosate as
an intravenous dose (9 or 93 g), > 95% of the
administered dose was excreted in the urine
(Wester et al., 1991). Nearly all the administered
dose was eliminated within 24 hours. In contrast,
in rhesus monkeys given glyphosate by dermal
application (5400 g/20 cm2), only 2.2% of the
administered dose was excreted in the urine
within 7days (Wester et al., 1991).
Overall, systemically absorbed glyphosate
is not metabolized efficiently, and is mainly
excreted unchanged into the urine.
in micronucleus formation in human lymphocytes at levels estimated to correspond to occupational and residential exposure (Mladinic et al.,
2009a). Sister-chromatid exchange was induced
by glyphosate (Bolognesi et al., 1997), and by
a glyphosate-based formulation (Vigfusson &
Vyse, 1980; Bolognesi et al., 1997) in human
lymphocytes exposed in vitro.
(b)
(i)
Experimental systems
NR
NR
Lymphocytes
Lymphocytes
Lymphocytes
Blood
Blood
Blood
Blood
Blood
+, positive; , negative
NR, not reported; vs, versus
Cell type
(if specified)
Tissue
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
DNA damage
End-point
Micronucleus
formation
Micronucleus
formation
Micronucleus
formation
Chromosomal
aberrations
DNA strand
breaks, comet
assay
Test
24 exposed individuals in northern
Ecuador; areas sprayed with glyphosatebased formulation (sampling 2 weeks to
2months after spraying); control group
was 21 non-exposed individuals
92 individuals in 10 communities,
northern border of Ecuador; sampling
2years after last aerial spraying with
herbicide mix containing glyphosate);
control group was 90 healthy individuals
from several provinces without
background of smoking or exposure to
genotoxic substances (hydrocarbons,
X-rays, or pesticides)
55 community residents, Nario,
Colombia; area with aerial glyphosatebased formulation spraying for coca and
poppy eradication (glyphosate was tankmixed with an adjuvant)
53 community residents, Putumayo,
Colombia; area with aerial glyphosatebased formulation spraying for coca and
poppy eradication (glyphosate was tankmixed with an adjuvant)
27 community residents, Valle del Cauca,
Colombia; area where glyphosate-based
formulation was applied through aerial
spraying for sugar-cane maturation
(glyphosate was applied without
adjuvant)
+ [P<0.001]
+ [P=0.01]
+ [P<0.001]
+ P<0.001
Responsea/
significance
Paz-y-Mio et al.
(2011)
Bolognesi et al.
(2009)
Bolognesi et al.
(2009)
Bolognesi et al.
(2009)
Paz-y-Mio et al.
(2007)
Reference
Comments
Glyphosate
47
DNA damage
DNA damage
DNA damage
DNA damage
DNA damage
Lymphocytes
Lymphocytes
Fibroblast GM 38
Fibroblast GM 5757
Fibrosarcoma
HT1080
Buccal carcinoma
TR146
Lymphocytes
Lymphocytes
DNA damage
Glyphosate
Liver Hep-2
Chromosomal
damage
Chromosomal
damage
DNA damage
End-point
Test
(+)
Without
metabolic
activation
Resultsa
(+)
NT
NT
NT
NT
NT
NT
NT
With
metabolic
activation
6 mM
[1015g/mL]
580 g/mL
4.75 mM
[803 g/mL]
20 g/mL
0.0007 mM
[0.12 g/mL]
4 mM
[676g/mL]
75 mM
[12680g/mL]
3.5 g/mL
3 mM
[507.2 g/mL]
Dose
(LED or HID)
Alvarez-Moya et al.
(2014)
Monroy et al. (2005)
Mladinic et al.
(2009b)
Reference
Dose-dependent
increase (P0.05)
Mladinic et al.
(2009a)
P<0.001
P<0.01; dose
response relationship
(r 0.90; P<0.05)
With the hOGG1
modified comet assay,
+ S9, the increase was
significant (P<0.01)
only at the highest
dose tested (580g/mL)
P0.01
Comments
Table 4.2 Genetic and related effects of glyphosate, AMPA, and glyphosate-based formulations in human cells in vitro
Glyphosate
49
50
Chromosomal
damage
Chromosomal
damage
Lymphocytes
Lymphocytes
Sister-chromatid
exchange
Sister-chromatid
exchange
+
(+)
NT
NT
NT
NT
NT
NT
NT
With
metabolic
activation
100 g/mL
250 g/mL
20 g/mL
5 ppm
1.8 mM
[200 g/mL]
4.5 mM
[500 g/mL]
1000 g/mL
Dose
(LED or HID)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Reference
P<0.05
Comments
DNA damage
Buccal carcinoma
TR146
Chromosomal
damage
Glyphosate-based formulations
Liver HepG2
DNA damage
Lymphocytes
Without
metabolic
activation
Resultsa
Chromosomal
aberrations
DNA damage
AMPA
Liver Hep-2
Sister-chromatid
exchange
Chromosomal
damage
Lymphocytes
Test
End-point
Glyphosate
Micronucleus formation was induced by
a glyphosate-based formulation (glyphosate,
36%) in earthworms (Muangphra et al., 2014),
and by a different glyphosate-based formulation
in caiman (Poletta et al., 2009, 2011), and frog
(Yadav et al., 2013).
Insects
In standard Drosophila melanogaster, glyphosate induced mutation in the test for somatic
mutation and recombination, but not in a cross
of flies characterized by an increased capacity
for CYP450-dependent bioactivation (Kaya
et al., 2000). A glyphosate-based formulation
also caused sex-linked recessive lethal mutations
in Drosophila (Kale et al., 1995).
(a)
Plants
In plants, glyphosate produced DNA damage
in Tradescantia in the comet assay (AlvarezMoya et al., 2011). Chromosomal aberration was
induced after exposure to glyphosate in fenugreek
(Siddiqui et al., 2012), and in onion in one study
(Frescura et al., 2013), but not in another (Rank
et al., 1993). A glyphosate-based formulation
also induced chromosomal aberration in barley
roots (Truta et al., 2011) and onion (Rank et al.,
1993), but not in Crepis capillaris (hawksbeard)
(Dimitrov et al., 2006). Micronucleus formation
was not induced by glyphosate in Vicia faba bean
(De Marco et al., 1992) or by a glyphosate-based
formulation in Crepis capillaris (Dimitrov et al.,
2006).
(iv) Non-mammalian systems in vitro
See Table 4.6
Glyphosate induced DNA strand breaks in
erythrocytes of tilapia fish, as demonstrated by
comet assay (Alvarez-Moya et al., 2014).
Glyphosate did not induce mutation in
Bacillus subtillis, Salmonella typhimurium
strains TA1535, TA1537, TA1538, TA98, and
TA100, or in Escherichia coli WP2, with or
without metabolic activation (Li & Long, 1988).
However, Rank et al. (1993) demonstrated that
(i) Humans
Studies in exposed humans
No data were available to the Working Group.
Human cells in vitro
In hormone-dependent T47D breast cancer
cells, the proliferative effects of glyphosate
(106 to 1 M) (see Section 4.2.4) and those of
17-estradiol (the positive control) were mitigated by the estrogen receptor antagonist, ICI
182780; the proliferative effect of glyphosate
was completely abrogated by the antagonist at a
concentration of 10nM (Thongprakaisang et al.,
2013). Glyphosate also induced activation of the
estrogen response element (ERE) in T47D breast
cancer cells that were stably transfected with a
triplet ERE-promoter-luciferase reporter gene
construct. Incubation with ICI 182780 at 10 nM
eliminated the response. When the transfected
cells were incubated with both 17-estradiol
and glyphosate, the effect of 17-estradiol was
reduced and glyphosate behaved as an estrogen
antagonist. After 6hours of incubation, glyphosate increased levels of estrogen receptors ER and
ER in a dose-dependent manner in T47D cells;
after 24 hours, only ER levels were increased
and only at the highest dose of glyphosate. [These
findings suggested that the proliferative effects of
glyphosate on T47D cells are mediated by ER.]
In human hepatocarcinoma HepG2 cells,
four glyphosate-based formulations produced
by the same company had a marked effect on
the activity and transcription of aromatase,
while glyphosate alone differed from controls,
but not significantly so (Gasnier et al., 2009).
51
52
Rat, SpragueDawley
(M, F)
Mouse, NMRIbom
(M, F)
Mouse, Swiss
CD1
(M)
Glyphosate
Mouse, Swiss
CD1
(M)
Mouse, Swiss
CD1
(M)
Mouse, Swiss
CD1
(M, F)
Mouse, Swiss
CD1
(M, F)
Mouse, Swiss
CD1
(M)
Mouse, Swiss
CD1
(M)
Mouse, CD-1
(M)
Species, strain
(sex)
Chromosomal
aberrations
Micronucleus
formation
Mutation
Uterus
after
mating
Chromosomal
damage
DNA damage
Kidney
Micronucleus
formation
DNA damage
Liver
Chromosomal
damage
DNA damage
Liver
Bone
marrow
(PCE)
Bone
marrow
(PCE)
DNA damage
Kidney
Chromosomal
damage
DNA damage
Kidney
DNA adducts,
8-OHdG by
LC/UV
DNA adducts,
8-OHdG by
LC/UV
DNA adducts,
32P-DNA post
labelling
DNA adducts,
32P-DNA post
labelling
DNA strand
breaks, alkaline
elution assay
DNA strand
breaks, alkaline
elution assay
Dominant
lethal test
Test
Bone
marrow
DNA damage
End-point
Liver
Tissue
Results
300 mg/kg bw
200 mg/kg bw
1000 mg/kg bw
2000 mg/kg bw
300 mg/kg bw
300 mg/kg bw
270 mg/kg bw
270 mg/kg bw
300 mg/kg bw
300 mg/kg bw
Dose (LED or
HID)
i.p.; 1; sampled
after 24 and 48 h
i.p.; 1; sampled
after 6, 12 and 24 h
Oral gavage; 1
i.p.; 1; sampled
after 4 and 24 h
i.p.; 1; sampled
after 4 and 24 h
i.p.; 1; sampled
after 24 h
i.p.; 1; sampled
after 24 h
i.p.; 1; sampled
after 8 and 24 h
i.p.; 1; sampled
after 8 and 24 h
Route, duration,
dosing regimen
Glyphosate
isopropylamine salt
Proportion of early
resorptions evaluated after
mating of non-treated
females with glyphosatetreated male mice
Single dose tested only
Glyphosate
isopropylammonium salt
Glyphosate
isopropylammonium salt
Comments
Bolognesi et al.
(1997)
EPA (1980)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Reference
Table 4.3 Genetic and related effects of glyphosate, AMPA, and glyphosate-based formulations in non-human mammals in vivo
Chromosomal
damage
Chromosomal
damage
End-point
Glyphosate-based formulations
Mouse, Swiss
Liver
DNA damage
CD1
(M)
Mouse, Swiss
Kidney
DNA damage
CD1
(M)
Mouse, Swiss
Kidney
DNA damage
CD1
(M, F)
Mouse, Swiss
Liver
DNA damage
CD1
(M, F)
Mouse, Swiss
Liver
DNA damage
CD1
(M)
Mouse, Swiss
Kidney
DNA damage
CD1
(M)
Mouse, C57BL Bone
Chromosomal
(M)
marrow damage
(PCE)
Bone
marrow
(PCE)
Bone
marrow
(PCE)
Mouse, Balb C
(M, F)
AMPA
Mouse, Balb C
(M, F)
Tissue
Species, strain
(sex)
DNA adducts,
8-OHdG by
LC/UV
DNA adducts,
8-OHdG by
LC/UV
DNA adducts,
32P-DNA post
labelling
DNA adducts,
32P-DNA post
labelling
DNA strand
breaks, alkaline
elution assay
DNA strand
breaks, alkaline
elution assay
Chromosomal
aberrations
Micronucleus
formation
Micronucleus
formation
Test
400 mg/kg bw
400 mg/kg bw
+
+
+
+
p.o. in distilled
water; 1;
sampled after 6,
24, 48, 72, 96 and
120h
i.p.; 1; sampled
after 24 h
i.p.; 1; sampled
after 24 h
Route, duration,
dosing regimen
200 mg/kg bw
400 mg/kg bw
Dose (LED or
HID)
Results
Glyphosate, 30.4%
Single dose tested only
P<0.05
Glyphosate
isopropylammonium salt,
30.4%
Glyphosate
isopropylammonium salt,
30.4%
Glyphosate, 30.4%
Single dose tested only
P<0.05 only after 4 h
Glyphosate, 30.4%
Single dose tested only
P<0.05 only after 4 h
Single dose tested only
Glyphosate, 30.4%
Single dose tested only
Dimitrov et al.
(2006)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Bolognesi et al.
(1997)
Maas et al.
(2009b)
Maas et al.
(2009a)
Reference
Comments
Glyphosate
53
54
Bone
marrow
Bone
marrow
(PCE)
Bone
marrow
(PCE)
Bone
marrow
(PCE)
Bone
marrow
(PCE)
Bone
marrow
Mouse, Swiss
albino
(M)
Mouse, NMRIbom
(M, F)
Mouse, Swiss
(M, F)
Mouse, Swiss
albino
(M)
Mouse, Swiss
CD1
(M)
Mouse, C57BL
(M)
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
End-point
Micronucleus
formation
Micronucleus
formation
Micronucleus
formation
Micronucleus
formation
Micronucleus
formation
Chromosomal
aberrations
Test
Results
1080 mg/kg bw
450 mg/kg bw
25 mg/kg bw
200 mg/kg bw
200 mg/kg bw
25 mg/kg bw
Dose (LED or
HID)
i.p.; 2within
24 h interval and
sampled 24 h after
the last injection
i.p.; 1; sampled
after 24, 48 and
72 h
i.p.; 1; sampled
after 24 h
i.p.; 1; sampled
after 24, 48 and
72 h
Route, duration,
dosing regimen
Glyphosate
isopropylamine salt, >41%
Significant induction of
micronuclei vs control at
both doses and all times
(P<0.05)
Glyphosate, 30.4%
Single dose tested only
P<0.05 after 6 h and 24 h
Glyphosate
isopropylamine salt, >41%
The percentage of aberrant
cells was increased vs
control in a dose- and
time-dependent manner
(P<0.05)
Glyphosate
isopropylammonium salt,
480g/L
The percentage of PCE
decreased
Glyphosate
isopropylammonium salt,
480g/L
Comments
Dimitrov et al.
(2006)
Bolognesi et al.
(1997)
Grisolia (2002)
Reference
Tissue
Species, strain
(sex)
CHO-K1
ovary cell line
AMPA
Hamster,
Chinese
Lymphocytes
Chromosomal
damage
Chromosomal
damage
Without
metabolic
activation
Resultsa
Sisterchromatid
exchange
Chromosomal
aberrations
Micronucleus
formation
Sisterchromatid
exchange
Chromosomal
aberrations
Micronucleus
formation
Unscheduled
DNA
synthesis
Hprt mutation
Test
NT
NT
NT
NT
With
metabolic
activation
56 M
[9.5g/mL]
1120 M
[190g/mL]
0.01 g/mL
17 M [3 g/mL]
10 g/mL
17 M [3 g/mL]
22 500 g/mL
125 g/mL
Dose
(LEC or HIC)
Glyphosate, 62%
Time of exposure, 24h
P<0.01, S9, at 56M
Glyphosate, 62%
Roustan et al.
(2014)
Sivikov &
Dianovsk
(2006)
Sivikov &
Dianovsk
(2006)
Roustan et al.
(2014)
Reference
P<0.05
Comments
Bovine
Glyphosate-based formulations
Bovine
Lymphocytes
Chromosomal
damage
Chromosomal
damage
Lymphocytes
Hamster,
Chinese
Bovine
DNA damage
End-point
CHO-K1BH4
Mutation
ovary, cell line
Lymphocytes Chromosomal
damage
CHO-K1
Chromosomal
ovary cell line damage
Hepatocytes
Tissue, cell
line
Hamster,
Chinese
Bovine
Glyphosate
Rat, Fisher F334
Species
Table 4.4 Genetic and related effects of glyphosate, AMPA, and glyphosate-based formulations in non-human mammalian
cells in vitro
Glyphosate
55
56
Oreochromis
niloticus (Nile
tilapia) branchial
erythrocytes
Oyster spermatozoa
Fish
Mutation
Mutation
Drosophila standard
cross
Drosophila
melanogaster, high
bioactivation cross
Insect
DNA damage
Insect
Oyster
DNA damage
DNA damage
DNA damage
Anguilla anguilla L.
(European eel), blood
cells
Danio rerio
(zebrafish), sperm
Fish
Fish
DNA damage
Prochilodus lineatus
(sbalo), erythrocytes
and gill cells
Glyphosate
Fish
Phylogenetic
class
SMART
DNA strand
breaks, comet
assay
SMART
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
DNA strand
breaks,
acridine
orange
method
DNA strand
breaks, comet
assay
Test
Resultsa
10 mM
[1.69mg/L]
1 mM
[0.169mg/L]
0.005 mg/L
7 M
[1.2mg/L]
10 mg/L
0.0179 mg/L
0.48 mg/L
Dose
(LED or HID)
Alvarez-Moya et al.
(2014)
Guilherme et al.
(2012b)
Reference
Purity, 96%
Kaya et al. (2000)
Increased frequency of
small single spots (1 mM)
and total spots (2mM)
P = 0.05
Purity, 96%
Kaya et al. (2000)
Time of exposure, 1h
Comments
Table 4.5 Genetic and related effects of glyphosate, AMPA, and glyphosate-based formulations in non-mammalian systems
in vivo
Chromosomal
damage
Chromosomal
damage
Chromosomal
damage
Trigonella foenumgraecum L.
(fenugreek)
Vicia faba (bean)
Plant systems
Plant systems
Plant systems
Chromosomal
damage
Anguilla anguilla L.
(European eel)
DNA damage
DNA damage
DNA damage
Anguilla anguilla L.
(European eel)
Glyphosate-based formulations
Fish
Anguilla anguilla L.
(European eel), blood
cells
Fish
Anguilla anguilla L.
(European eel), blood
cells
Fish
AMPA
Fish
Chromosomal
damage
DNA damage
Tradescantia clone
4430 (spiderworts),
staminal hair nuclei
Plant systems
Plant systems
Phylogenetic
class
Resultsa
DNA strand
+
breaks, comet
assay
DNA strand
+
breaks,
comet assay
improved with
the DNAlesion-specific
FPG and Endo
III
Other (ENA)
DNA strand
breaks, comet
assay
Micronucleus
formation
Chromosomal
aberrations
Chromosomal
aberrations
Chromosomal
aberrations
DNA strand
breaks, comet
assay
Test
0.058 mg/L
0.058 mg/L
0.0236 mg/L
0.0118 mg/L
1400 ppm
(1400g/g of
soil)
0.2%
2.88 g/mL
3%
0.0007 mM
[0.12g/mL]
Dose
(LED or HID)
P<0.05
Positive doseresponse
relationship
Glyphosate-based
formulation, 30.8%
Time of exposure, 1 and
3days
With FPG, P<0.05; with
comet assay alone, P< 0.05
at 116 g/L
Glyphosate isopropylamine
salt
P<0.01 for directly
exposed nuclei (dosedependent increase) and
plants
Single dose tested only
Partial but significant
reversal with distilled water
Glyphosate isopropylamine
Comments
Guilherme et al.
(2012b)
Guilherme et al.
(2010)
Guilherme et al.
(2014b)
Guilherme et al.
(2014b)
De Marco et al.
(1992)
Alvarez-Moya et al.
(2011)
Reference
Glyphosate
57
58
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
DNA damage
DNA damage
Prochilodus lineatus
(sbalo), erythrocytes
and bronchial cells
Prochilodus lineatus
(sbalo), erythrocytes
and gill cells
Poecilia reticulata
DNA damage
(guppy) gill
erythrocytes
Channa punctatus
DNA damage
(bloch), blood and gill
cells
Fish
Fish
Fish
Fish
DNA strand
breaks, comet
assay
DNA damage
Anguilla anguilla L.
(European eel), liver
Fish
DNA strand
+
breaks,
comet assay
improved with
the DNAlesion-specific
FPG and Endo
III
DNA strand
+
breaks,
comet assay
improved with
the DNAlesion-specific
FPG and Endo
III
DNA strand
+
breaks, comet
assay
DNA damage
Anguilla anguilla L.
(European eel), blood
cells
Fish
Resultsa
Test
Phylogenetic
class
3.25 mg/L
2.83 L/L
[1.833 mg/L]
1 mg/L
10 mg/L
0.058 mg/L
0.116 mg/L
Dose
(LED or HID)
Glyphosate-based
formulation, 485 g/L
Time of exposure, 3days
P<0.05
Comments
Cavalcante et al.
(2008)
Guilherme et al.
(2014a)
Reference
DNA damage
Chromosomal
damage
Chromosomal
damage
Carassius auratus
(goldfish),
erythrocytes
Prochilodus lineatus
(sbalo) erythrocytes
Corydoras paleatus
(blue leopard
corydoras, mottled
corydoras and
peppered catfish),
blood and hepatic
cells
Fish
Fish
DNA damage
Micronucleus
formation
Micronucleus
formation
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
Fish
Fish
DNA strand
breaks, comet
assay
Corydoras paleatus
(blue leopard
corydoras, mottled
corydoras and
peppered catfish),
blood and hepatic
cells
Cyprinus carpio
Linnaeus (carp),
erythrocytes
Fish
DNA damage
Test
Phylogenetic
class
Resultsa
0.0067 mg/L
10 mg/L
5 ppm
2 mg/L (10%
LC50, 96h)
0.0067 mg/L
Dose
(LED or HID)
Glyphosate, 48%
(corresponding to
3.20g/L)
Single dose tested only, for
3, 6, and 9days
P<0.01, in blood and in
liver cells
Glyphosate, equivalent to
360 g/L
Single dose tested only, for
16 days
P<0.01
Glyphosate equivalent to
360 g/L
Time of exposure, 2, 4 and
6days
After 48 h: P<0.05
(5mg/L) and P<0.001 (10
and 15 mg/L)
Single dose tested only, for
6, 24, and 96h
Nuclear abnormalities
(lobed nuclei, segmented
nuclei and kidney-shaped
nuclei)
Glyphosate, 48%
(corresponding to
3.20g/L)
Single dose tested only, for
3, 6 and 9days
Comments
Cavalcante et al.
(2008)
Gholami-Seyedkolaei
et al. (2013)
Reference
Glyphosate
59
60
Chromosomal
damage
Chromosomal
damage
Poecilia reticulata
(guppy) gill
erythrocytes
Cnesterodon
decemmaculatus
(Jenyns, 1842)
peripheral blood
erythrocytes
Cnesterodon
decemmaculatus
(Jenyns, 1842)
peripheral blood
erythrocytes
Fish
Fish
Chromosomal
damage
Chromosomal
damage
Carassius auratus
(goldfish),
erythrocytes
Fish
Fish
Micronucleus
formation
Chromosomal
damage
Tilapia rendalli
(redbreast tilapia)
blood erythrocytes
Fish
Micronucleus
formation
Micronucleus
formation
Micronucleus
formation,
ENA
Micronucleus
formation
Test
Phylogenetic
class
Resultsa
22.9 mg/L
3.9 mg/L
1.41 L/L
[0.914 mg/L]
5 ppm
42mg/kg bw
Dose
(LED or HID)
Glyphosate, 480 g/L
Increased frequency of
micronucleus formation
vs control (P<0.05) in
blood samples collected 4
days after a single intraabdominal injection of 42,
85, or 170 mg/kg bw
Glyphosate equivalent to
360 g/L
Time of exposure, 2, 4 and
6days
Statistically significant
differences: 96 h (P<0.05);
144h (P<0.01)
Glyphosate, 64.8%, m/v
(648g/L)
Micronucleus formation,
P<0.01
Other nuclear
abnormalities, P<0.05
at 1.41 to 5.65L/L;
concentration-dependent
(r2=0.99)
Glyphosate, 48%
Time of exposure, 48 and
96h
P<0.05, with 3.9 and
7.8mg/L for 48 and 96h
Glyphosate, 48%
Time of exposure, 48 and
96h
P<0.01, with 22.9 and
45.9mg/L, and P<0.05 at
68.8mg/L, for 96h
Comments
Vera-Candioti et al.
(2013)
Vera-Candioti et al.
(2013)
Grisolia (2002)
Reference
Chromosomal
aberrations
Chromosomal
damage
Chromosomal
damage
DNA damage
DNA damage
Chromosomal
damage
Prochilodus lineatus
(sbalo) erythrocytes
Anguilla anguilla
L. (European eel),
peripheral mature
erythrocytes
Caiman latirostris
(broad-snouted
caiman), erythrocytes
Caiman latirostris
(broad-snouted
caiman), erythrocytes
Caiman latirostris
(broad-snouted
caiman), erythrocytes
Fish
Fish
Caiman
Caiman
Caiman
Micronucleus
fomation
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
Other (ENA)
Test
Phylogenetic
class
Resultsa
0.500 mg/egg
19 800 mg/L
0.500 mg/egg
0.058 mg/L
10 mg/L
Dose
(LED or HID)
Single dose tested only, for
6, 24, and 96h
Nuclear abnormalities
(lobed nuclei, segmented
nuclei and kidney-shaped
nuclei)
Time of exposure, 1 and
3days
Chromosomal breakage
and/or chromosomal
segregational abnormalities
after 3days of exposure,
P<0.05
Glyphosate, 66.2%
In-ovo exposure; blood
sampling at the time of
hatching
P<0.05 in both
experiments (501000g/
egg in experiment 1; 500
1750g/egg in experiment 2)
Glyphosate, 66.2%
Single dose tested only; inovo exposure
First spraying exposure
at the beginning of
incubation period, a second
exposure on day 35, then
incubation until hatching
Glyphosate, 66.2%
In-ovo exposure; blood
sampling at the time of
hatching
P<0.05 in both
experiments (501000g/
egg in experiment 1; 500
1750g/egg in experiment 2)
Comments
Guilherme et al.
(2010)
Cavalcante et al.
(2008)
Reference
Glyphosate
61
62
DNA damage
DNA damage
Chromosomal
damage
DNA damage
Rana catesbeiana
(ouaouaron), blood
Eleutherodactylus
johnstonei (Antilles
coqui), erythrocytes
Euflictis cyanophlyctis
(Indian skittering
frog), erythrocytes
Biomphalaria
alexandrina,
haemolymph
Oysters, spermatozoa
Frog tadpole
Frog
Frog
Snail
Oyster
DNA damage
Micronucleus
fomation
Chromosomal
damage
Caiman latirostris
(broad-snouted
caiman), erythrocytes
Caiman
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
Micronucleus
formation
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
Test
Phylogenetic
class
Resultsa
5 g/L
10 mg/L
1mga.e./L
0.5ga.e./cm2
19.8g/L
Dose
(LED or HID)
Glyphosate, 66.2%
One dose tested; in-ovo
exposure
First spraying exposure
at the beginning of
incubation period, a second
exposure on day 35, then
incubation until hatching.
Micronucleus formation,
P<0.001
Damage index, P<0.001
Time of exposure, 24h
P<0.05, with 6.75mg/L;
and P<0.001 with 27mg/L
(with 108mg/L, all died
within 24h)
Glyphosate-based
formulation, 480g/L
Exposure to an homogenate
mist in a 300cm2 glass
terrarium
Time of exposure: 0.5, 1, 2,
4, 8 and 24h
P<0.05
Glyphosate isopropylamine
salt, 41%
Time of exposure: 24, 48,
72, and 96h
P<0.001 at 24, 48, 72 and
96h
Glyphosate, 48%
Single dose tested only,
for 24h. The percentage of
damaged DNA was 21% vs
4% (control)
No statistical analysis
Glyphosate, 200g
equivalent/L
Time of exposure, 1h
Comments
Mohamed (2011)
Meza-Joya et al.
(2013)
Clements et al.
(1997)
Reference
Earthworm, Eisenia
andrei, coelomocytes
Earthworm,
Pheretima peguana,
coelomocytes
Earthworm,
Pheretima peguana,
coelomocytes
Worm
Worm
Worm
Chromosomal
damage
DNA damage
DNA damage
DNA damage
DNA damage
Utterbackia imbecillis
(Bivalvia: Unionidae)
glochidia mussels
(larvae)
Earthworm, Eisenia
andrei, coelomocytes
Mussels
Worm
DNA strand
breaks, comet
assay
DNA damage
Corbicula fluminea
(Asian clam)
haemocytes
Clam
Micronucleus
formation
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
DNA strand
breaks, comet
assay
Test
Phylogenetic
class
Resultsa
251.50 g/cm2
251.50g/cm2
15 g a.e./cm2
240 g a.e./cm2
5 mg/L
10 mg/L
Dose
(LED or HID)
Time of exposure, 96 h
Significant increase when
atrazine (2 or 10mg/L)
was added to glyphosate
(P<0.05)
No increase after exposure
to atrazine or glyphosate
separately
Glyphosate, 18%
Doses tested: 2.5 and
5mg/L for 24h
NOEC, 10.04mg/L
Monoammonium salt,
85.4%, a.e.
Epidermic exposure during
72 h (on filter paper)
Monoammonium salt,
72%, a.e.
Epidermic exposure during
72h (on filter paper)
P<0.001
Active ingredient, 36%
(w/v)
Epidermic exposure 48 h on
filter paper; LC50, 251.50g/
cm2
Active ingredient, 36%
(w/v)
Exposure, 48h on filter
paper; LC50, 251.50g/cm2
filter paper
P<0.05, for total
micro-, bi-, and trinuclei
frequencies at 0.25g/cm2;
when analysed separately,
micro- and trinuclei
frequencies significantly
differed from controls only
at the LC50
Comments
Muangphra et al.
(2014)
Muangphra et al.
(2014)
Reference
Glyphosate
63
64
Chromosomal
damage
Chromosomal
damage
Crepis capillaris
(hawksbeard)
Hordeum vulgare L.
cv. Madalin (barley
roots)
Crepis capillaris
(hawksbeard)
Plant systems
Micronucleus
formation
(+)
Resultsa
0.5%
360 g/mL
(0.1%)
0.5%
1.44g/mL
1ppm
Dose
(LED or HID)
Glyphosate-based
formulation, 480g/L
The doses of formulation
were calculated as
glyphosate isopropylamine
P<0.005
The highest dose tested
(1%) was toxic
Reported as significant
Comments
Dimitrov et al.
(2006)
Dimitrov et al.
(2006)
Truta et al. (2011)
Reference
Plant systems
Chromosomal
damage
Chromosomal
damage
Plant systems
Plant systems
Sex-linked
recessive
lethal
mutations
Chromosomal
aberrations
Mutation
Drosophila
melanogaster
Insect
Chromosomal
aberrations
Chromosomal
aberrations
Test
Phylogenetic
class
DNA damage
Differential
toxicity
Mutation
Microcystis
viridis
(cyanobacteria)
Bacillus B.
subtilis
Salmonella
typhimurium
TA1535, TA1537,
TA1538, TA98
and TA100
Escherichia coli
WP2
Prokaryote
(bacteria)
Prokaryote
(bacteria)
Prokaryote
(bacteria)
Mutation
DNA damage
Anabaena
spherica
(cyanobacteria)
Prokaryote
(bacteria)
Prokaryote
(bacteria)
DNA damage
Scytonema
javanicum
(cyanobacteria)
Prokaryote
(bacteria)
End-point
DNA damage
Test system
(species; strain)
Oreochromis
niloticus
(Nile tilapia),
erythrocytes
Glyphosate
Eukaryote
Fish
Phylogenetic
class
Without
metabolic
activation
Resultsa
Reverse
mutation
Reverse
mutation
Rec assay
DNA strand
(+)
breaks, FADU
assay
DNA strand
(+)
breaks, FADU
assay
DNA strand
(+)
breaks, FADU
assay
DNA strand
breaks, comet
assay
Test
NT
NT
NT
NT
NT
With
metabolic
activation
Comments
5000 g/plate
5000 g/plate
Glyphosate
isopropylamine, 96%
P0.001; positive dose
response relationship for
doses 7 M
10 M
Co-exposure to
[1.7g/mL] (in
glyphosate (not tested
combination with alone; single dose tested
UVB)
only) enhanced UVBinduced increases
10 M
Co-exposure to
[1.7g/mL] (in
glyphosate (not tested
combination with alone; single dose tested
UVB)
only) enhanced UVBinduced increases
10 M
Co-exposure to
[1.7g/mL] (in
glyphosate (not tested
combination with alone; single dose tested
UVB)
only) enhanced UVBinduced increases
2000 g/disk
7 M [1.2g/mL]
Concentration
(LEC or HIC)
Wang et al.
(2012)
Alvarez-Moya
et al. (2014)
Reference
Table 4.6 Genetic and related effects of glyphosate and glyphosate-based formulations on non-mammalian systems in vitro
Glyphosate
65
66
Prophage
superhelical PM2
DNA
Acellular
systems
Reverse
mutation
Reverse
mutation
Mutation
DNA strand
breaks
Test
Mutation
DNA damage
End-point
()
Without
metabolic
activation
Resultsa
NT
With
metabolic
activation
720 g/plate
360 g/plate
75 mM
[12.7mg/mL] (in
combination with
H2O2 (100M)
Concentration
(LEC or HIC)
Glyphosate
isopropylammonium
salt, 480g/L
Glyphosate
isopropylammonium
salt, 480g/L
Glyphosate inhibited
H2O2-induced damage
of PM2 DNA at
concentrations where
synergism was observed
in cellular DNA damage
(data NR)
Comments
Lueken et al.
(2004)
Reference
Glyphosate-based formulations
Prokaryote
Salmonella
(bacteria)
typhimurium
TA98
Prokaryote
Salmonella
(bacteria)
typhimirium
TA100
Test system
(species; strain)
Phylogenetic
class
Glyphosate
Additionally, although all four glyphosate-based
formulations dramatically reduced the transcription of ER and ER in ERE-transfected HepG2
cells, glyphosate alone had no significant effect.
Glyphosate and all four formulations reduced
androgen-receptor transcription in the breast
cancer cell line MDA-MB453-kb2, which has a
high level of androgen receptor, with the formulations showing greater activity than glyphosate
alone.
In a human placental cell line derived from
choriocarcinoma (JEG3 cells), 18 hours of
exposure to a glyphosate-based formulation
(IC50 = 0.04%) decreased aromatase activity
(Richard et al., 2005). Glyphosate alone was
without effect. The concentrations used did not
affect cell viability.
Glyphosate, at non-overtly toxic concentrations, decreased aromatase activity in fresh
human placental microsomes and transformed
human embryonic kidney cells (293) transfected
with human aromatase cDNA (Benachour
et al., 2007). A glyphosate-based formulation, at
non-overtly toxic concentrations, had the same
effect. The formulation was more active at equivalent doses than glyphosate alone.
In human androgen receptor and ER and
ER reporter gene assays using the Chinese
hamster ovary cell line (CHO-K1), glyphosate had neither agonist nor antagonist activity
(Kojima et al., 2004, 2010).
(ii)
In vivo
No data were available to the Working Group.
In vitro
Benachour et al. (2007) and Richard et al.
(2005) reported that glyphosate and a glyphosate-based formulation inhibited aromatase
activity in microsomes derived from equine
testis. Richard et al. (2005) reported an absorbance spectrum consistent with an interaction
67
Other pathways
(i) Humans
Studies in exposed humans
No data were available to the Working Group.
Human cells in vitro
Glyphosate did not exhibit agonist activity in
an assay for a human pregnane X receptor (PXR)
reporter gene in a CHO-K1 cell line (Kojima
et al., 2010).
(ii)
In vivo
In rats, glyphosate (300 mg/kg bw, 5days per
week, for 2 weeks) had no effect on the formation
of peroxisomes, or the activity of hepatic carnitine acetyltransferase and catalase, and did not
cause hypolipidaemia, suggesting that glyphosate
does not have peroxisome proliferator-activated
receptor activity (Vainio et al., 1983).
In vitro
Glyphosate was not an agonist for mouse
peroxisome proliferator-activated receptors
PPAR or PPAR in reporter gene assays using
CV-1 monkey kidney cells in vitro (Kojima et al.,
2010). Glyphosate was also not an agonist for the
aryl hydrocarbon receptor in mouse hepatoma
Hepa1c1c7 cells stably transfected with a reporter
plasmid containing copies of dioxin-responsive
element (Takeuchi et al., 2008).
(iii) Non-mammalian experimental systems
As a follow-up to experiments in which
injection of glyphosate, or incubation with a
glyphosate-based formulation (glyphosate,
48%), caused chick and frog (Xenopus laevis)
cephalic and neural crest terata characteristic of
retinoic acid signalling dysfunction, Paganelli
et al., (2010) measured retinoic acid activity in
tadpoles exposed to a glyphosate-based formulation. Retinoic activity measured by a reporter
68
Oxidative stress
(i) Humans
Studies in exposed humans
No data were available to the Working Group.
Human cells in vitro
Several studies examined the effects of
glyphosate on oxidative stress parameters in the
human keratinocyte cell line HaCaT. Gehin et al.
(2005) found that a glyphosate-based formulation was cytotoxic to HaCaT cells, but that
addition of antioxidants reduced cytotoxicity.
Elie-Caille et al. (2010) showed that incubation
of HaCaT cells with glyphosate at 21 mM (the
half maximal inhibitory concentration for cytotoxicity, IC50) for 18 hours increased production
of hydrogen peroxide (H2O2) as shown by dichlorodihydrofluorescein diacetate assay. Similarly,
George & Shukla (2013) exposed HaCaT cells
to a glyphosate-based formulation (glyphosate,
41%; concentration, up to 0.1 mM) and evaluated oxidative stress using the dichlorodihydro
fluorescein diacetate assay. The formulation
(0.1 mM) increased maximum oxidant levels
by approximately 90% compared with vehicle,
an effect similar to that of H2O2 (100 mM).
Pre-treatment of the cells with the antioxidant N-acetylcysteine abrogated generation of
oxidants by both the formulation and by H2O2.
N-Acetylcysteine also inhibited cell proliferation
induced by the glyphosate-based formulation
(0.1 mM). [The Working Group noted the recognized limitations of using dichlorodihydrofluorescein diacetate as a marker of oxidative stress
(Bonini et al., 2006; Kalyanaraman et al., 2012),
Glyphosate
and that the studies that reported this end-point
as the sole evidence for oxidative stress should
thus be interpreted with caution.]
Chaufan et al. (2014) evaluated the effects
of glyphosate, AMPA (the main metabolite of
glyphosate), and a glyphosate-based formulation
on oxidative stress in HepG2 cells. The formulation, but not glyphosate or AMPA, had adverse
effects. Specifically, the formulation increased
levels of reactive oxygen species, nitrotyrosine
formation, superoxide dismutase activity, and
glutathione, but did not have an effect on catalase or glutathione-S-transferase activities.
Coalova et al. (2014) exposed Hep2 cells to a
glyphosate-based formulation (glyphosate as
isopropylamine salt, 48%) at the LC20 (concentration not otherwise specified) and evaluated
various parameters of oxidative stress. Exposure
to the formulation for 24 hours increased catalase
activity and glutathione levels, but did not have
an effect on superoxide dismutase or glutathioneS-transferase activity.
Using blood samples from non-smoking
male donors, Mladinic et al. (2009b) examined
the effects of in-vitro exposure to glyphosate on
oxidative DNA damage in primary lymphocyte
cultures and on lipid peroxidation in plasma. Both
parameters were significantly elevated at glyphosate concentrations of 580 g/mL (~3.4 mM),
but not at lower concentrations. Kwiatkowska
et al. (2014) examined the effects of glyphosate,
its metabolite AMPA, and N-methylglyphosate
(among other related compounds) in human
erythrocytes isolated from healthy donors. The
erythrocytes were exposed at concentrations
of 0.015 mM for 1, 4, or 24 hours before flow
cytometric measurement of the production of
reactive oxygen species with dihydrorhodamine
123. Production of reactive oxygen species was
increased by glyphosate ( 0.25 mM), AMPA
(0.25 mM), and N-methylglyphosate (0.5 mM).
(ii)
(i) Humans
Studies in exposed humans
No data were available to the Working Group.
Human cells in vitro
Nakashima et al. (2002) investigated the
effects of glyphosate on cytokine production
in human peripheral blood mononuclear cells.
Glyphosate (1 mM) had a slight inhibitory effect
on cell proliferation, and modestly inhibited
the production of IFN-gamma and IL-2. The
production of TNF- and IL-1 was not affected
by glyphosate at concentrations that significantly
inhibited proliferative activity and T-cell-derived
cytokine production.
(ii)
Glyphosate
in haematological and immune-system parameters in silver catfish (Rhamdia quelen) exposed
to sublethal concentrations (10% of the median
lethal dose, LC50, at 96 hours) of a glyphosate-based herbicide. Numbers of blood erythrocytes, thrombocytes, lymphocytes, and total
leukocytes were significantly reduced after 96
hours of exposure, while the number of immature
circulating cells was increased. The phagocytic
index, serum bacteria agglutination, and total
peroxidase activity were significantly reduced
after 24 hours of exposure. Significant decreases
in serum bacteria agglutination and lysozyme
activity were found after 10 days of exposure.
No effect on serum bactericidal and complement
natural haemolytic activity was seen after 24
hours or 10 days of exposure to glyphosate.
el-Gendy et al. (1998) demonstrated effects
of a glyphosate-based formulation (glyphosate,
48%) at 1/1000 of the concentration recommended for field application on humoral and
cellular immune response in bolti fish (Tilapia
nilotica). The mitogenic responses of splenocytes
to phytohaemagglutinin, concanavalin A, and
lipopolysaccharide in fish exposed to glyphosate for 96 hours were gradually decreased and
reached maximum depression after 4 weeks.
Glyphosate also produced a concentration-dependent suppression of in-vitro plaque-forming
cells in response to sheep erythrocytes.
In vivo
In male Wistar rats, glyphosate (10 mg/kg
bw, injected intraperitoneally three times per
week for 5 weeks) reduced, but not significantly,
the inner mitochondrial membrane integrity of
the substantia nigra and cerebral cortex (Astiz
et al. 2009a). Caspase 3 activity was unaltered in
these tissues. Mitochondrial cardiolipin content
was significantly reduced, particularly in the
substantia nigra, where calpain activity was
substantially higher. Glyphosate induced DNA
fragmentation in the brain and liver.
Glyphosate
(ii)
In vitro
In adult Sprague Dawley rat testicular cells
exposed in vitro, glyphosate (up to 1%; for 24 or
48 hours) did not provoke cell-membrane alterations (Clair et al., 2012). However, caspase 3 and
7 activity increased with exposure in Sertoli cells
alone, and in Sertoli and germ cell mixtures. On
the other hand, a glyphosate-based formulation (a
0.1% solution, containing 0.36 g/L of glyphosate)
induced membrane alterations and decreased
the activity of caspase 3 and 7 in Leydig cells, and
in Sertoli and germ cell mixtures. In a separate
study, glyphosate increased apoptosis in primary
Sertoli cell cultures from mice (Zhao et al., 2013).
Glyphosate (540 mM, for 12, 24, 48, or 72
hours) significantly increased cell death in a
time- and concentration-dependent manner
in differentiated rat pheochromocytoma PC12
(neuronal) cells Gui et al. (2012). Apoptotic
changes included cell shrinkage, DNA fragmentation, decreased Bcl2 expression, and increased
Bax expression. Both autophagy and apoptosis
were implicated, as pre-treatment with the
pan-caspase inhibitor Z-VAD or the autophagy
inhibitor 3-MA inhibited cell loss.
Induction of apoptosis by glyphosate or
glyphosate-based formulations was also studied
in other cell lines. Glyphosate (10 M) induced
apoptosis in rat heart H9c2 cells, the effect being
enhanced when glyphosate was given in combination with the adjuvant TN-20 (5 M), (Kim
et al., 2013). A glyphosate-based formulation
induced apoptosis in mouse 3T3-L1 fibroblasts,
and inhibited their transformation to adipocytes
(Martini et al., 2012). A glyphosate-based formulation (10 mM) did not increase rat hepatoma
HTC cell death, but did affect mitochondrial
membrane potential (Malatesta et al., 2008).
Glyphosate (up to 30 M) did not activate
caspase 3 or show cell proliferation potential
(5-bromo-2-deoxyuridine) in a mouse neuroprogenitor cell line, but did activate Tp53 at the
Glyphosate
There is little information available on occupational or community exposure to glyphosate.
Glyphosate can be found in soil, air, surface
water and groundwater, as well as in food. It
has been detected in air during agricultural
herbicide-spraying operations. Glyphosate was
detected in urine in two studies of farmers in
the USA, in urban populations in Europe, and in
a rural population living near areas sprayed for
drug eradication in Columbia. However, urinary
concentrations were mostly below the limit of
detection in several earlier studies of forestry
workers who sprayed glyphosate. Exposure of
the general population occurs mainly through
diet.
75
Glyphosate
on the distribution of glyphosate. In a study in
rats, the half-life of glyphosate in plasma was
estimated to be more than 1day, indicating that
glyphosate is not rapidly eliminated.
In the environment, glyphosate is degraded
by soil microbes, primarily to aminomethyl
phosphonic acid (AMPA) and carbon dioxide.
Glyphosate is not efficiently metabolized in
humans or other mammals. In rats, small
amounts of AMPA were detected in the plasma
and in the colon, with the latter being attributed
to intestinal microbial metabolism. In humans,
small amounts of AMPA are detectable in blood
in cases of deliberate glyphosate poisoning.
Few studies examined the possible effects of
glyphosate-based formulations on metabolizing
enzymes, but no firm conclusions could be drawn
from these studies.
Studies in rodents showed that systemically
absorbed glyphosate is excreted unchanged
into the urine, and that the greatest amount is
excreted in the faeces, indicating poor absorption.
Glyphosate was detected in the urine of humans
who were exposed occupationally to glyphosate.
AMPA has also been detected in human urine.
Glyphosate is not electrophilic.
A large number of studies examined a wide
range of end-points relevant to genotoxicity with
glyphosate alone, glyphosate-based formulations, and AMPA.
There is strong evidence that glyphosate
causes genotoxicity. The evidence base includes
studies that gave largely positive results in human
cells in vitro, in mammalian model systems in
vivo and in vitro, and studies in other non-mammalian organisms. In-vivo studies in mammals
gave generally positive results in the liver, with
mixed results for the kidney and bone marrow.
The end-points that have been evaluated in these
studies comprise biomarkers of DNA adducts
and various types of chromosomal damage.
Tests in bacterial assays gave consistently negative results.
77
6. Evaluation
6.1 Cancer in humans
There is limited evidence in humans for the
carcinogenicity of glyphosate. A positive association has been observed for non-Hodgkin
lymphoma.
6.4 Rationale
In making this overall evaluation, the
Working Group noted that the mechanistic and
other relevant data support the classification of
glyphosate in Group 2A.
In addition to limited evidence for the carcinogenicity of glyphosate in humans and sufficient
evidence for the carcinogenicity of glyphosate in
experimental animals, there is strong evidence
that glyphosate can operate through two key
characteristics of known human carcinogens,
and that these can be operative in humans.
Specifically:
There is strong evidence that exposure to
glyphosate or glyphosate-based formulations
is genotoxic based on studies in humans in
vitro and studies in experimental animals.
Glyphosate
One study in several communities in individuals exposed to glyphosate-based formulations also found chromosomal damage in
blood cells; in this study, markers of chromosomal damage (micronucleus formation)
were significantly greater after exposure than
before exposure in the same individuals.
There is strong evidence that glyphosate, glyphosate-based formulations, and
aminomethylphosphonic acid can act to
induce oxidative stress based on studies in
experimental animals, and in studies in
humans in vitro. This mechanism has been
challenged experimentally by administering
antioxidants, which abrogated the effects of
glyphosate on oxidative stress. Studies in
aquatic species provide additional evidence
for glyphosate-induced oxidative stress.
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