Revised Glyphosate Issue Paper:
	
Evaluation of Carcinogenic Potential 
EPA’s Office of Pesticide Programs 
December 12, 2017 
DP Barcode: D444689 
TXR#: 0057688  
 
    
 
 
   
   
   
   
 
   
   
     
   
   
   
   
   
   
   
   
   Table of Contents
	
List of Acronyms ........................................................................................................................... 7
	
List of Tables ............................................................................................................................... 10
	
1.0 Introduction ...................................................................................................................... 12
	
1.1 Background ...................................................................................................................... 12
	
1.2 Evaluation of Carcinogenic Potential............................................................................. 12
	
1.3 Overview of “Framework for Incorpo rating Human Epidemiologic & Incident Data 
in Health Risk Assessment” .................................... ................................................................... 14
	
1.4 Summary of the Exposure Profile in the United States ................................................ 15
	
1.5 Organization of this Document ................................. ...................................................... 19
	
2.0 Systematic Review & Data Collection ........................... ................................................. 19
	
2.1 Data Collection: Methods & Sources ............................ ................................................. 20
	
2.1.1 Open Literature Search ................................................................................................... 20
	
2.1.2 Studies Submitted to the Agency .................................................................................... 21
	
2.2 Evaluation of Relevant Studies ....................................................................................... 22
	
3.0 Data Evaluation of Epidemiology ................................................................................... 23
	
3.1 Introduction ...................................................................................................................... 23
	
3.2 Considerations for Study Quality Evaluation and Scope of Assess ment .................... 23
	
3.2.1 Study Designs ................................................................................................................... 24
	
3.2.1.1 Analytical Studies ..................................................................................................... 26
	
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   3.2.1.2 Descriptive Studies ........................................... ........................................................ 27
	
3.2.2 Exposure Measures .......................................................................................................... 28
	
3.2.3 Outcome Measures ........................................................................................................... 28
	
3.2.4 Confounding ..................................................................................................................... 28
	
3.2.5 Statistical Analyses........................................................................................................... 29
	
3.2.6 Risk of Bias .................................................. ..................................................................... 29
	
3.3 Review of Quality Results ..................................... .......................................................... 30
	
3.3.1 “High” Quality Group .......................................... ........................................................... 31
	
3.3.2 “Moderate” Quality Group ............................................................................................. 32
	
3.3.3 “Low” Quality Group ........................................... ........................................................... 32
	
3.4 Assessment of Epidemiological St udies for Relevance to Analysis ............................. 44
	
3.5 Summary of Relevant Epidemiological Studies ............................................................ 45
	
3.5.1 Solid Tumor Cancer Studies .................................... ....................................................... 45
	
3.5.2 Non-Solid Tumor Cancer Studies ................................ .................................................. 53
	
3.6 Discussion ..................................................... ..................................................................... 63
	
4.0 Data Evaluation of Animal Carcinogenicity Studies ............. ....................................... 69
	
4.1 Introduction ...................................................................................................................... 69
	
4.2 Consideration of Study Quality fo r Animal Carcinogenicity Studi es ......................... 69
	
4.3 Assessment of Animal Carcinogenicity Studies ............................................................ 71
	
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   4.4 Summary of Animal Carcinogenicity Studies ............................................................... 74
	
4.5 Rat Carcinogenicity Studies with Glyphosate ................... ............................................ 74
	
4.5.1 Lankas, 1981 (MRID 00093879) ..................................................................................... 74
	
4.5.2 Stout and Ruecker, 1990 (MRID 41643801) .................................................................. 75
	
4.5.3 Atkinson et al. , 1993a (MRID 49631701) ....................................... ................................ 79
	
4.5.4 Brammer, 2001 (MRID 49704601) ................................................................................. 80
	
4.5.5 Pavkov and Wyand 1987 (MRIDs 40214007, 41209905, 41209907) ............................ 80
	
4.5.6 Suresh, 1996 (MRID 49987401) ...................................................................................... 81
	
4.5.7 Enemoto, 1997 (MRID 50017103-50017105) ........................ ......................................... 81
	
4.5.8 Wood et al. , 2009a (MRID 49957404)........................................ ..................................... 81
	
4.5.9 Summary of Rat Data ...................................................................................................... 82
	
4.6 Mouse Carcinogenicity Studies with Glyphosate ................. ......................................... 85
	
4.6.1 Reyna and Gordon, 1973 (MRID 00061113) ................................................................. 85
	
4.6.2 Knezevich and Hogan, 1983 (MRID 00130406) ..................... ....................................... 85
	
4.6.3 Atkinson, 1993b (MRID 49631702) ................................................................................ 87
	
4.6.4 Wood et al. , 2009b (MRID 49957402) ....................................... ..................................... 88
	
4.6.5 Sugimoto, 1997 (MRID 50017108 - 50017109) .............................................................. 89
	
4.6.6 Pavkov and Turnier, 1987 (MRIDs 40214006, 41209907) ........................................... 90
	
4.6.7 Summary of Mouse Data ................................................................................................. 90
	
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  4.7 Absorption, Distribution, Metabolism, Excretion (ADME) ........ ................................. 93
	
4.8 Discussion ..................................................... ..................................................................... 94
	
5.0 Data Evaluation of Genetic Toxicity .............................................................................. 98
	
5.1 Introduction ...................................................................................................................... 98
	
5.2 Scope of the Assessment Considerations for Study Quality Evalua tion ..................... 99
	
5.3 Tests for Gene Mutations for Glyphosate Technical .................................................. 100
	
5.3.1 Bacterial Mutagenicity Assays ...................................................................................... 100
	
5.3.2 In vitro Tests for Gene Mutation s in Mammalian Cells .................. ........................... 106
	
5.4 In vitro Tests for Chromosomal Abnormalities........................................................... 108
	
5.4.1 In vitro Mammalian Chromosomal Aberration Test ........................ .......................... 108
	
5.4.2 In vitro Mammalian Micronucleus Test ....................................................................... 109
	
5.5 In Vivo  Genetic Toxicology Tests .................................................................................. 114
	
5.5.1 In Vivo  Assays for Chromosomal Abnormalities ........................................................ 114
	
5.5.1.1 Mammalian Bone Marrow Chromosomal Aberration Assays ........................... 114
	
5.5.1.2 Rodent Dominant Lethal Test ................................... ............................................ 114
	
5.5.1.3 In Vivo  Mammalian Erythrocyte Micronucleus Assays .................... ................. 115
	
5.6		 Additional Genotoxicity Assays E valuating Primary DNA Damage ........................ 122
	
5.7		 Summary and Discussion ........................................ ...................................................... 129
	
6.0		 Data Integration & Weight-of-Ev idence Analysis Across Multiple Lines of Evidence
	
132
	
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  6.1 Background .................................................................................................................... 132
	
6.2 Dose-Response and Temporal Concordance ............................................................... 132
	
6.3 Strength, Consistenc y, and Specificity ........................ ................................................. 133
	
6.4 Biological Plausibility and Coherence ......................... ................................................. 135
	
6.5 Uncertainty ................................................... .................................................................. 136
	
6.6 Evaluation of Cancer Classification per the 2005 EPA Guidelines  for Carcinogen 
Risk Assessment ........................................................................................................................ 138
	
6.6.1 Introduction .................................................................................................................... 138
	
6.6.2 Discussion of Evidence to Support  Cancer Classification Descrip tors ..................... 141
	
6.7 Proposed Conclusions Regarding t he Carcinogenic Potential of Glyphosate .......... 143
	
7.0 Collaborative Research Plan for Glyphosate and Glyphosate Formu lations .......... 145
	
8.0 References ....................................................................................................................... 147
	
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 List of Acronyms 
ADME: Absorption, Distribution, M etabolism, and Excretion 
AHS: Agricultural Health Study 
AOP: Adverse Outcome Pathway  AMPA: Aminomethylphosphonic Acid BrdU: Bromodeoxyuridine CA: Chromosomal Aberration CARC: Cancer Assessment Review Committee CBPI: Cytokinesis Block Proliferation Index CHL: Chinese Hamster Lung CHO: Chinese Hamster Ovary CPRC: Carcinogenicity Peer Review Committee EFSA: European Food Safety Authority EPSPS: 5-enolpyruvylshikimate-3-phosphate synthase FAO: Food and Agriculture Organization FIFRA: Federal Insecticide , Fungicide, and Rodenticide Act 
FISH: Fluorescence in situ  Hybridization 
GC-MS: Gas Chromatography-Mass Spectrometry HL: Hodgkin Lymphoma  HPLC: High-Performance Liquid Chromatography HPRT: Hypoxanthine-Guanine  Phosphoribosyl Transferase 
IARC: International Agen cy for Research on Cancer 
JMPR: Joint FAOWHO Meeting on Pesticide Residues  MGUS: Monoclonal Gammopathy of  Undetermined Significance 
MN: Micronuclei MOA: Mode of Action MPCE: Micronucleated Polychromatic Erythrocytes  MRID: Master Record I dentifier (a unique number assigned to eac h study submitted to EPA) 
MTD: Maximum Tolerated Dose NB: Nuclear Bud NCR: National Research Council NHL: Non-Hodgkin Lymphoma NPB: Nucleoplasmic Bridges NTP: National Toxicology Program OCSPP: Office of Chemical Safet y and Pollution Prevention 
OECD: Organization for Economic  Cooperation and Development 
OPP: Office of Pesticides Program PCE: Polychromatic Erythrocytes PK: Pharmacokinetic PPE: Personal Protective Equipment PWG: Pathology Work Group RED: Registration E ligibility Decision 
ROS: Reactive Oxygen Species SAP: Scientific Advisory Panel SCE: Sister Chromatid Exchange  
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 SCGE: Single Cell Gel Electrophoresis 
TAC: Total Antioxidant Capacity 
TK: Thymidine Kinase UDS: Unscheduled DNA Synthesis  USGS: United States Geological Survey UV: Ultraviolet WHO: World Health Organization XPRT: Xanthine-Guanine Phosphoribosyl Transferase 
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  List of Figures 
Figure 1.1. Source to outcome pathway (adapted from NRC, 2007)
	
Figure 1.2. Glyphosate ag ricultural usage (pounds applied annu ally) from 1987- 2014. Boxes 
indicate years when glyphosate-re sistant crops were introduced.  Source: Proprietary Market 
Research Data (1987 – 2014) 
Figure 1.3. Map of estimated agricultural use for glyphosate in  1994 from USGS 
Figure 1.4. Map of estimated agricultural use for glyphosate in  2014 from USGS 
Figure 3.1. Study evaluation proces s for epidemiological studi es
	
Figure 3.2. Forest plot of effect  estimates (denoted as ES for effect sizes) and associated 95% 
confidence intervals (CI) for non-Hodgkin lymphoma (NHL) Figure 7.1. Results of HepG2 e xposures following 24 hour incub ation using different glyphosate 
formulations 
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 List of Tables 
Table 3.1 Epidemiology Study Quality Considerations 
Table 3.2. Summary of Study Desig n Elements Impacting Study Qu ality Assignment and 
Overall Ranking 
Table 3.3. Summary of Findings: Solid Tumor Cancer Studies 
Table 3.4. Summary of Findings: N on-Solid Tumor Cancer Studies 
Table 4.1. Testicular Interstitia l Cell Tumors in Male Sprague -Dawley Rats (Lankas, 1981) 
Cochran-Armitage Trend Test & Fisher’s Exact Test Results 
Table 4.2. Pancreatic Islet Cell Tumors in Male Sprague-Dawley  Rats (Stout and Ruecker, 
1990) Cochran-Armitage Trend Test & Fisher’s Exact Test Results 
Table 4.3. Historical Control Data  — Pancreatic Islet Cell Ade nomas in Male Sprague-Dawley 
Rats (MRID No. 41728701)  
Table 4.4. Hepatocellular Tumors in Male Sprague-Dawley Rats ( Stout and Ruecker, 1990) 
Cochran-Armitage Trend Test & Fisher’s Exact Test Results 
Table 4.5. Historical Control Data  - Hepatocellular Tumors in Male Sprague- Dawley Rats 
(MRID No. 41728701). 
Table 4.6. Thyroid C-Cell Tumors  in Male Sprague-Dawley Rats (Stout and Ruecker, 1990) 
Cochran-Armitage Trend Test & Fisher’s Exact Test Results 
Table 4.7. Thyroid C-Cell Tumors  in Female Sprague Dawley Rats  Cochran-Armitage Trend 
Test & Fisher’s Exact Test Re sults (Stout and Ruecker, 1990) 
Table 4.8. Historical Control Data - Thyroid C-Cell Tumors in Female Sprague-Dawley Rats 
(MRID No. 41728701). 
Table 4.9. Thyroid Non-Neoplastic Lesions (Stout and Ruecker, 1990) 
Table 4.10. Liver Adenomas in Mal e Wistar Rats (Brammer, 2001)  Cochran-Armitage Trend 
Test and Fisher’s Exact Test Results 
Table 4.11. Mammary Gland Tumor I ncidences in Female Rats (Woo d et al., 2009a) 
Fisher’s Exact Test and Cochran-Armitage Trend Test Results 
Table 4.12. Summary of Rat Car cinogenicity Studies 
Table 4.13. Renal Tubular Cell Tumors in Male CD-1 Mice (Kneze vich and Hogan, 1983) 
Cochran-Armitage Trend Test & Fisher’s Exact Test Results Table 4.14. Historical Control Da ta- Kidney tumors in CD-1 Mice (TXR #0007252
). 
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  Table 4.15. Kidney Histopathologic al Alterations in Male CD-1 Mice (Knezevich and Hogan, 
1983) 
Table 4.16. Hemangiosarcomas in Male CD-1 Mice (Atkinson, 1993 b) Cochran-Armitage Trend 
Test and Fisher’s Exact Test Results 
Table 4.17. Lung Tumors in Mal e CD-1 Mice (Wood et al., 2009b) Fisher’s Exact Test and 
Cochran-Armitage Trend Test Results Table 4.18. Malignant Lymphomas in Male CD-1 Mice (Wood et al. , 2009b) Fisher’s Exact 
Test and Cochran-Armitage Trend Test Results Table 4.19. Hemangioma Inciden ces (Sugimoto, 1997) Fisher’s Ex act Test and Cochran-
Armitage Trend Test Results Table 4.20. Summary of Mouse Carcinogenicity Studies 
Table 5.1 . In vitro  Test for Gene Mutations in Bacteria: Glyphosate Technical 
Table 5.2 . In vitro  Mammalian Gene Mutation Assays: Glyphosate Technical 
Table 5.3. In vitro  Tests for Chromosome Aberrati ons in Mammalian Cells- Glyphosat e 
Technical Table 5.4. In vitro  Tests for Micronuclei Inducti on in Mammalian Cells- Glyphosate  Technical 
Table 5.5. In Vivo  Tests for Chromosomal Aberrations in Mammals- Glyphosate Techn ical 
Table 5.6. In Vivo Tests for Micr onuclei Induction in Mammals-  Glyphosate Technical 
Table 5.7 Assays for Detecting Pri mary DNA Damage- Glyphosate Technical 
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  1.0 Introduction 
1.1 Background 
Glyphosate is a non-selective, pho sphonomethyl amino acid herbi cide registered to control 
weeds in various agricultural and non-agricultural settings.  T he herbicide acts by inhibiting the 
5-enolpyruvylshikimate-3-phospha te synthase (EPSPS) enzyme, which is not present in 
mammalian systems.  Glyphosate wa s initially registered in 1974 .  Since then, several human 
health analyses have been c ompleted for glyphosate.  In 1986, EPA issued the Glyphosate 
Registration Standard which updated the agency’s toxicity database for this compound.  In 1993, 
EPA issued the registration elig ibility decision (RED) that ind icated that glyphosate was eligible 
for re-registration. 
Currently, glyphosate is undergoing Registration Review1, a program where all registered 
pesticides are reviewed at le ast every 15 years as mandated by the Federal Insecticide, Fungicide, 
and Rodenticide Act (FIFRA). T he initial docket opening for gl yphosate occurred in 2009 with 
the publication of the human health scoping document and prelim inary work plan2. As part of 
this process, the hazard and expos ure of glyphosate are reevalu ated to determine its potential risk 
to human and environmental health.  Risks are assessed using cu rrent practices and policies to 
ensure pesticide products can still be used safely.  Registration Review also allows the agency to 
incorporate new science. For human health risk assessment, both non-cancer and cancer effects are evaluated for glyphosate and its metabolites, aminomethylph osphonic acid (AMPA) and N -
acetyl-glyphosate; however, this document will focus on the can cer effects only.  EPA expects to 
complete its complete human health risk assessment in 2017 that  will include an assessment of 
risk from anticipated exposures  resulting from registered uses of glyphosate in residential and 
occupational settings. 
1.2 Evaluation of Carcinogenic Potential 
Since its registration, the car cinogenic potential of glyphosate has been evaluated by EPA several 
times.  In 1985, the initial peer rev iew of glyphosate was cond ucted in accordance with the 
Proposed Guidelines for Carcinogen Risk Assessment.  The agency classified glyphosate as a 
Group C chemical (Possible Human Carcinogen), based on the pres ence of kidney tumors in 
male mice.  In 1986, the agency requested that the FIFRA Scient ific Advisory Panel (SAP) 
evaluate the carcinogenic potential of glyphosate.  The panel d etermined that the data on renal 
tumors in male mice were equivocal (only an increase in adenomas was observed and the increase did not reach statistica l significance).  As a result,  the panel recommended a Group D 
chemical classification (Not Classifiable as to Human Carcinoge nicity) for glyphosate and 
advised the agency to issue a data call-in notice for further studies in rats and/or mice to clarify the unresolved questions  (FIFRA SAP Report, 1986)
3. 
1 Additional information on the Registration Review process can be found at: https://www.epa.gov/pesticide-
reevaluation/registration-review-process
2 Documents of the Registration Review can be found in the publi c docket at: EPA-HQ-OPP- 2009-0361, accessible 
at www.regulations.gov . 
3 Review available at: http://www.epa.gov/pesticides/chem_search /cleared_reviews/csr_PC-103601_24-Feb-
86_209.pdf 
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 With the submission of two rat car cinogenicity studies followin g this data call-in, a second peer 
review was conducted in 1991 by the agency’s Carcinogenicity Peer Review Committee (CPRC) 
to incorporate the new data.  In accordance with the agency’s 1 986 Draft Guidelines for 
Carcinogen Risk Assessment, the CPRC classified glyphosate as a  Group E Chemical: 
“Evidence of Non-Carcinogenicity for Humans” based upon lack of  evidence for carcinogenicity 
in mice and rats and the lack of  concern for mutagenicity (TXR#  0008897). 
Most recently, in September 2015, a third review was done by th e Cancer Assessment Review 
Committee (CARC).  Relevant glyphos ate data available to EPA at  that time for glyphosate were 
reevaluated, including studies submitted by the registrant and studies published in the open 
literature. The agency performed this evaluation in support of  Registration Review in 
accordance with the 2005 Guidelin es for Carcinogen Risk Assessm ent, classified glyphosate as 
“Not Likely to be Carcinogenic to Humans” (CARC, 2015; TXR #005 7299). 
In recent years, several interna tional agencies have evaluated the carcinogenic potential of 
glyphosate. In March 2015, the Int ernational Agency for Resear ch on Cancer (IARC), a 
subdivision of the World Health O rganization (WHO), determined that glyphosate was a 
probable carcinogen (group 2A) (IARC, 2015).  Later, in Novembe r 2015, the European Food 
Safety Authority (EFSA) determin ed that glyphosate was unlikely  to pose a carcinogenic hazard 
to humans (EFSA, 2015).  In May 2 016, the Joint Food and Agriculture Organization 
(FAO)/WHO Meeting on Pesticide Residues (JMPR), another subdivi sion of the WHO, 
concluded that glyphosate was  unlikely to pose a carcinogenic r isk to humans from exposure 
through the diet (JMPR, 2016). Som e individual countries in Eu rope (e.g., France, Sweden) 
have considered banning glyphosate  uses based on the IARC decision, while other countries 
(e.g., Japan, Canada, Australia, N ew Zealand) have continued to  support their conclusion that 
glyphosate is unlikely to pose a carcinogenic risk to humans. 
The recent peer review performed by CARC served as an initial a nalysis to update the data 
evaluation for glyphosate at tha t time.  Based on an evaluation  of the studies included in the 
recent analyses by IARC, JMPR, and EFSA, the agency then became  aware of additional 
relevant studies not available  to EPA.  As a result, EPA also r equested information from 
registrants about studies tha t existed, but had never been submitted to the agency.  The current 
evaluation incorporates these a dditional studies. In addition, the agency conducted a systematic 
review of the open literature and toxicological databases for g lyphosate by using a “Framework 
for Incorporating Human Epidemiologic & Incident Data in Health  Risk Assessment”.  As such, 
the current evaluation also provi des a more thorough evaluation  than the 2015 CARC review.  
In December 2016, the FIFRA SAP w as convened to evaluate the ag ency’s Issue Paper 
regarding the human carcinogenic potential of glyphosate.  The panel’s report was published in 
March 2017 and the current document incorporates revisions base d on the panel’s report (G. 
Akerman; 12-DEC-2017; TXR#005 7689).  Additionally, information from a recently published 
analysis of glyphosate use and cance r incidence in the Agricult ural Health Study (AHS) cohort 
(Andreotti et al., 2017) with a longer follow-up than the previously published data (De Roos et 
al., 2005) has been considere d in this evaluation. 
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 1.3 Overview of “Framework for Inc orporating Human Epidemiologic & Incident Data 
in Health Risk Assessment” 
In 2010, the Office of Pesticide Pr ograms (OPP) developed a dra ft “Framework for Incorporating 
Human Epidemiologic & Incident D ata in Health Risk Assessment” which provides the 
foundation for evaluating multiple lines of scientific evidence  in the context of understanding of 
the mode of action (MOA)/advers e outcome pathway (AOP) (U.S. EPA, 2010).  The draft 
framework, which includes two key components, problem formulati on and use of the MOA/AOP
pathway frameworks, was reviewe d favorably by the FIFRA SAP in 2010 (FIFRA SAP, 2010).  
In 2016, a final version of the  framework was published4, which incorporated improvements 
based on recommendations from the SAP, public comments, and the  experience gained since 
2010 conducting assessments on several pesticides for which epi demiological data were 
available. Recently, EPA has applied this framework to the evaluation of atrazine and 
chlorpyrifos5. 
OPP’s framework is consistent w ith updates to the World Health Organization/International 
Programme on Chemical Safety MOA/ human relevance framework, whi ch highlights the 
importance of problem formulati on and the need to integrate inf ormation at different levels of 
biological organization (Meek et al. , 2014). Consistent with recommendations by the National 
Research Council (NRC)  in its 2009 report on Science and Decisions , OPP’s framework 
describes the importance of us ing problem formulation at the be ginning of a complex scientific 
analysis. The problem formulati on stage starts with planning d ialogue with risk managers to 
identify goals for the analysis and possible risk management strategies.  This initial dialogue 
provides the regulatory context fo r the scientific analysis and  helps define the scope of such an 
analysis. The problem formulati on stage also involves consideration of the available information 
regarding the pesticide use/usag e, toxicological effects of con cern, and exposure pathways and 
duration along with key gaps in data or scientific information.  Specific to glyphosate, the 
scoping document prepared for Reg istration Review (J. Langsdale et al. , 2009) along with the 
review conducted by the CARC (CARC, 2015) represent the problem  formulation analyses for 
the weight-of-evidence evalua tion for carcinogenic potential.  A summary of the US exposure 
profile is provided in Section 1.4 to  provide context for inter preting the various lines of evidence. 
One of the key components of the agency’s framework is the use of the MOA framework/AOP 
concept (Figure 1.1) as a tool f or organizing and integrating i nformation from different sources 
to inform the causal nature of links observed in both experimental and observational studies.  
Specifically, the modified Bradford Hill Criteria (Hill, 1965) are used to evaluate strength, 
consistency, dose response, tem poral concordance and biological plausibility of multiple lines of 
evidence in a weight-of-evidence analysis. 
4 https://www3.epa.gov/pesticides /EPA-HQ-OPP-2008- 0316-DRAFT-0075.pdf
	
5 Chlorpyrifos Revised Human Health Risk Assessment for Registra tion Review; 29-DEC-2014; D424485. 
U.S. EPA 2010 SAP Background White Paper – Re-evaluation of Hum an Health Effects of A trazine: Review of 
Experimental Animal and In Vitro Studies and Drinking Water Mon itoring Frequency. EPA-HQ-OPP-2010-0125. 
U.S. EPA 2011 SAP Issue Paper – Re-evaluation of Human Health E ffects of Atrazine: Review of Cancer 
Epidemiology, Non-cancer Experimental Animal and In Vitro Studi es and Drinking Water Monitoring Frequency. 
EPA-HQ-OPP-2011-0399. 
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Figure 1.1.  Source to outcome pathway (adapted from NRC, 2007) . 
1.4 Summary of the Exposure Profile in the United States
	
All pesticide products provide c ritical information about how t o safely and legally handle and 
use pesticide products.  Pesticide labels are legally enforceab le and all carry the statement “it is a 
violation of Federal law to use this product in a manner incons istent with its labeling.”  In other 
words, the label is law. As a result, a key function of the pe sticide product label is to manage the 
potential risk from pesticides. 
Labeled uses of glyphosate inc lude over 100 terrestrial food cr ops as well as other non-
agricultural sites, such as greenhouses, aquatic areas, and res idential areas.  It is also registered 
for use on glyphosate-resistant (t ransgenic) crop varieties suc h as corn, soybean, canola, cotton, 
sugar beets, and wheat.  Registered tolerances in the United St ates include residues of the parent 
compound glyphosate and N-acetyl-glyphosate, a metabolite found in/on glyphosate-toleran t 
crops6. 
Dietary (food and water) exposures  are anticipated from applica tions to crops.  Since there are 
registered uses of glyphosate that may be used in residential s ettings, residential handlers may be 
exposed to glyphosate during applications.  Exposures may also occur from entering non-
occupational areas that have been previously treated with glyph osate.  Occupational/commercial 
workers may be exposed to glyphosate while handling the pesticide prior to application (mixing and/or loading), during application, or when entering treated sites.  The agency considers all of the anticipated exposure pathways as part of their evaluation for human health. 
Oral exposure is considered the primary route of concern for gl yphosate.  Oral absorption has 
been shown to be relatively low for glyphosate (~30% of adminis tered doses) with negligible 
accumulation in tissues and rapid excretion (primarily unchange d parent) via the urine.  Due to 
its low vapor pressure, inhalati on exposure to glyphosate is ex pected to be minimal.  Dermal 
penetration has also been shown to be relatively low for human skin (<1%) indicating dermal 
exposure will only contribute slig htly to a systemic biological  dose.  Furthermore, in route-
6 All currently registered toleran ces for residues of glyphosate  can be found in the Code of  Federal Regulations (40 
CFR §180.364). 
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 specific inhalation and dermal t oxicity studies, no adverse eff ects were observed.  This all 
suggests that there i s low potential for a sustainable biologic al dose following glyphosate 
exposure. 
In residential/non-occupationa l settings, child ren 1-2 years ol d are considered the most highly 
exposed subpopulation with oral e xposures from dietary (food an d water) ingestion and 
incidental oral ingestion (e.g., hand-to-mouth activities) in t reated areas.  There is also potential 
for dermal exposures in previous ly treated areas.  Using OPP’s standard exposure assessment 
methodologies which are based on pe er-reviewed and validated ex posure data and models7, a 
high-end estimate of combined e xposure for children 1-2 years old is 0.47 mg/kg/day (see 
Appendix E). At the time of initial regist ration (1974), total use of glyphosate in the United States was 
approximately 1.4 million pounds (Benbrook, 2016).  In 1995, to tal use of glyphosate increased 
to approximately 40 million pounds with agriculture accounting for 70% of use.  With the 
introduction of transgenic crop va rieties in the United States circa 1996, (such as soybean, 
cotton, and corn) use of glyphosat e increased dramatically (Gre en and Owen, 2011), and in 2000 
the total use of glyphosate in the United States was approximat ely 98.5 million pounds.  By 
2014, total annual use of glyphosate was approximately 280-290 million pounds (based on 
Benbrook, 2016 and industry proprietar y data accessible to EPA)  with agriculture accounting for 
90% of use. Although glyphosate use has continuously increased  up to 2012, the stabilization of 
glyphosate usage in recent years is due to the increase in a number of glyphosate-resistant weed 
species, starting with rigid ryegrass identified in California in 1998 and currently totaling 16 
different weed species in the United States as of March 2016.  Figure 1.2 below provides a visual 
representation of the increased  agricultural use of glyphosate in the United States using 
proprietary market research data from 1987-2014. 
The increased use of glyphosate may be partly attributed to an increase in the number of farmers 
using glyphosate; however, it is m ore likely that individuals already using glyphosate increased 
their use and subsequent exposur e.  With the introduction of tr ansgenic crop varieties, glyphosate 
use shifted from pre-emergent t o a combination of pre- and post -emergent applications.  
Additionally, application rates increased in some instances and  more applications were allowed 
per year (2-3 times/year).  Maps from the United States Geological Survey (USGS) displaying 
glyphosate use in the United S tates indicate that although use has drastically increased since 
1994, areas treated with glyphosat e for agricultural purposes a ppear to be approximately the 
same over time (Figures 1.3-1.4).  T he introduction of transgen ic crops in some cases led to a 
shift in crops grown on individual farms, such that more acreage within the farm would be 
dedicated to growing the glyphosat e-tolerant crops replacing other crops.  In addition, during the 
2000s there was also an increase in growing corn for ethanol pr oduction, which could also have 
resulted in increased acreage  dedicated glyphosate-tolerant cor n.   
7 Available: http://www2.epa.gov/pesticide-science-and-assessing- pesticide-risks/standard-operating-procedures-
residential-pesticide 
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 0 300,000,000 
1987
1988
1989
1990
19911992
1993
1994
1995
19961997
1998
19992000
2001
2002
2003
20042005
2006
20072008
2009
2010
2011
20122013
2014 Pounds 
AI 
Years Soybean and 
Canola Cotton Corn Alfalfa 
and 
Sugar 
Figure 1.2. Glyphosate agricultural usage (pounds applied annu ally) from 1987- 2014. Boxes indicate years when 
glyphosate-resistant crops were introduced.  Source: Proprietar y Market Research Data (1987 – 2014). 
Figure 1.3. Map of estimated agricultural use for glyphosate in  1994 from USGS 
(http://water.usgs.gov/nawqa/pnsp/ usage/maps/show_map.php?year= 1994&map=GLYPHOSATE&hilo=H) 
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Figure 1.4. Map of estimated agricultural use for glyphosate in  2014 from USGS 
(http://water.usgs.gov/nawqa/pnsp/ usage/maps/show_map.php?year= 2014&map=GLYPHOSATE&hilo=H) 
The potential exposure to occupational handlers is dependent on  the formulation, specific task 
(mixer, loader, and/or applicat or), rate of application, and ac reage treated.  Using HED’s 
standard occupational exposure as sessment methodologies which a re based on peer-reviewed 
and validated exposure data and models8, mixer/loaders result in t he highest potential exposure 
estimates.  Assuming no personal prot ective equipment (PPE), ex posure estimates for 
mixer/loaders range from 0.03-7 mg/kg/day using the maximum app lication rate for high acreage 
agricultural crops  (6 lb ai/acre)9. For applicators, exposure wo uld be lower with estimates 
ranging from 0.02-0.03 mg/kg/day usi ng the same application rat e and acreage. 
The maximum potential exposures from currently registered uses of glyphosate in residential and 
occupational settings in the United States are used in the curr ent evaluation to aid in the 
determination of whether findings  in laboratory studies are rel evant for human health risk 
assessment.  In Sections 4.0 a nd 5.0, descriptions are provided  for animal carcinogenicity and 
genotoxicity studies, respectivel y.  Results from these studies , particularly those administering 
high doses, are put into context with the human exposure potent ial in the United States.   
8 Available: https://www.epa.gov/p esticide-scien ce-and-assessing -pesticide-risks/occupational-pesticide-handler-
exposure-data 
9 Based on use information provid ed by the Joint Glyphosate Task  Force for the following end-use products: EPA 
Registration Nos.: 100-1182, 228-713, 524-343, 524-475, 524-537 , 524-549, 524-579, 4787-23, and 62719-556. 
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 1.5 Organization of this Document 
In this analysis of the human carcinogenic potential of the act ive ingredient glyphosate, the 
agency has performed a comprehen sive analysis of available data  from submitted guideline 
studies and the open literature. T his includes epidemiological, animal carcinogenicity, and 
genotoxicity studies. Consistent with the framework described in Section 1.3, the agency has 
evaluated these multiple lines of evidence and conducted a weig ht-of-evidence analysis.  
Although there are studies ava ilable on glyphosate-based pestic ide formulations, the agency is 
soliciting advice from the FIF RA SAP on this evaluation of human carcinogenic potential for the 
active ingredient gl yphosate only at this time.  The remainder of this document is organized by 
the following: 
	 Section 2.0 Systematic Review  & Data Collection Methods  provides a description of 
methods used to compile all releva nt studies used in the curren t evaluation.  
	 Section 3.0 Data Evalua tion of Epidemiology describes the available epidemiological 
studies, evaluates relevant s tudies for study quality, and discusses reported effect 
estimates. 
 Section 4.0 Data Evaluation of An imal Carcinogenicity Studies provides a description 
and evaluation of the available an imal carcinogenicity studies for glyphosate.   
 Section 5.0 Data Evaluation of Genetic Toxicity  summarizes and discusses the various 
genotoxicity assays that have  been tested with glyphosate. 
	 Section 6.0 Data Integration & Weight of Evidence Analysis Across Multiple Lines of 
Evidence  integrates available data discussed in Sections 3.0-5.0 to con sider concepts, 
such as strength, consistency, dos e response, temporal concorda nce and biological 
plausibility in a weight-of-evid ence analysis.  This section al so provides discussion of the 
data in the context of cancer de scriptors provided in the 2005 Guidelines for Carcinogen 
Risk Assessment. 
	 Section 7.0 Collaborative Research Plan fo r Glyphosate and Glyphosate Formulations 
provides a discussion of planned r esearch that is intended to e valuate the role of 
glyphosate in product formulati ons and the differences in formu lation toxicity.  
2.0 Systematic Review & Data Collection 
In recent years, the National Academy of Sciences National Rese arch Council (NRC) has 
encouraged the agency to move towards systematic review process es to enhance the transparency 
of scientific literat ure reviews that support chemical-specific  risk assessments to inform 
regulatory decision making (NRC , 2011).  The NRC defines system atic review as “a scientific 
investigation that focuses on a specific question and uses expl icit, pre-specified scientific 
methods to identify, select, asse ss, and summarize the findings of similar but separate studies" 
(NRC, 2014). Consistent with NRC’ s recommendations, EPA’s Offi ce of Chemical Safety and 
Pollution Prevention (OCSPP) is currently developing systematic  review policies and 
procedures. In short, OCSPP employs “fit for purpose” systematic reviews that rely on standard 
methods for collecting, evaluating, and integrating  the scientific data supporting the agency’s 
decisions. The concept of fit for purpose implies that a particular activity or method is suitable for its intended use.  Inherent in this definition is the conce pt that one size does not fit all 
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 situations and thus flexibili ty is allowed.  However, it is notable that with flexibility comes the 
importance of transparency of documented processes; including the importance of transparency 
and clarity in approaches to data collection, evaluation, and i ntegration.  These are described 
throughout the document with data  collection in Sections 2.1.1- 2.1.2, evaluation in Sections 3-5, 
and integration in Section 6. 
As a result, more recent evalua tions are starting to reflect th is progression in the agency’s 
process. Similar to the framewo rk for incorporating human epidemiologic and incident data, 
systematic review begins with a problem formulation to determin e the scope and purpose of the 
search. Studies are considere d based on their relevance to ans wer specific questions and those 
studies deemed relevant are the n further considered for their u sefulness in risk assessment. 
The agency strives to use high-qua lity studies when evaluating the hazard potential of pesticidal 
chemicals and considers a broad s et of data during this process.  This includes registrant 
generated studies required under FIFRA, as well as peer-reviewe d scientific journals and other 
sources, such as other governments and academia.  A wide range of potential adverse effects are 
assessed using acute, subchronic,  chronic, and route-specific s tudies; predominately from studies 
with laboratory animals, in addition to epidemiologic and human incident data.  All studies are 
thoroughly reviewed to ensure appropriate conduct and methodolo gies are utilized, and that 
sufficient data and details are provided.  In this way, hazards  are identified and potential risks 
characterized to ensure that decisions are informed by the best  science available. 
2.1 Data Collection: Methods & Sources 
Data were collected by searching the open literature (Section 2 .1.1) and other publicly available 
sources (e.g., recent internal reviews, evaluations by other or ganizations) (Section 2.1.2).  
Internal databases were also searched for submitted studies con ducted according to Organization 
for Economic Cooperation and Development (OECD) test guidelines, OCSPP harmonized test guidelines, and other pesticide test guidelines (OPP guidelines) (Section 2.1.2).    
It should be noted that glyphosate is primarily manufactured as  various salts with cations, such as 
isopropylamine, ammonium, or sodium.  These salts are derivativ es of the active substance 
glyphosate and increase the sol ubility of technical-grade glyph osate acid in water.  All of these 
forms were considered for t he current evaluation. 
2.1.1 Open Literature Search 
As part of the evaluation of the human carcinogenic potential o f glyphosate, the literature review 
described here uses concepts c onsistent with fit for purpose sy stematic review, such as detailed 
tracking of search terms and whic h literature have been include d or excluded.  The primary goal 
of the literature search was to identify relevant and appropria te open literature studies that had 
the potential to inform the agen cy on the human carcinogenic po tential of glyphosate.  Therefore, 
non-mammalian studies were not con sidered, and several terms were used in the search string in 
an attempt to exclude non-mammalian studies. 
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 To obtain literature studies, OPP worked with EPA librarians to  conduct searches in PubMed, 
Web of Science, and Science Dire ct.  A search was conducted on May 6, 2016 in PubMed and 
Web of Science using the followi ng search string to yield 141 and 225 results, respectively: 
((glyphosate OR "1071-83-6" OR roundup OR "N-(Phosphonomethyl)g lycine") AND 
(aneuploid* OR chromosom* OR clastogenic* OR "DNA damag*" OR "D NA adduct*" OR 
genome* OR genotoxic* OR micronucle* OR cancer* OR carcinogen* OR oncogenic* OR 
mutagen* OR cytotoxic* OR tumor* OR tumour* OR malignanc* OR ne oplasm* OR *oma)) 
NOT (fish* OR frog* OR tadpole* OR insect* OR eco* OR amphibian * OR reptil* OR 
invertebrate* OR fly OR flies OR aquatic OR bird* OR aqueous OR  water OR yeast* OR worm* 
OR earthworm* OR bacteria* OR lichen OR resist* OR "herbicide r esist") 
Due to differences with using Sci ence Direct, the  search string  was slightly changed.  This search 
was also conducted on May 6, 2016 and yielded 459 results: 
((glyphosate OR "1071-83-6" OR roundup OR "N-(Phosphonomethyl)g lycine") AND 
(aneuploid* OR chromosom* OR clastogenic* OR (DNA pre/2 (damag* OR adduct*)) OR 
genome* OR genotoxic* OR micronucle* OR cancer* OR carcinogen* OR oncogenic* OR 
mutagen* OR cytotoxic* OR tumor* OR tumour* OR malignanc* OR ne oplasm* OR *oma)) 
AND NOT (eco* OR fish* OR frog* OR tadpole* OR invertebrate* OR  bird* OR insect* OR fly 
OR flies OR amphibian* OR reptil*  OR yeast* OR aquatic OR aqueo us OR water OR worm* 
OR earthworm* OR bacteria* OR lichen OR resist* OR "herbicide r esist”) 
After cross-referencing the resu lts obtained from the three open literature searches for duplicates, 
a total of 735 individual article s were obtained (Appendix A) a nd one additional study (Alvarez-
Moya et al., 2014) not identified in the search was added to th is list for a total of 736 individual 
articles. Three staff members i ndependently evaluated all of t he studies and came to consensus 
on which studies would be consider ed relevant to the issue of c oncern (i.e., human carcinogenic 
potential of glyphosate). Many of  the articles were not consid ered to be within the scope of the 
search or not considered relevant in general (657 articles).  A dditionally, 27 articles were not 
appropriate due to the type of a rticle (i.e., correspondence, a bstract only, not available in English, 
retraction). Of the 52 relevant articles, 42 were used in the current evaluati on (31 genotoxicity, 9 
epidemiological, and 2 animal carci nogenicity).  Three articles also reported on the potential of 
glyphosate and its metabolites t o be developed into therapeutic drugs for cancer treatment.  The 
remaining 7 articles evaluate d effects on glyphosate or glyphos ate formulations on cellular 
processes, mostly focusing on epidermal cells, and were not con sidered informative for the 
current evaluation. 
2.1.2 Studies Submitted to the Agency 
For all pesticides, there are toxicology data requirements that  must be submitted to the agency 
for registration. These studi es, defined under the 40 CFR Part  158 Toxicology Data 
Requirements, provide information on a wide range of adverse health outcomes, routes of 
exposure, exposure durations, s pecies, and lifestages.  They typically follow OECD, OCSPP, or 
OPP accepted protocols and guidelines, which ease comparisons a cross studies and chemicals.  
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 The toxicological dat abases for glyphosate10 were reviewed and all relevant animal, 
genotoxicity, and metabolism studi es were collected for conside ration.   
Several resources were used to ens ure all relevant studies were included in the current 
evaluation. The list of studies  obtained from the toxicologica l database and the open literature 
search were cross-referenced wit h recent internal reviews (CARC, 2015; S. Recore et al. , 2014). 
This list was also cross-referenced with review articles from t he open literature [Chang and 
Delzell (2016), Greim et al. (2015), Kier and Kirkland (2013), Kier (2015), Mink et al. (2012), 
Schinasi and Leon (2014), and Williams et al.  (2000)]11. EPA requested studies from registrants 
that were not previously avail able to the EPA.  As a result, nu merous studies were subsequently 
submitted to the agency.  Study reports for one animal carcinog enicity study and 17 genotoxicity 
studies were not available to t he agency and have been noted in  the relevant sections below.  For 
these studies, data and study summa ries provided in Greim et al . (2015) and Kier and Kirkland 
(2013) were relied upon for the current evaluation. 
2.2 Evaluation of Relevant Studies 
Studies submitted to the agency are evaluating based on OECD, O CSPP, or OPP test guideline 
requirements to determine whethe r studies are acceptable for us e in risk assessment.  In the 
current evaluation, animal carc inogenicity, genotoxicity, and m etabolism studies located in the 
internal databases with access to full study reports were evalu ated in this manner.  Those 
classified as unacceptable were noted and subsequently excluded  from the current evaluation. 
In order to evaluate open literat ure studies, criteria described in the OPP guidance for 
considering and using open literature toxicity studies to suppo rt human health risk assessment 
was utilized (U.S. EPA, 2012). Thi s guidance assists OPP scien tists in their judgement of the 
scientific quality of open literature publications.  More speci fically, the document discusses how 
to screen open literature studies  for journal articles/publicat ions that are relevant to risk 
assessment, how to review potentia lly useful journal articles/p ublications and categorize them as 
to their usefulness in risk assessment, and how the studies may  be used in the risk assessment.  
As with submitted studies, those deemed unacceptable were noted  and subsequently excluded 
from the current evaluation. 
10 Glyphosate pesticide chemical (PC) codes: 103601, 103603, 103604, 103605, 103607, 103608, 103613, 128501, 
and 417300. 
11 All review articles, except Schinasi and Leon (2014), were fun ded and/or linked to Monsanto Co. or other 
registrants.
	
Page 22 of 216
	 
 
  
 
 
  
 
 3.0 Data Evaluation of Epidemiology 
3.1 Introduction 
Epidemiological studies are valu able for risk assessment since they may provide direct evidence 
on whether human exposure to a chemical may cause cancer.  Stud ies of high quality and 
adequate statistical power are p referable and remove the need t o account for extrapolation from 
animals to humans or extrapola tion from high to low doses.  Epi demiological studies can also be 
integrated with experimental evidence when determining or clari fying the carcinogenic potential 
of a chemical for risk assessment.  The key considerations in e valuating epidemiologic studies 
are study design, exposure assessment, outcome assessment, confounding control, statistical 
analyses, and risk of other bias. 
OPP routinely evaluates the ava ilable epidemiological literatur e.  As part of Registration Review 
of glyphosate, an evaluation was initially conducted in 2014 (S . Recore et al. , 2014) and 
subsequently another evalua tion was performed in 2015 (CARC, 20 15).  The 2015 evaluation 
began with the epidemiological st udies previously identified in  the 2014 evaluation and included 
three additional studies tha t were not included in the 2014 eva luation.  These studies were 
identified in review articles, included in the evaluation by IA RC (2015), or were published since 
the 2014 OPP evaluation. Both the 2014 and 2015 OPP evaluation s considered the design and 
overall quality of the epidemiological studies; however, formal  study quality evaluations and 
rankings were not conducted. In th e current review, all of the  studies in the 2015 r eport, as well 
as additional epidemiological art icles identified from a compre hensive search and cross-
referencing with available resou rces as described under Section  2.0, were considered in the 
current evaluation. The followi ng sections provide a description of how epidemiological studies 
were evaluated for study qualit y and subsequent overall ranking s, a summary of relevant studies, 
and a discussion of the overall results. 
3.2 Considerations for Study Quality Evaluation and Scope of As sessment 
This section summarizes how specific study characteristics were  factored into the determination 
of a study’s overall quality cate gory.  It should be noted that  these study quality considerations 
are specific to the issue of concern (i.e., carcinogenic potent ial of glyphosate).  These 
considerations are considered ‘ fit-for-purpose’ under this cont ext and could differ in another 
regulatory or scientific contex t.  Although the basic concepts apply broadly, the study quality 
considerations are tailored sp ecifically to studies investigati ng the association between 
glyphosate exposure and cancer outc omes.  As with all research studies, the desi gn elements of 
an epidemiological study have  potential impacts on study qualit y and relevance to the research 
question under investigation. E ach study was, therefore, judge d to be of high, moderate, or low 
quality in each of the following six domains affecting study qu ality: study design, exposure 
assessment, outcome assessment, confounder control, statistical  analysis, and susceptibility to 
bias (See Section 3.2.1 and Table 3.1  for general consideration s under each domain).  A similar 
approach was recently used by OPP for the evaluation of epidemi ological studies for 
organophosphate pesticides (A. Lowit et al.,  2015). 
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 Primary literature and associated meta-analyses evaluating the association between glyphosate 
exposure and a cancer outcome were  the focus of this analysis. Reviews were only used to 
identify individual studies that should be considered for study  evaluation. Commentaries, 
correspondence, and letters to the editor without original data  were excluded.  Of the relevant 
studies identified, studies with the most complete analyses uti lizing the greatest number of cases 
and controls (e.g. , pooled case-control studies) were evaluated for ranking (see A ppendix B for 
visual representation of these studies).  If studies did not co llect exposure information on 
glyphosate from individual subjects,  did not assess an outcome (e.g., biomonitoring studies), 
and/or did not provide a quantit ative measure of an association  between glyphosate and a cancer 
outcome, then these studies were assigned a low quality ranking  and were not further evaluated 
in detail (see Figure 3.1).  A similar process was used by JMPR  for their identification of 
epidemiological studies for eva luating the carcinogenic potenti al of glyphosate and two other 
pesticides (JMPR, 2016). 
Figure 3.1.  Study evaluation pr ocess for epidemiological studi es. 
3.2.1 Study Designs 
In judging an individual study’s co ntribution to the strength of evidence in the epidemiologic 
literature base, the following general hierarchy of observational study designs was considered 
(from most to least preferred) :  prospective cohort study (including nested case-c ontrol studies), 
case-control study, and cross-sectional study. It is important  to note, however, that this hierarchy 
of study designs reflects the potential for the collection of high quality information (related to 
exposure, outcome, confounders, and effect modifiers) and potential  for efficient and valid 
estimation of the true associat ion.  Thus, in deliberating on q uality, care has been taken to 
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   consider the circumstances and particulars of each individual s tudy to consider whether the study 
was well conducted independent  of the type of study design.   
The study designs used in the epi demiological literature review ed were analytical  and descriptive 
studies. Cohort and case-contro l study designs are analytical studies used to evaluate relative 
incidence of health and diseas e outcomes by exposure status.  Cross-sectional and ecological 
studies are generally considere d descriptive or  hypothesis-gene rating study designs; however, 
they can also be used to test hypo theses regarding prevalence o f health outcomes and, under 
certain conditions, incidence as well. 
Table 3.1. Epidemiological Study Quality Considerationsa. 
Parameter High Score Moderate Score Low Score 
Study Design Cohort Case-contro l Cross-sectional/Ecological 
Exposure Assessment Questionnaire and/or 
interview answered by 
subjects for chemical-
specific exposure Questionnaire and/or interview for chemical-specific exposure answered 
by subjects or proxy 
individuals Low-quality questionnaire and/or interview; information 
collected for  groups of 
chemicals rather than 
chemical-specific; no 
chemical-specific exposure 
information collected; ever/never use of pesticides 
in general evaluated 
Outcome Assessment State or National registries, 
physicians, and/or special 
surveillance programs with 
cases verified by histopathological evaluation 
for tumors; appropriate 
consideration of prevalent vs. incident cases; analysis by 
valid method specific for 
biomarkers State or National registries, 
physicians, and/or special 
surveillance programs without histopathological 
verification for tumors; 
analysis by assays that are less specific for biomarkers 
of interest No outcome evaluated; 
unclear/no consideration for whether prevalent or incident 
cases are appropriate; 
biomarker methods not validated 
Confounder Control Good control for important confounders related to 
cancer, standard 
confounders, and known confounders for glyphosate 
and cancer outcomes (e.g., 
exposure to multiple 
pesticides) through study 
design or analytic control with well measured co-
exposures (i.e., cumulative 
exposure) Moderately good control 
for confounders related to cancer; standard variables 
accounted for and; attempt 
to control for known confounders via a less 
efficient measure of co-
exposure (e.g., ever/never 
use) No adjustments for 
confounders 
Statistical Analyses Appropriate to study question and design, 
supported by relatively 
adequate sample size, maximal use of data, 
reported well  Acceptable methods, lower/questionable study 
power or sample size  Minimal attention to statistical analyses, sample 
size evidently low, 
comparison not performed or described clearly 
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 Table 3.1. Epidemiological Study Quality Considerationsa. 
Parameter High Score Moderate Score Low Score 
Risk of (Other) Bias Major sources of other 
potential biases not likely 
present, present but analyzed, 
unlikely to influence 
magnitude and direction of 
effect estimate, no/low 
potential of selection bias Other sources of bias present, acknowledged but not addressed in study, 
may influence magnitude 
but not direction of 
estimate, evidence of 
potential selection bias 
with low impact on effect estimate Major study biases present, unacknowledged or 
unaddressed in study, cannot 
exclude other explanation for 
study findings, evidence of 
selection bias with high 
potential to impact effect estimate 
a Overall study quality ranking based on comprehensive assessmen t across the parameters. 
3.2.1.1 Analytical Studies 
(1) Cohort Study 
In a typical cohort study, such a s the AHS, individuals are cla ssified according to exposure status 
(i.e., presence, absence, or magnitude of exposure) and then followed over time to quantify and 
compare the development (i.e., i ncidence) of the health outcome  of interest by exposure group.  
Conceptually, the non-exposed com parison group in a cohort stud y provides an estimate of the 
incidence of the outcome am ong the exposed, had they, counter-t o-fact, not been exposed.  Apart 
from chance variations, a valid  cohort study comparing exposed individuals to non-exposed 
individuals provides an estimate  of the relative risk (or rate) of the disease associated with 
exposure. Ideally, the expose d and non-exposed groups are exchangeable, in the sense that 
switching the exposed to non-e xposed, and non-exposed to expose d would yield the same 
measure of association (e.g., rela tive risk).  If this were the  case then, apart f rom chance, a cohort 
study would yield a measure of association equivalent to that p roduced in a corresponding 
(intervention) study where exposure status was randomly assigne d.  
The chief advantage of the cohort study design is that it affords the investigator the opportunity to avoid and/or adjust for poten tial biases (i.e., selection bias, information bias, and 
confounding); however, these bias es may also be avoided in othe r well-designed study designs, 
such as a case-control study. Cohort studies also allow for di scernment of the chronological 
relationship between exposure and outcome, and can be particula rly efficient for studying 
uncommon exposures. The primary di sadvantage of the cohort stu dy design is logistical 
inefficiency with respect to the necessary time, expense, and o ther resources needed to conduct 
them.  Cohort studies are particularly inefficient for evaluati ng associations w ith rare outcomes 
and diseases with long induction o r latency periods.  Case-cont rol studies that are nested within a 
cohort study (nested case-control studies) share the attributes of the cohort study and may be 
more efficient. However, whe n follow-up throughout the study p eriod is incomplete, the 
potential for selection bias is i ncreased, especially if follow -up rates are related to exposure 
status. 
Two sub-categories of cohort stud ies – prospective and retrospe ctive – are often applied to 
distinguish between studies in w hich the health outcome has occurred (retrospective study), or 
has not occurred (prospective study) at the time the investigators initiate the study.  This 
distinction is important primar ily as it pertains to the potent ial differences in the quality (e.g., 
Page 26 of 216
	 
 
  
 
 
 
  
 
 completeness, accuracy, and precision) of information that can be ascertained by the 
investigators, and also as it rela tes to potential sources of bias.  Although not always true, the 
prospective study design is consid ered the preferable of the two, as investigators can potentially 
have more choices in determining how exposure, outcome, and cov ariate information is 
collected. In a retro spective study conducted to evaluate the same hypothesis, by contrast, the 
investigators would have to rely on exposure information based on self-reporting or historical 
records. Such reporting is subj ect to (human) errors in recall , however when such errors are 
uncorrelated with disease state , there can be a bias towards th e null due to random exposure 
measurement error (informati on bias) and only when such errors are correlated with the disease 
state can there be bias a way from the null.   
 (2)Case-Control Study 
In a typical case-control study, individuals are classified acc ording to their outcome status (i.e., 
cases who have developed the outco me of interest, and controls who represent the population 
from which the cases arise).  T he relative odds of exposure are then compared between cases and 
controls. The primary advantage of  case-control studies is tha t they are logistically efficient 
relative to cohort studies, often being conduc ted at a fraction  of the cost and in a fraction of the 
time as a corresponding cohort st udy.  Case-control studies can  be used to examine associations 
between multiple exposures and a given health outcome.  They are particularly efficient for 
evaluating rare outcomes, but a re inefficient for studying unco mmon exposures.  An important 
point to evaluate in each case-control study is the potential f or selection bias, which arises if the 
exposure distribution among the c ontrol subjects is not represe ntative of the exposure 
distribution among the population t hat gave rise to the cases. When participation rates between 
cases and controls are low or distinctly imbalanced, the potential for selection bias is increased, especially if participation rates are related to exposure statu s.  Case-control studies that rely on 
self-reported exposure measures  are also potentia lly susceptibl e to information bias which could 
result in bias towards the null or away from the null. 
3.2.1.2 Descriptive Studies 
Cross-sectional studies are use d to evaluate associations betwe en exposure and outcome 
prevalence in a population at a single point in (or period of) time. The primary advantage of a 
cross-sectional study is logist ical efficiency.  They are relat ively quick and inexpensive to 
conduct, as a long period of fo llow-up is not required, and exp osure and outcome assessments 
occur simultaneously.  Cross-sect ional studies have three prima ry potential  disadvantages: 1) 
potential difficulty in discerning the temporal relationships ( i.e., whether the exposure precedes 
the outcome); 2) estimating outcome prevalence rather than inci dence of the outcome; and 3) the 
possible overrepres entation of cases of t he outcome with long d uration relative to the average in 
the population, and often with a better prognosis. 
Ecological studies are used to eva luate associations between exposures and outcomes using 
population-level rather than indi vidual-level data.  The primary advantages of ecological studies 
are related to logistical effi ciency, as they often rely on pre -existing data sources and require no 
individual-level exposure, outco me, or covariate assessments.  The primary weakness of the 
ecologic study is the potentia l for confounding and resultant inappropriate extrapolation of 
associations observed on the aggr egate-level to associations on  an individual level.  The 
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 discrepancy that associations obs erved at the population level are not observed at the individual 
level is referred to a s the ecological fa llacy.  Semi-ecologica l studies are less susceptible to the 
ecological fallacy due to incor poration of individual-level data on outcomes and/or confounders.  
The quality of these studies de pends on the ability of the grou p exposure data to represent 
individual exposure and the re search question of interest. 
3.2.2 Exposure Measures 
As described in Section 3.2 and Fi gure 3.1, studies assigned a low quality ranking based on an 
initial evaluation were not fu rther evaluated in detail.  In all of the studies i ncluded in the 
analysis that were reviewed a nd ranked for stu dy quality, expos ure information was collected 
from subjects and/or proxy individuals via questionnaires and/o r interviews.  These exposure 
assessments typically include que stions to determine the amount  of direct pesticide use or to 
collect information on behaviors an d conditions associated with  pesticide use (e.g., occupation, 
tasks). This type of reporting lik ely misclassifies actual pes ticide exposure.  If conducted as part 
of a prospective exposure assessm ent, these errors are likely t o be non-differential with respect to 
the outcome(s) of interest.  In a  retrospective assessment, the subject or proxy has knowledge of 
the outcome; therefore, these e rrors may be differential or non -differential.  Studies that 
exclusively used subjects rat her than inclu ding proxy individuals were considered more reliable 
and given a higher weight given that the subjects would have a more accurate recollection of 
their own exposure. 
3.2.3 Outcome Measures 
All of the studies evaluated i n detail, except one, utilized state or national cancer registries, 
physicians, and/or special surve illance programs to determine outcome status (i.e., subjects with 
or without a cancer of interest) .  In several studies, the cases were also verified by 
histopathological evaluation. Overall, outcome measures were relatively consistent across 
studies and these assessments ar e likely to have minimal errors .  The remaining study evaluated 
in detail (Koureas et al., 2014) assessed oxidative DNA damage rather than a type of cancer.  For 
this evaluation, the oxidati on by-product 8-hydroxydeoxyguanosi ne (8-OHdG) was measured by 
enzyme immunoassay.  This type of assay generally exhibits low specificity.  More sensitive quantitative methods are availab le to analyze genomic DNA for 8 -OHdG by high-performance 
liquid chromatography (HPLC) with electrochemical detection, gas chromatography-mass spectrometry (GC-MS), and HPLC tandem mass spectrometry.  Consideration of incident or prevalent cases should also be  carried out.  By using only inci dent cases, there is greater 
confidence that exposures occurred prior to the development of the outcomes.  Inclusion of prevalent cases can lead to an ove r-representation of cases wit h a long course of disease. 
3.2.4 Confounding 
The degree to which confounders wer e controlled varied across s tudies.  Some studies adjusted 
for particular medical variable s, while others did not.  Some s tandard variables, such as age, 
geographical location, and sex, wer e either adjusted for analyt ically or by matching in case-
control studies. Several st udies collected information on pote ntial confounders; however, not all 
of these variables were evaluated or results of the evaluation were not reported.  The direction and magnitude for confounders are, in general, difficult to det ermine because they are dependent 
Page 28 of 216
	 
 
  
 
 
 
 
 upon the relationship of each confounding factor with glyphosat e and the cancer under 
investigation. Several studies c onsidered the potential for co nfounding from co-exposure to 
other pesticides; however, only a  few reported effect estimates  between glyphosate exposure and 
cancer risk adjusted for the use of other pesticides.  Given mo st people in the epidemiological 
studies who use pesticides occ upationally will  be exposed to mu ltiple pesticides and, in some 
instances, those other pesticides  were observed to be risk fact ors for the same cancer, this is a 
particularly important concern t o address in either the study d esign or in the statistical analyses.  
Across numerous studies, co-exposur es to other pesticides was f ound to be positively correlated 
with exposure to glyphosate and ex posure to those other pesticides appear to increase the risk of 
some cancers.  As a result, t he direction of confounding would be to inflate any true effect of 
glyphosate in the absence of statistical control.  This underli nes the importance of adjusting for 
co-exposures to other pesticides. 
For NHL, other potential confounde rs, such as exposure to diese l exhaust fumes, solvents, 
ultraviolet radiation, livestoc k, and viruses, have been identi fied.  Some of these are more 
plausible than others. For exa mple, occupational exposure to d iesel exhaust fumes (e.g., 
McDuffie et al., 2002; Karunanaya ke et al. 2008; Baris et al. 2 001; Maizlish et al. 1998) and 
solvents (Wang et al., 2009; K ato et al., 2005; Olsson and Bran dt, 1988) are considered likely to 
increase the risk of NHL. Agricul tural workers are exposed to diesel fumes when using 
agricultural vehicles  when applying pesticides, such as glyphos ate, and when using heavy 
equipment during mixing, loadi ng, and/or applying pesticides.  Agricultural workers are also 
exposed to solvents. Solvents ar e often used in pesticide prod ucts to aid the delivery of the 
active ingredient and enhance e fficacy.  Solvents are also used for cleaning and 
maintenance/repair of agricultu ral equipment used for mixing, l oading, and/or applying 
pesticides. With an associat ion between exposure and outcome o f interest, it is reasonable to 
consider diesel exhaust fumes and solvents as probable confound ers; however, neither of these 
factors were accounted for in any of  the studies evaluated in d etail.  There is also evidence that 
ultraviolet (UV) radiation may i ncrease the risk of NHL (Karipidis et al., 2007; Zhang et al., 
2007). As a result, there is a s upport that UV radiation is also a potential confounder given the 
extended amount of time agricultu ral workers spend outside perf orming activities, including 
those associated with pesticide  use.  Lastly, con tact with farm  and other animals has been 
investigated as a suspected ris k factor for hematopoietic and l ymphoid tumors (McDuffie et al., 
2002). Hypothesized mechanisms to e xplain this association inc lude viral transmissions, chronic 
antigenic stimulation, and expos ure to endotoxins, fungi, and m ycotoxins.  None of the 
aforementioned potential confounders were accounted for in the studies evaluated in detail. 
3.2.5 Statistical Analyses 
Statistical analyses that were appropriate to the study questio n and study design, supported by 
adequate sample size, maximize d the use of available data, and were well characterized in the 
report were weighted most highly .  Acceptable statistical metho ds, questionable study power or 
sample size, and analytical choices  that resulted in the loss of information were given moderate 
weight. Reports with only minimal attention paid to the conduc t and reporting of the statistical 
analyses were given the lowest weight. 
3.2.6 Risk of Bias 
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 The internal validity of the s tudies reviewed was judged by noting the design strategies and 
analytic methods used in each study to constrain or eliminate s election bias, information bias, 
and confounding. Selection bias can occur when the sampling of  the population by the 
investigator yields a study populat ion that is not representative of the exposure and outcome 
distributions in the population s ampled.  Put simply, selection  bias occurs if selection of the 
study sample yields a different estimate of the measure of asso ciation than that which would 
have been obtained had the entire target population been evaluated.  Although there are 
numerous sources of selection bias, there are several mechanisms that may have induced selection bias in the s tudies reviewed: low  participation rates  of eligible individuals due to non-
responsiveness or ref usal (self-selection bi as); loss to follow -up (i.e. , failure to retain all study 
participants initially enrolled in the study); and, in a case-control study, contro l selection bias 
arising because the exposure dist ribution in the control sample does not represent the exposure 
distribution of the study base (i.e. , the population that gave rise t o the cases or more formally, t he 
person-time experience of that population). 
Information bias (also referred t o as observation bias) arises when study participants are 
incorrectly categorized with res pect to their e xposure or outco me status, or when errors arise in 
the measurement of exposure or  outcome, in the case of continuo usly distributed measures.  
Epidemiologists often distingu ish between two mechanisms or typ es of misclassification – those 
that are non-differential (or ra ndom) and those that are differential (non-random).  Non-
differential misclassification of e xposure (or non-differential exposure measurement error) 
occurs when the probability or m agnitude of error in the classi fication or measurement of 
exposure is independent of the outcome status of the study participants.  Non-differential 
exposure measurement error typica lly results in a bias towards the null which may obscure any 
true effect of the exposure of  interest.  Similarly, non-differential misclassification of outcome 
(or outcome measurement error) occurs when the probability or m agnitude of error in the 
assignment of outcome status or l evel is independent of exposure status.  Non-differential 
outcome measurement error typi cally does not cause bias but doe s decrease the precision of 
effect estimates and therein inf lates the width of confidence i ntervals.  In contrast, differential 
exposure misclassification (or m easurement error) occurs when t he error in the exposure 
assignment is not independent of the outcome status.  The mecha nisms that cause non-
differential misclassification i n the currently reviewed litera ture include random errors in 
exposure recall from subjects or proxy respondents.  The mechan isms that could induce 
differential misclassification in clude recall bias and interviewer/observer bias.  Note that 
mismeasurement of confounders can result in residual confoundin g of the association of interest, 
even when adjustment for that confounder has been conducted in the analysis. 
Studies in which major sources of  potential biases were not lik ely to be present, studies in which 
potential sources of bias were present, but effectively address ed and analyzed to maximize the 
study validity, and studies in whi ch sources of bias were unlik ely to influence the magnitude and 
direction of the effect estimate were given more weight than st udies where sources of bias may 
be present, but not a ddressed in the study.   
3.3 Review of Quality Results 
Each study was judged to be of hi gh, moderate, or low quality i n each of the six domains 
affecting study quality, as disc ussed above and in Table 3.1.  The results of the quality 
Page 30 of 216
	 
 
  
 
 
 
 
 
 
 assessment are presented separ ately for each group below.  The quality rankings presented are 
specific to the current evaluat ion of the carcinogenic potentia l of glyphosate.  As noted above 
and in Table 3.2, several studies w ere not included in the rank ing evaluation because they did not 
represent the most complete analysis.  Rat her, the subjects wer e included in a larger analysis 
(e.g., pooled case-control study) to produce a greater number of cases and controls (see 
Appendix B for visual representat ion of these studies).  For ex ample, Cantor et al.  (1992) was 
not individually evaluated for ranking because the data from th is study were pooled with data 
from other studies in De Roos et al.  (2003), which was included. 
3.3.1 “High” Quality Group 
Three studies were given a  high quality ranking: De Roos et al. (2005), Eriksson et al.  (2008), 
and Koutros et al.  (2013). 
De Roos et al.  (2005) was a prospective cohort  study that evaluated associati ons between various 
pesticide exposures, including gl yphosate, and cancer incidence for numerous solid and non-
solid tumors in the AHS.  The aim  of the AHS is to evaluate the  role of agricultural exposures in 
the development of cancer and oth er diseases in the farming com munity.  AHS recruited 52,934 
licensed private pes ticide applicator s along with 32,345 of the ir spouses between 1993 and 1997.  
In the first two phases of the study, the cohort also included 4,916 commercial pesticide 
applicators from Iowa.  As a prospective analysis of the AHS co hort, information was obtained 
from exposed subjects at enrollment and no proxies were necessa ry.  Exposure was evaluated as 
ever/never use, cumulative lifetime exposure, and intensity-wei ghted cumulative exposure.  Due 
to the study design, the potential for many biases were reduced .  Additionally, the study adjusted 
and/or considered numerous factors, including use of other pest icides.  Study participants 
provided detailed pesticide exposure information prior to enrol lment in the study and this 
information has been incorporat ed into the study evaluation by determining tertile cut points and 
calculating effect estimates by comparing to the lowest tertile.  Additional evaluations with quartiles and quintiles were perf ormed for cancers with elevate d effect estimates in the study and 
for NHL. As noted earlier in thi s document, an analysis of the  AHS cohort was recently 
published (Andreotti et al. , 2017) and the findings were cons idered as part of this evaluation. 
Eriksson et al.  (2008) was a population-based cas e-control study that recruite d a consecutive 
series of incident cases of NHL in several regions of Sweden fr om physicians treating lymphoma 
within specified health service a reas.  Cases were verified pat hologically and matched to 
randomly selected controls from the national pop ulation registr y by age, sex and health service 
area. Exposure information was collected from exposed individu als (i.e., no use of proxy 
respondents) using a comprehensive  questionnaire including a to tal work history with in depth 
questions about exposures to pesticides, solvents, and other ch emicals.  Interviewers were 
blinded to case/control stat us.  The study only reported minima l demographic information on 
subjects (age and sex) and a tab le with subject characteristics  (e.g., smoking status, alcohol 
intake, physical activ ity, education) that could potentially be  used to adjust effect estimates was 
not provided. Glyphosate exposur e was reported in 29 cases and 18 controls during the study 
period. Multivariate analyses we re adjusted for co-exposure to different agents, including 
MCPA, “2,4,5-Y and/or 2,4-D”, mer curial seed dressing, arsenic, creosote, and tar.  An analysis 
for a potential exposure-respons e relationship was also conducted; however, it was not clear 
Page 31 of 216
	 
 
  
 
 
 
 
 
 
 
 whether this analysis adjusted for co-exposure to other pesticides based on the statistical methods 
description. The number of cases  and controls were also not reported for this analysis.   
Koutros et al.  (2013) was a prospective cohort study within the AHS that eval uated the 
association betwee n pesticide use and prostate cancer.  Exposure information was collected from 
exposed subjects (no proxies necessary) through the enrollment questionnaires, as well as in a 
follow-up questionnaire administered 5 years after enrollment. This study evaluated the 
association between glyphosate a nd prostate cancer diagnoses fr om enrollment (1993-1997) 
through 2007 resulting in a longer follow-up time than many of the other case-control studies 
that utilized AHS subjects. The study used lifetime cumulative  exposure and inten sity-weighted 
cumulative exposure metrics.  A nalyses were also conducted usin g unlagged exposure and 15-
year lagged exposure, which excluded the most recent 15 years o f exposure for both exposure 
metrics.  Although the effect estimate reported for glyphosate in this study was not adjusted for 
co-exposure to other pesticides, a dditional analyses were not c onsidered necessary since there 
was no association observed. 
3.3.2 “Moderate” Quality Group 
Twenty-one case-control studies  were assigned a moderate qualit y rating (Table 3.2).  In general, 
these studies share many study design characteristics.  Exposur e information was collected from 
subjects and/or proxy individua ls, the outcome measurement(s) u tilized state/national registries 
and surveillance programs, appropr iate statistical analyses were performed, some covariates but 
maybe not all relevant covariates w ere evaluated and/or considered, and risks of bias were 
minimized to some extent.  Sample sizes varied across studies. Case-control studies 
investigating solid tumors in cluded study populations in the Un ited States and Canada.  For non-
solid tumors, study populations were located in the United States, Canada, Sweden, France, 
Germany, Italy, Ireland, Spain, and the Czech Republic.  Althou gh several nested case-control 
studies shared most of the chara cteristics of the AHS cohort st udy, these studies were primarily 
given a moderate quality ranki ng since co-exposure to other pes ticides was not accounted for in 
the analyses. 
3.3.3 “Low” Quality Group 
Seven case-control and 27 cross-se ctional/ecological studies we re assigned a low quality 
ranking. All of these studies, e xcept one case-control study ( Cocco et al. , 2013) and one 
descriptive study (Koureas et al., 2014), were not subjected to a detailed evaluation because they 
did not report a quantitative m easure of an association between  glyphosate exposure and a cancer 
outcome, did not collect infor mation on glyphosate exposure fro m all subjects, and/or did not 
evaluate risk to a cancer outco me (Appendix D).  In many instances, effect estimates were 
reported only for total pesticide  exposure.  Additionally, expo sure was assumed and glyphosate-
specific exposure information w as not collected.  In other studies, the aim of the study was to 
assess exposure methods for epide miological studies and/or to evaluate the impact of exposure 
misclassification; therefore, there was no evalu ation of a canc er outcome.   
It should be noted that some of the studies assigned a low qual ity ranking in the current 
evaluation were included in the  recent evaluation by IARC.  The re were a number of descriptive 
studies that evaluated the ge notoxicity in human populations; however, these studies did not 
Page 32 of 216
	 
 
  
 
 
 meet the criteria for inclusi on in the ranking as described in Section 3.2 and Figure 3.1.  In most 
instances, these studies reported effect estimates for total pesticide exposure and/or assumed 
glyphosate exposure without col lecting glyphosate-specific exposure information.  For case-
control studies, Cocco et al. (2013), Dennis et al. (2010) and Ruder et al. (2004) were included in 
the 2015 IARC evaluation, but were not considered informative in the current evaluation.   
Detailed evaluations were not pe rformed in the current evaluati on for Dennis et al. (2010) and 
Ruder et al. (2004) because a quantitative measure of an associ ation between glyphosate and a 
cancer outcome was not reporte d.  Cocco et al. (2013) received a detailed evaluation and was 
assigned a low quality ranking.  This case-control study, which evaluated lymphoma risk across 
six European countries, was not c onsidered informative due to a  combination of numerous 
limitations in the study.  The sam ple size of the study was low  with only four cases and two 
controls exposed to glyphosate. C ontrol ascertainment was not consistent across countries, with 
a mix of hospital- and populati on-based controls used.  The ove rall participation rate for 
population-based controls was f ound to be much lower than the o verall participat ion rates of the 
cases or hospital-based controls .  Lastly, the study was limite d to ever/never use of glyphosate 
and did not adjust for confounders , in particular co-exposure t o other pesticides.  Although this 
study was included in the IARC ev aluation, IARC also stated that the study had very limited 
power to assess the effects  of glyphosate on risk of NHL. 
The other study subjected to a detailed evaluation and assigned  a low quality ranking was 
Koureas et al. (2014). This cross-sectional study evaluated the association  between glyphosate 
exposure and oxidative DNA damage  in 80 Greek pesticide sprayers.  Although the study 
reported a non-statistic ally significant effect estimate for gl yphosate, it is limited in its ability to 
contribute to the overall evalua tion of the carcinogenic potent ial of glyphosate.  The effect 
estimate was not adjusted for a ny standard covariates or potent ial confounders, including co-
exposure to other pesticides. T he sample size of the study was questionable.  There were 80 
subjects, but the number exposed t o glyphosate was not reported.  The outcome is measured 
using an immunoassay that is less specific for measuring the biomarker of interest than other 
available analytical methods.  L astly, the study evaluates prim ary DNA damage, but does not 
measure the consequence of genetic damage.  An increase in oxid ative DNA damage may lead to 
cell death or initiate DNA repair  rather than lead to a mutatio n.   
Due to the limitations in the studies assigned a low quality ra nking, they do not provide reliable 
information to evaluate associa tions between glyphosate exposur e and cancer outcomes.  
Therefore, the remaining secti ons of this document do not furth er discuss these studies except to 
note when a study is included in meta-analyses. 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
Alavanja et al.  (2003) This study was not included in the study quality rankin g because the data were used in the updated analysis by Koutros et al.  (2013). 
Andreotti et al. (2009) Nested Case-
control Questionnaire answered by subjects at study 
enrollment followed by 
take-home questionnaire; 
examined exposure for 
glyphosate as ever/never, 
and intensity-weighted 
cumulative exposure 
days; spouses either self-
administered 
questionnaire (81%) or 
telephone interview 
(19%) State cancer registries 
without histopathological 
verification; exclusion of 
subjects with prevalent 
cancer at enrollment; 
follow-up ~ 9 years Adjusted for age, smoking, and diabetes 
for both exposure 
metrics as well as 
applicator type 
forever/never exposure 
metric 
No adjustment for co-
exposure to other 
pesticides or other potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Unconditional logistic regression 
to obtain OR and 
95% CI Exposure misclassification 
particularly for spouses, 
low response rate to take-
home questionnaire 
(40%) but unclear if 
affected cases and 
controls differently, 
insufficient power for 
pesticide exposure 
interactions Moderate 
Band et al. (2011) Population-based 
case-control 
Males only Self-administered 
questionnaire answered 
by subjects or proxies for 
deceased subjects 
requesting work history 
and demographic 
information; use of a job 
exposure matrix to 
estimate exposure to 
pesticides Cancer registry with 
histopathological 
verification;  excluded 
farmers that worked all outside of British 
Columbia; included 
prostate cancer cases 
prior to the PSA era Adjustment for alcohol 
consumption, cigarette 
years, education level, 
pipe years, and 
respondent type. 
Marital status and 
ethnicity not 
significant 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Conditional logistic 
regression to obtain 
ORs and 95% CIs Recall bias, use of proxy for deceased, exposure 
misclassification, 
participation rates cited 
from another study, use of cancer patients as 
controls (excluding lung 
and unknown cancer) Moderate 
Brown et al. (1990) Pooled population-
based case-control 
Males only In-person interviews 
using standardized 
questionnaire with 
subjects or proxies for 
deceased/incapacitated; 
supplementary 
questionnaire 
administered by 
telephone for Iowa 
subjects to obtain more State cancer registry (Iowa) and special 
surveillance network 
including hospitals and 
pathology laboratories 
(Minnesota); cases 
ascertained 
retrospectively and 
prospectively (2 years 
after start of study); Adjusted for vital status, age, state, ever 
used tobacco daily, 
close relative with 
lymphopoietic cancer, 
nonfarming job related 
to risk of leukemia in 
the study, exposure to 
substances related to 
risk in this study Unconditional logistic models to 
obtain OR and 95% 
CI; questionable 
sample size (15 
cases) Recall bias; exposure misclassification, use of 
proxy respondents Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
detailed information ~26% of cases deceased (benzene, napthalene, 
from those indicating or too ill when identified hair dyes) 
pesticide use and ~15% deceased or 
too ill at time of No adjustment for co-
interview; exposure to other 
histopathological pesticides or other 
verification by potential confounders 
pathologists (e.g., solvents, diesel 
fumes, UV radiation) 
Brown et al. (1993) Population-based 
case-control 
Males only In person interviews with 
standardized 
questionnaire to obtain 
detailed information on 
farm activitie s and use of 
pesticides from subjects or proxies State cancer registry (Iowa) ascertained 
retrospectively and 
prospectively (2 years 
after start of study); 
~26% of cases deceased 
or too ill when identified 
and ~15% deceased or 
too ill at time of 
interview; 
histopathological 
verification by 
pathologists Adjusted for vital status and age; 
smoking and education 
evaluated and not 
found to be significant 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Logistic models to obtain OR and 95% 
CI; questionable 
sample size (11 
cases) Recall bias; exposure misclassification, use of 
proxy respondents Moderate 
Cantor et al. (1992) This study was not included in the study quality ranki ng because the data were used i n the pooled analysis conducted by De Roos et al.  (2003). 
Carreon et al.  (2005) This study was not included in the study quality rankin g because the data were used i n the pooled analysis conducted b y Yiin et al. (2012). 
Cocco et al. (2013) European multi-center case-control 
Hospital-based and 
population-based 
(mixed for 2 
countries, only 
hospital-based for 
the rest) Trained interviewers conducted in person 
interviews using 
structured questionnaire 
answered by subjects; 
those identified as 
agricultural worker on 
questionnaire given 
subsequent questions 
about pesticide use, 
crops, etc. Surveillance centers, 
20% of slides from each 
center reviewed by 
pathologist Adjustment for age, 
sex, education, and 
center. 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Unconditional logistic regression 
to obtain ORs and 
95% CIs; Low 
sample size (4 
cases, 2 controls) Recall bias, selection 
bias (low response rate 
for population-based 
controls and differed 
from cases), exposure 
misclassification, mix of 
hospital- and population-
based controls,  Low 
De Roos et al. (2003) Population-based case-control 
Males only Pooled analysis of Interviews with subjects 
or proxy for deceased 
subjects. Different 
interview techniques 
across states.  One study 
collected information on State cancer registries (one state chose a 
random sample, other 
states chose all cases), 
surveillance programs, 
and hospitals without Adjustment for age, study site, and other 
pesticides. 
First degree relative 
with haematopoietic Logistic regression 
and hierarchical 
regression to obtain 
ORs and 95% CIs Recall bias, exposure 
misclassification, , use of 
proxy for deceased, , 
varying quality of  
questionnaire/interview 
techniques across studies Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
Cantor et al. , 1992; pesticide use and then histopathological cancer, education, and 
Hoar et al., 1986; followed-up with verification smoking not found to 
Zahm et al.,  1990 questions on selected be important 
specific pesticides, confounders. 
another study had a 
direct question about a No adjustment for 
selected list of specific other potential 
pesticides, and the last confounders (e.g., 
study used an open ended solvents, diesel fumes, 
question without UV radiation) 
prompting for specific 
pesticides 
De Roos et al. (2005) Prospective cohort (licensed pesticide 
applicators) Questionnaire answered by subjects at enrollment 
and with subsequent 
take-home questionnaire; 
examined exposure as 
ever/never, cumulative 
lifetime days, and 
intensity-weighted 
cumulative exposure 
days State cancer registries 
without histopathological 
verification; follow-up 
~7 years Adjustment for state of 
residence, age, 
education, smoking 
history, alcohol 
consumption, family 
history of cancer, use 
of other common 
pesticides 
No adjustment for 
other potential 
confounders (e.g., 
solvents, diesel fumes, 
UV radiation) Poisson regression 
to obtain RRs and 
95% CIs Major sources of 
potential biases unlikely, 
potential exposure 
misclassification due to 
any changes in exposure 
since enrollment, follow-
up period may be limited  High 
Engel et al. (2005) Nested case-control 
Females only Take-home questionnaire 
from spouses of enrolled 
applicators used to obtain 
farm exposures, general 
health information, and 
reproductive health 
history; Information 
obtained from applicators 
used as measure of 
possible indirect 
exposure to spouses State cancer registries 
identifying malignant 
breast cancer; ~5 years 
average follow-up time Adjusted for age, race and state. 
Evaluated BMI, age at 
menarche, parity, age 
at first birth, 
menopausal status, age 
at menopause, family 
history of breast 
cancer, physical 
activity, smoking, 
alcohol consumption, 
fruit and vegetable 
consumption and 
education but none Poisson regression 
to obtain RRs and 
95% CIs Exposure misclassification, 
exposure to other 
pesticides (however no 
association observed), 
lack of information on 
length of marriage could 
result in overestimating 
exposure based on 
husband Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
found to be significant 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) 
Eriksson et al. (2008) Population-based 
case-control Questionnaire answered by subjects; follow-up by 
phone if incomplete 
answers; excluded 
exposures that occurred during the same calendar 
year and year before 
diagnosis (cases) or 
enrollment (controls); 
minimal demographic 
information reported Physicians treating 
lymphoma within specified health service 
areas and verified by 
pathologists Adjustment for age, sex, year of 
diagnosis/enrollment, 
as well as exposure to 
other pesticides in 
multivariate analyses. 
Not stated what 
adjustments were 
made for other 
pesticides in latency 
analyses. 
No adjustment other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Unconditional 
logistic regression 
and multivariate 
analyses to obtain 
ORs and 95% CIs; 
not clear how 
multivariate was 
performed; 
questionable sample 
size (29 cases, 18 
controls); also 
included analysis of 
≤10 vs. >10 years 
exposure Recall bias, exposure misclassification, lack of 
subject demographics/ 
characteristics (e.g., 
smoking, alcohol 
consumption, race, etc) High 
Flower et al. (2004) Nested case-
control Questionnaire answered by applicators at 
enrollment; spouses 
enrolled through a 
questionnaire brought 
home by applicator; 
females (appl icators and 
spouses) were asked to State cancer registry to 
identify childhood cancer 
cases (diagnosed from 
birth through 19 yrs of 
age) for children of 
parents enrolled; hybrid Child’s age at parent’s enrollment was 
included in model; 
parental age at child’s 
birth, child’s sex, 
child’s birth weight, 
history of parental 
smoking, paternal 
history of cancer, and 
maternal history of Logistic regression 
to obtain OR and 
95% CI; calculated 
standardized 
incidence ratios to 
compare observed 
number of 
childhood cancer 
cases identified to Exposure 
misclassification, lack of 
timing data to determine 
if exposure occurred 
prior to conception or 
during pregnancy, 
exposure to other Moderate 
complete a questionnaire on female and family 
health that collected 
information on children 
born during or after 1975 prospective/retrospective 
ascertainment; excluded 
female applicators miscarriage were 
evaluated but not 
found to be significant 
and not included in 
model 
No adjustment for co-the expected 
number; 
low/questionable 
sample size (6 
parental cases, 13 
maternal cases) pesticides (however no association observed and 
lack of power for 
adjustment) 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) 
Hardell and Eriksson (1999) This study was not included in the study quality ranking becaus e the data were used in the pool ed analysis conducted by Hardell et al.  (2002). 
Hardell  et al . (2002) Population-based 
case-control 
Males only Pooled analysis of 
Hardell and 
Eriksson 1999 and 
Nordstrom et al. , 
1998 Questionnaire answered 
by subjects or proxy for 
deceased subjects to 
obtain complete working 
history and exposure to 
different chemicals; 
follow-up with interview 
for clarification Registries with histopathological 
verification Adjustment for age, 
vital status, and county 
(by matching). 
Exposure to other 
pesticides in 
multivariate analysis. 
No adjustment for 
other potential 
confounders (e.g., 
solvents, diesel fumes, 
UV radiation) Conditional logistic 
regression to obtain 
OR and 95% CI 
(univariate and 
multivariate 
analyses). 
Questionable 
sample size (8 
cases/8 controls) Recall bias, exposure misclassification, use of 
proxy for deceased Moderate 
Hohenadel et al. (2011) This study was not incl uded in the study quality ranki ng because a more com plete analysis was c onducted by McDuffie et al.  (2001). 
Kachuri et al.  (2013) 
(extended analysis of Pahwa et al. 2012) Population-based case-control 
Males only Questionnaire answered 
by subjects or proxies; 
pesticide use collected 
via detailed  telephone 
interview on all participants with 10+ 
hours of pesticide use 
during lifetime and 15% 
random sample of those 
who did not; exposure 
based on lifetime 
exposure to glyphosate Cancer registries or 
hospitals in 6 Canadian 
provinces with 
histopathological 
verification for 36.55% 
of samples Adjustment for age, province, selected 
medical conditions, 
family history of 
cancer, use of proxy 
respondent, smoking 
status 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Unconditional logistic regression 
to obtain OR and 
95% CI; trends examined using 
multiple logistic 
regression Recall bias, exposure 
misclassification, control 
selection based on three 
different sources 
depending on province of residence, low 
participation rates among 
controls, use of proxy 
respondents Moderate 
Karunanayake et al.  (2012) Population-based 
case-control 
Males only Questionnaire answered 
by subjects; pesticide use 
collected via detailed 
telephone interview on 
all participants with 10+ 
hours of pesticide use 
during lifetime and 15% Cancer registries or 
hospital in 6 Canadian 
provinces with 
histopathological 
verification for 49% of 
samples; difficulty 
recruiting control Adjusted for age, 
province of residence, 
and significant 
medical history 
variables 
No adjustment for co-Conditional logistic 
regression to obtain 
OR and 95% CI Recall bias, exposure 
misclassification, control 
selection based on three 
different sources 
depending on province of 
residence, low 
participation rates among Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
random sample of those participants for older age exposure to other controls, unable to 
who did not; exposure groups pesticides or other evaluate Epstein-barr 
based on lifetime potential confounders virus exposure 
exposure to glyphosate (e.g., solvents, diesel 
fumes, UV radiation) 
Koureas et al. (2014) Cross-sectional Questionnaire answered by pesticide sprayers Genomic DNA extracted 
from peripheral blood 
samples and oxidation 
by-product 8-
hydroxydeoxyguanosine 
(8-OHdG) was 
determined by enzyme No adjustments. In univariate, 
occupational exposure, 
sex and alcohol 
consumption were 
statistically significant For univariate, chi-square test used to 
obtain RR and 95% 
CI; 8-OHdG levels 
transformed into 
binary variables 
(categorized as high 
and low using the 
75
th percentile cut-
off); unknown Recall bias, did not control for risk factors 
identified as statistically 
significant for univariate 
analysis, does not Low 
immunoassay; more specific methods (HPLC, 
GC-MS) are available for 
measurement while DAP concentrations and 
smoking were not.  number of exposed 
and unexposed 
cases (questionable 
sample size possible 
given total number 
of subjects is only 
80) measure the consequence 
of genetic damage 
Koutros et al.  (2013) Prospective cohort 
Males only Questionnaire answered 
by subjects at study 
enrollment; examined 
exposure as cumulative 
lifetime days and 
intensity-weighted 
cumulative exposure State cancer registries 
with histopathological 
verification; total and 
aggressive prostate 
cancers evaluated Adjustment for age, state, race, smoking, 
fruit servings, family 
history of prostate 
cancer, and leisure 
time physical activity 
in the winter. 
No adjustment for co-
exposure to other Poisson regression 
to obtain RRs and 
95% CIs; also 
included unlagged 
vs. lagged analysis Exposure misclassification  High 
days pesticides or other potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) 
Landgren et al. (2009) Nested case-
control
a 
Males only Questionnaire answered by subjects at enrollment 
in AHS cohort and 
subsequent take-home 
questionnaire to collect Venous blood collected 
from antecubital vein and 
analyzed for MGUS; 
same method as used for 
controls group in Adjusted for age and 
education level 
Association with other 
pesticides examined Logistic regression 
models to obtain 
OR and 95% CI 
comparing to 
population-based Exposure 
misclassification, control 
group not from 
geographical area (used 
control group with Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
information on 50 Minnesota and not found to be screening study in similar demographics 
pesticides; occupational significant so no Olmsted County, from Minnesota) 
expoures, medical adjustment performed Minnesota; 
histories, and lifestyle questionable sample 
factors updated with 5- No adjustment for size (27 cases; 11 
year follow-up interview; other potential controls) 
subjects with prior confounders (e.g., 
history of solvents, diesel fumes, 
lymphoproliferative UV radiation) 
malignancy excluded  
Lee et al. (2004a) This study was not included in the study quality rank ing because the data were used  in the pooled analysis conducted  by De Roos et al.  (2003). 
Lee et al. (2004b) Population-based 
case-control 
White males and 
females only Subjects or proxies were interviewed by 
telephone; those 
living/working on a farm 
asked for detailed history 
of pesticide use and 
farming information State cancer registry or 
review of discharge 
diagnosis and pathology 
records at 14 hospitals; 
only newly diagnosed 
cases with confirmed 
adenocarcinoma of 
stomach or esophagus 
retained; controls 
randomly selected from a Adjusted for age and 
sex; evaluated BMI, 
smoking, alcohol 
consumption, 
educational level, 
family history of 
stomach or esophageal 
cancer, respondent 
type, dietary intake of 
particular vitamins and 
minerals, protein, and 
carbohydrates 
(included in model if 
changed value of OR 
by more than 10%) Unconditional logistic regression 
to obtain OR and 
95% CI; 
questionable sample 
size (12 cases for 
stomach; 12 cases 
for esophagus) Recall bias, exposure misclassification, use of 
proxy respondents, 
control selection Moderate 
prior study conducted in geographical area No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) 
Lee et al. (2005) Population-based 
case-control Questionnaire and/or interview with subject or 
proxy individuals to 
collect information on 
use of specific pesticides; 
telephone follow-up for 
unclear responses Referral by hospitals or 
through state cancer 
registries with 
histopathological 
verification; controls 
selected from a previous 
study Adjusted for age and respondent type; 
evaluated history of 
head injury, marital 
status, education level, 
alcohol consumption, 
medical history of 
diabetes mellitus, Unconditional logistic regression 
to obtain OR and 
95% CI Recall bias, exposure misclassification, large 
number of proxy 
respondents, control 
selection (historical 
control group from 
another cancer 
evaluation, differences in Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
dietary intake of α- and exposure time period 
β-carotene, and dietary evaluated, needed to add 
fiber (included in younger controls, 
model if changed value exposure information 
of OR by more than collected for different 
10%) time periods for cases vs. 
controls) 
No adjustment for co-
exposure to other 
pesticides or other potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) 
Lee et al. (2007) Nested case-
control Questionnaire answered by subjects at enrollment 
in AHS cohort and 
subsequent take-home 
questionnaire to collect 
information on 50 
pesticides State cancer registries without histopathological 
verification; follow-up ~ 
7 years Adjustment for age, 
smoking, state, total 
days of pesticide 
application 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Unconditional multivariate logistic 
regression to obtain 
OR and 95% CI Exposure misclassification, 
limited data on dietary 
factors, NSAID drug use 
and family can cer history Moderate 
McDuffie et al., 2001 Population based case-control 
Males only Questionnaire answered 
by subjects; pesticide use 
collected via detailed 
telephone interview on 
all participants with 10+ 
hours of pesticide use 
during lifetime and 15% 
random sample of those 
who did not; exposure 
based on lifetime 
exposure to glyphosate Cancer registries or hospital in 6 Canadian 
provinces with 
histopathological 
verification for 84% of 
samples; ascertainment 
of cases stopped in each 
province once target 
numbers were reached Adjustment for age, province, and 
significant medical 
variables (including 
history of cancer in 
study participants and 
family history). 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Conditional logistic regression to obtain 
OR and 95% CI Recall bias, exposure 
misclassification, control 
selection based on three 
different sources 
depending on province of 
residence, relatively low 
participation rates Moderate 
Nordstrom et al., 1998 This study was not included in the study quality ranking because the data were used i n the pooled analysis conducted b y Hardell et al.  (2002). 
Orsi et al., 2009 Hospital-based case-control Data collection in 2 stages: 1) self-Hospital catchment area with histopathological/ Adjustment for age, center, and Unconditional logistic regression Recall bias, exposure misclassification, Moderate 
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 Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
Males only 
(occupationally 
exposed) administered questionnaire on 
socioeconomic 
characteristics, family 
medical history, and 
lifelong residential and 
occupational histories 
and more specific 
information for each job 
held for at least 6 months, and 2) face-to-
face interview with 
trained staff (blinded) 
using standardized 
questionnaire cytological verification 
Controls were hospital 
based with no prior 
history of lymphoid 
neoplasms, excluding 
patients with cancer or a 
disease directly related to 
occupation, smoking or 
alcohol abuse (but history of any of these 
did not prevent selection 
as a control) socioeconomic category.  Education 
and housing not found to impact results. Flu 
immunization, previous history of 
mononucleosis, skin 
type, smoking, and 
drinking did not 
change results. Evaluated particular 
crops and animal 
husbandry as well.   
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) to obtain OR and 
95% CI. 
Questionable 
sample size (12 
cases/24 controls) hospital-based controls 
Pahwa et al. (2011) Population-based 
case-control 
Males only Questionnaire answered 
by subjects; pesticide use 
collected via detailed 
telephone interview on 
all participants with 10+ 
hours of pesticide use 
during lifetime and 15% 
random sample of those 
who did not; exposure 
based on lifetime 
exposure to glyphosate Cancer registries or 
hospitals in 6 Canadian 
provinces with 
histopathological 
verification for 30% of 
samples Adjustment for age 
group, province of 
residence, and 
statistically significant 
medical history 
variables 
No adjustment for co-
exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) Conditional logistic regression to obtain 
OR and 95% CI; 
trends examined 
using multiple 
logistic regression  Recall bias, exposure 
misclassification, control 
selection based on three 
different sources 
depending on province of 
residence, low 
participation rates among 
controls Moderate 
Pahwa et al. (2012) Population-based 
case-control 
Males only Questionnaire answered 
by subjects; pesticide use 
collected via detailed 
telephone interview on 
all participants with 10+ 
hours of pesticide use 
during lifetime and 15% 
random sample of those Cancer registries or 
hospitals in 6 Canadian 
provinces with 
histopathological 
verification for 36.5% of 
samples Adjustment for age 
group, province of 
residence, and 
statistically significant 
medical history 
variables 
No adjustment for co-Conditional logistic 
regression to obtain 
OR and 95% CI; 
trends examined 
using multiple 
logistic regression  Recall bias, exposure 
misclassification, control 
selection based on three 
different sources 
depending on province of 
residence, low 
participation rates among 
controls Moderate 
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     Table 3.2. Summary of Study Design Elements Impacting Study Qu ality Assignment and Overall Ranking. 
Journal Article Study Design Exposure Assessment Outcome Assess ment Confounder Control Statistical Analyses Risk of (Other) Bi as Overall 
Ranking 
who did not; exposure 
based on lifetime 
exposure to glyphosate exposure to other 
pesticides or other 
potential confounders 
(e.g., solvents, diesel 
fumes, UV radiation) 
Yiin et al. (2012) Population-based case-control 
Pooled analysis of 
men with women 
analyzed in 
Carreon et al. 
(2005) Questionnaire and/or interview for chemical-
specific exposure 
answered by subjects or 
proxy individuals Cases referred by physicians or through 
state cancer registries 
with histopathological 
verification; controls 
matched within state, but 
not county of residence Adjustment for age, 
education, sex, and , 
sex, and farm 
pesticide exposure 
(yes/no) 
No adjustment for 
other potential 
confounders (e.g., 
solvents, diesel fumes, 
UV radiation) Unconditional 
logistic regression 
to obtain ORs and 
95% CIs Acknowledge other sources of bias. Recall 
bias, exposure 
misclassification, control 
selection (low number of 
deceased controls 
obtained) Moderate 
a Mixed methods used in the Landgr en et al (2009) study, with cross-sectional study design used t o calculate prevalence rates c omparing the AHS to a reference population MN.  
Pesticide risk estimates (incl uding glyphosate) calculated usin g nested case-control approach , comparing AHS exposed/unexposed  (ever/never) study participants. 
Page 43 of 216
	 
 
  
 
 
 
 
 3.4 Assessment of Epidemiological Studies for Relevance to Anal ysis 
Using the criteria summari zed in Section 3.2, a total of 63 ind ividual literature studies were 
identified in the literature review and were judged as high, mo derate, or low quality.  The data 
from 7 of these studies were us ed in pooled analyses by other s tudies; therefore, they were not 
subjected to detailed evaluation. Overall, 3 studies, 19 studie s, and 34 studies were assigned 
high, moderate, or low rankings, r espectively.  A ll of the high  and moderate quality studies were 
considered relevant to the current evaluation.  Additionally, t he findings of a recently published 
analysis of the AHS cohort (Andreotti et al. , 2017) have been considere d in this evaluation, when 
appropriate. 
The majority of the studies wer e case-control studies evaluating a wide-range of cancers in the 
United States and Canada. There w ere several case-control stud ies from Canada that utilized the 
same study population (Kachuri et al. , 2013; Karunanayake et al. , 2012; McDuffie et al. , 2001; 
Pahwa et al.,  2011; Pahwa et al. , 2012). In a similar fashion, nume rous studies in the United 
States were nested case-control studies, where the AHS cohort served as the source population 
for selecting cases and controls (Andreotti et al., 2009; Engel et al., 2005; Flower et al ., 2004; 
Landgren et al., 2009; Lee et al., 2007). In these studies, a subset of the AHS cohort was 
selected based on their outcome sta tus for a particular cancer and exposure information was used 
from the AHS enrollment quest ionnaire and/or during follow-up interviews.  Nested case-control 
studies allow for testing of hypotheses not anticipated when th e cohort was initially assembled.  
In the AHS prospective cohort studies (De Roos et al. , 2005; Koutros et al ., 2013; Andreotti et 
al., 2017), exposure and demographic information were also obtaine d from the questionnaires at 
enrollment; however, subjects we re enrolled prior to developing  cancer outcomes of interest.  
Subjects were then followed from enrollment to a subsequent tim e point to determine if subjects 
developed cancer outcomes of interest.  As such, all available subjects in the cohort are included 
in the evaluation of whether t here was an association between a  risk factor (e.g., glyphosate 
exposure) and outcome.   The moderate studies included a  varying degree of control for c onfounding and biases across 
studies. As moderate studies, t hey encompass a combination of strengths and limitations.  In 
particular, important factors t hat impacted the quality assessm ent for these studies included 
whether there was adjustment for known confounders, identificat ion of control selection issues, 
sample size issues, and lengt h of follow-up.  As noted previously, most people in these 
epidemiological studies used pesticides occupationally and were  exposed to multiple pesticides 
over their working lifetime.  Therefore, exposure to other pest icides is a particularly important 
factor to adjust for and studies t hat made this adjustment were  given more weight than those that 
did not. Similarly, control selection issues were noted in a few studies and were given less 
weighting than those without cont rol selection issues.  The iss ues ranged from concerns using 
hospital-based controls, using different population sources to ascertain controls within the same 
study, and appropriateness of using c ontrols ascertained for an other research question.  
Numerous studies were limited by s mall sample sizes, which resu lts in large confidence intervals 
and reduces the reliability of t he results to demonstrate a tru e association.  Studies demonstrating 
low or questionable sample size were therefore given less weigh ting.  Lastly, the length of 
follow-up time varied across studies. 
Page 44 of 216
	 
 
  
 
 
 
 
 
 
 
 
 
 3.5 Summary of Relevant Epidemiological Studies 
A summary of the relevant studi es evaluating the association be tween glyphosate exposure and 
cancer are discussed below. Resu lts of the studies reporting d ata on glyphosate exposure and 
solid tumors (non-lymphohematopoietic) at various anatomical si tes are presented in Table 3.3.  
Results of the studies reporting data on glyphosate exposure an d non-solid tumors 
(lymphohematopoietic) are presen ted in Table 3.4.  For study de tails, see Table 3.2 above and 
Appendix C. 
3.5.1 Solid Tumor Cancer Studies 
(1) Cancer at Multiple Sites from the AHS Cohort 
De Roos et al ., (2005)  evaluated associations betwee n glyphosate exposure and cancer incidence 
of all cancers combined in the AHS cohort study and did not fin d an association  [ever/never use 
relative risk ratio (RR) =1.0 wit h 95% confidence interval (CI)  of 0.90–1.2) when adjusting for 
age, demographic and lifestyle  factors, and exposure to other p esticides].  In addition, De Roos et 
al., 2005 evaluated cancer at specifi c anatomical sites.  Along w ith several nested case-control 
studies, no statistical evidence  of an association with glyphos ate was observed at any specific 
anatomical site (Table 3.3).  Sp ecifically, AHS researchers rep orted no evidence of an 
association between glyphosate use and cancers of the oral cavi ty (De Roos et al., 2005), colon 
(De Roos et al ., 2005; Lee et al., 2007), rectum (De Roos et al ., 2005; Lee et al., 2007), lung (De 
Roos et al ., 2005), kidney (De Roos et al ., 2005), bladder (De Roos et al., 2005), pancreas (De 
Roos et al ., 2005; Andreotti et al., 2009), breast (Engel et al., 2005), prostate (De Roos et al., 
2005; Koutros et al., 2013) or melanoma (De Roos et al., 2005). The adjusted RR or odds ratio 
(OR) and 95% CI for these studi es are provided in Table 3.3. 
Findings from the recently published analysis of the AHS cohort  (Andreotti et al., 2017) with a 
longer follow-up period than De Roos et al.  (2005) also did not find associations between 
glyphosate exposure and inciden ce of all cancers based on inten sity-weighted lifetime days of 
glyphosate use. Furthemore, the re was no evidence of an associ ation between glyphosate use 
and cancers of the oral cavit y, colon, rectum, pancreas, lung, melanoma, prostate, testes, bladder, 
or kidney. Although there was evide nce of a significant positive association in one quartile only 
relative to intensity-weighte d lifetime days of glyphosate exposure for pancreatic and lung 
cancer, there was no evidence of a significant positive associa tion in any other quartile for either 
cancer type and the exposure-respons e trends were not statistic ally significant.  As a result, these 
isolated findings were not cons idered suggestive of an associat ion.   
(2) Prostate Cancer 
In a Canadian population-based study (Band et al. , 2011), researchers reported non-statistically 
significant elevated odds of prostate cancer in relation to gly phosate use (OR=1.36; 95% 
CI=0.83–2.25). There was no adjustm ent made for exposure to ot her pesticides.  This study 
included prostate cancer cases from 1983- 1990, prior to the pro state-specific antigen (PSA) era.  
Consequently, the study included more advanced tumors before di agnosis.  The AHS related 
studies (De Roos et al ., 2005; Koutros et al., 2013; Andreotti et al ., 2017), reflect PSA-era cases 
Page 45 of 216
	 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 (i.e., cases which are typicall y identified at an earlier stage  in the progression of the disease) and 
also did not identify an associ ation with prostate cancer. 
(3) Brain (Glioma) Cancer 
Lee et al. (2005) investigated the assoc iation between brain cancer with  farming and agricultural 
pesticide use. Matching for age, sex, vital status, and region , study authors reported a non-
significant elevated odds of glio ma (OR=1.5; 95% CI=0.7–3.1) in  relation to glyphosate use by 
male farmers; however, the resu lts were significantly different  between those who self-reported 
pesticide use (OR=0.4; 95% CI=0.1–1.6), and for those for whom a proxy respondent was used 
(OR=3.1; 95% CI=1.2–8.2), indicating recall bias was a potentia l factor in this study.  
Furthermore, there was no adjustm ent for co-exposure to other pesticides and issues noted with 
control selection. 
A population-based case-control study evaluated the risk of brain cancer, specifically, glioma 
risk, among men and women particip ating in the Upper Midwest He alth Study (Yiin et al., 
2012). Using a quantitative measure of pesticide exposure (in contrast to an ever-use metric), 
Yiin et al. (2012) observed no statistical evidence of an association with glyphosate with effect 
estimates roughly equal to the nu ll value following adjustment for age, education, sex, and use of 
other pesticides (home and garden use: OR=0.98; 95% CI=0.67–1.4 3; non-farm jobs: OR=0.83; 
95% CI=0.39–1.73). 
(4) Stomach and Esophageal Cancer 
In a population-based case-contro l study in eastern Nebraska, L ee et al. (2004b) investigated 
pesticide use and stomach and esophageal adenocarcinomas.  Ther e was no association observed 
between glyphosate exposure and either stomach cancer (OR=0.8; 95% CI=0.4–1.5) or 
esophageal cancer (OR=0.7; 95% CI=0.3–1.4) after adjustment for age and sex.  No adjustment 
was made for exposure to other pesticides. 
(5) Soft Tissue Sarcoma 
A Canadian case-control study (Pahwa et al., 2011) examined exposure to pesticides and soft 
tissue sarcoma and found no rela tion with the use of glyphosate after adjustment for age, 
province of residence, and medical  history variables (OR=0.90; 95% CI= 0.58–1.40); however, 
control selection issues were not ed, including low response rat e and selection from three 
different sources depending on the province of residence.    
(6) Total Childhood Cancer 
Flower et al . (2004), a nested case-control study in the AHS cohort, examined the relation 
between parental pesticide use a nd all pediatric cancers report ed to state registries among 
children of AHS participants and d id not observe a significant association with maternal use 
exposure to glyphosate (OR= 0.61; 95% CI= 0.32–1.16) or paternal (prenatal) exposure to 
glyphosate (OR=0.84; 95% CI= 0.35–2.54). The models adjusted f or the child’s age at the time 
of parents’ enrollment.  There was no adjustment for exposure t o other pesticides. 
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 Table 3.3. Summary of Findings:  Solid Tumor Cancer Studies 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
All Cancers Combined 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.0 (0.9-1.2) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.0 (0.9-1.1) 1.0 (0.9-1.1) Age, demographic and lif estyle factors, and 
other pesticides
b 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
0.9 (0.8-1.0) 0.9 (0.8-1.1) Age, demographic and lif estyle factors, and 
other pesticides
b 
Lung 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 0.9 (0.6-1.3) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
0.9 (0.5-1.5) 
0.7 (0.4-1.2) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
1.1 (0.7-1.9) 0.6 (0.3-1.0) Age, demographic and lif estyle factors, and 
other pesticides
b 
Oral Cavity 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.0 (0.5-1.8) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
0.8 (0.4-1.7) 
0.8 (0.4-1.7) Age, demographic and lif estyle factors, and 
other pesticidesb 
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 Table 3.3. Summary of Findings:  Solid Tumor Cancer Studies 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
1.1 (0.5-2.5) 1.0 (0.5-2.3) Age, demographic and lif estyle factors, and 
other pesticides
b 
Kidney 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.6 (0.7-3.8) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
0.6 (0.3-1.4) 
0.7 (0.3-1.6) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
0.3 (0.1-0.7) 
0.5 (0.2-1.0) Age, demographic and lif estyle factors, and 
other pesticidesb 
Bladder 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.5 (0.7-3.2) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.0 (0.5-1.9) 
1.2 (0.6-2.2) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
0.5 (0.2-1.3) 
0.8 (0.3-1.8) Age, demographic and lif estyle factors, and 
other pesticidesb 
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 Table 3.3. Summary of Findings:  Solid Tumor Cancer Studies 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Melanoma 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.6 (0.8-3.0) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.2 (0.7-2.3) 
0.9 (0.5-1.8) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
0.6 (0.3-1.1) 0.7 (0.3-1.2) Age, demographic and lif estyle factors, and 
other pesticides
b 
Colon 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.4 (0.8-2.2) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.4 (0.9-2.4) 0.9 (0.4-1.7) Age, demographic and lif estyle factors, and 
other pesticides
b 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
0.8 (0.5-1.5) 1.4 (0.8-2.5) Age, demographic and lif estyle factors, and 
other pesticides
b 
Lee et al. (2007) Nested Case-Control USA: Iowa and 
North Carolina Ever/never 1.0 (0.7-1.5) Age, smoking, state, total days of pesticide 
application 
Rectum 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.3 (0.7-2.3) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.3 (0.7-2.5) 
1.1 (0.6-2.3) Age, demographic and lif estyle factors, and 
other pesticidesb 
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 Table 3.3. Summary of Findings:  Solid Tumor Cancer Studies 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
1.0 (0.5-2.0) 
0.9 (0.5-1.9) Age, demographic and lif estyle factors, and 
other pesticidesb 
Lee et al. (2007) Nested Case-Control USA: Iowa and 
North Carolina Ever/never 1.6 (0.9-2.9) Age, smoking, state, total days of pesticide 
application 
Colorectal 
Lee et al. (2007) Nested Case-Control USA: Iowa and 
North Carolina Ever/never 1.2 (0.9-1.6) Age, smoking, state, total days of pesticide 
application 
Pancreas 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 0.7 (0.3-2.0) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.6 (0.6-4.1) 
1.3 (0.5-3.6) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
2.5 (1.0-6.3) 0.5 (0.1-1.9) Age, demographic and lif estyle factors, and 
other pesticides
b 
Andreotti et al. (2009) Nested Case-Control USA: Iowa and 
North Carolina Ever/never 1.1 (0.6-1.7) Age group, cigarette s moking, diabetes, and 
applicator type 
Intensity-Weighted Exposure Days 
(by control median): 
≤184 ≥185 1.4 (0.9-3.8) 0.5 (0.2-1.3) Age group, cigarette smoking, and diabetes 
Prostate 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.1 (0.9-1.3) Age, demographic and lif estyle factors, and 
other pesticides
b 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
0.9 (0.7-1.1) 1.1 (0.9-1.3) Age, demographic and lif estyle factors, and 
other pesticides
b 
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 Table 3.3. Summary of Findings:  Solid Tumor Cancer Studies 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
1.0 (0.8-1.2) 1.1 (0.9-1.3) Age, demographic and lif estyle factors, and 
other pesticides
b 
Koutros et al.  (2013)c Prospective cohort USA: Iowa and 
North Carolina Intensity-Weighted C umulative Exposure 
Days (by quartile): 
Q1 
Q2 
Q3 
Q4 Total prostate cancer: 
0.91 (0.79-1.06) 0.96 (0.83-1.12) 
1.01 (0.87-1.17) 
0.99 (0.86-1.15) Age, state, race, smoking, fruit servings, 
family history of prostate cancer, and 
leisure time physical activity in the winter 
Intensity-Weighted C umulative Exposure 
Days  (by quartile): 
Q1 
Q2 
Q3 
Q4 Aggressive prostate cancer: 
0.93 (0.74-1.16) 0.91 (0.73-1.13) 
1.01 (0.82-1.25) 
0.94 (0.75-1.18) Age, state, race, smoking, fruit servings, 
family history of prostate cancer, and 
leisure time physical activity in the winter 
Band et al. (2011) Case-Control Canada: British 
Columbia Ever/never 1.36 (0.83-2.25) Alcohol consumption,  cigarette years, 
education level, pipe years, and respondent 
type 
Esophagus 
Lee et al. (2004b) Case-Control USA: Nebraska Ever/never 0.7 (0.3-1.4) Age and sex 
Stomach 
Lee et al. (2004b) Case-Control USA: Nebraska Ever/never 0.8 (0.4-1.5) Age and sex 
Breast 
Engel et al. (2005) Nested Case-Control USA: Iowa and 
North Carolina Ever/never Wives who apply 
pesticides: 
0.9 (0.7-1.1) 
Wives who never used 
pesticides: 
1.3 (0.8-1.9) Age, race, and state of residence 
Soft Tissue Sarcoma 
Pahwa et al. (2011) Case-Control Canada Ever/never 0.90 (0.58-1.40) Age group, province of residence, and 
statistically significant medical history 
variables 
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 Table 3.3. Summary of Findings:  Solid Tumor Cancer Studies 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Brain (glioma) 
Lee et al. (2005) Case-Control USA: Nebraska Ever/never Overall: 
1.5 (0.7-3.1) 
Self-reported: 
0.4 (0.1-1.6) 
Proxy respondents: 
3.1 (1.2-8.2) Age for overall analysis; age and 
respondent type for other analyses 
Yiin et al. (2012) Case-Control USA: Iowa, 
Michigan, 
Minnesota, and 
Wisconsin Ever/never House/garden use: 
0.98 (0.67-1.43) 
Non-farm jobs: 
0.83 (0.39-1.73) Age, education, sex, and use of other 
pesticides 
Total Childhood 
Flower et al. (2004) Nested Case-Control USA: Iowa and 
North Carolina Ever/never Maternal use: 
0.61 (0.32-1.16) 
Paternal use: 
0.84 (0.35-2.34) Child’s age at enrollment 
a Some studies report multiple quantitative risk measurements. This table reports the most hi ghly adjusted qua ntitative measur ements.
	
b De Roos et al. (2005) excluded subjects missing c ovariate data for demographic  and lifestyle factors and exposure to other pesticides; theref ore, the number of subjects included
	
in each analysis varies.
	
c Effect estimates for  glyphosate reported in  the supplemental we b material for Koutros et al. (2013).
	
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  3.5.2 Non-Solid Tumor Cancer Studies 
(1) Leukemia 
De Roos et al . (2005) reported no association be tween leukemia and glyphosate-exposed 
(ever/never used) pesticide a pplicators in the AHS cohort.  For applicators with the full data set 
(54,315), the RR was 1.1 (95% C I=0.6–2.4) with only adjustment for age.  In the fully adjusted 
model, the RR was similar (RR=1.0; 95% CI=0.5–1.9).  The number of participants included in 
the adjusted analysis was lower (n=40,716) due to the exclusion  of subjects with missing 
covariate data. Effect estimates  using cumulative lifetime exp osure and intensity-weighted 
cumulative exposure were als o found to be non-statistically sig nificant and did not demonstrate a 
trend with increasing exposure.  In the recently published anal ysis of the AHS cohort with a 
longer follow-up period (Andreotti et al., 2017), there was no associ ation reported between 
chronic lymphocytic leukemia/small lymphocytic lymphoma and chr onic myeloid leukemia.  For 
acute myeloid leukemia, an ele vated but non-statistically signi ficant association w as reported in 
only one quartile relative to glyphosate exposure; however, there was a low number of observed 
cases in each of the quartiles and the overall trend was not si gnificant.  There are no other studies 
available evaluating acute myelo id leukemia.  Given the limitat ions of the acute myeloid 
leukemia analysis, the agency will continue to follow the liter ature regarding the association 
between glyphosate exposure and r isk of acute myeloid leukemia. 
In a population-based case-contro l study in Iowa and Minnesota, Brown et al. (1990) did not 
observe an association with the  ever-use of glyphosate (OR=0.9;  95% CI=0.5–1.6).  A limitation 
in the study was the low numb er of cases exposed to glyphosate (n=15).  Adjustments were made 
for several covariates, including vital status, age, tobacco use, family history of lymphopoietic cancer, high risk occupations, and high risk exposures; however , no adjustment was made for 
exposure to other pesticides. 
Chang and Delzell (2016) conducte d a meta-analysis exploring glyphosate exposure and 
leukemia using 3 studies (De Roos et al., 2005; Brown et al., 1990; and Kaufman et al., 2009). 
I
2 values were reported, which rep resented the percentage of the total variance explained by 
study heterogeneity and measure inconsistency in results.  Larg er I2 values indicate greater 
inconsistency. A meta-risk r atio of 1.0 (95% CI=0.6-1.5) was obtained with an I2 value of 0.0%, 
indicating consistency across th e data sets.  It should be noted that this analysis included data 
from Kaufman et al.  (2009), which is not considere d in the current evaluation beca use it was 
assigned a low quality ranking because a quantitative measure o f an association between 
glyphosate and a cancer outcome w as not reported for that study. 
(2) Multiple Myeloma 
In a follow-up analysis of the study population from Iowa and M innesota used in Brown et al. 
(1990), Brown et al.  (1993) investigated whether pest icide use was related to multi ple myeloma.  
Among men in Iowa, the authors  observed a non-statistically sig nificant elevated association 
with glyphosate use (OR=1.7; 95%  CI=0.8–3.6; 11 exposed cases);  however, no adjustment was 
made for exposure to other pest icides.  The authors cautioned that while the study may lend 
Page 53 of 216
	 
 
  
 
 
 
 
 
   
 
 
 
                                                 support to the role of pesticides in general, the study limitat ions preclude use of the evidence as a 
definitive finding for any one compound. 
De Roos et al . (2005) reported a suggestive association between multiple mye loma and 
glyphosate-exposed pesticide applicators based on 32 multiple myeloma cases observed in the 
AHS cohort. For applicators with t he full data set, the RR was  1.1 (95% CI=0.5–2.4) with only 
adjustment for age.  In the fu lly adjusted model excluding subjects with missing covariate data, 
there was a non-statistically significant elevated risk followi ng adjustment for age, demographic 
and lifestyle factors , and exposure to other pesticides (RR=2.6 ; 95% CI=0.7–9.4).  The authors 
postulated that the increased m yeloma risk could be due to bias  resulting from a selection of 
subjects in adjusted analyses tha t differed from subjects inclu ded in unadjusted analyses or may 
be due to a confounder or effect mod ifier that is prevalent amo ng the subgroup and has not been 
accounted for in the analyses.  W hen exposure data were also stratified by tertiles  with the lowest 
tertile of exposure as the referent category, trend analyses were not statistically significant.  Non-statistically significant el evated RRs of 1.9 (95% CI: 0.6-6.3) and 2.1 (95% CI: 0.6-7.0) were 
estimated for the highest tertil e of both cumulative and intensity-weighted exposure days, 
respectively. The study authors did note that small sample size precluded prec ise estimation 
(n=19 for adjusted analyses). W hen using never exposed as the referent category, the trend 
analysis was again non-statisti cally significant, but the RRs r anged from 2.3 (95% CI: 0.6-8.9) to 
4.4 (95% CI: 1.0-20.2) from the lowe st tertile to the highest tertile, respectively.  When stratified 
by quartiles, a statistically signi ficant trend is achieved and the RR increased to 6.6 (95% CI: 
1.4-30.6); however, the authors noted that the cases were spars ely distributed for these analyses.  
In the recently published analysis  of the AHS cohort with a lon ger follow-up period and 88 
exposed cases (Andreotti et al., 2017), there was no association observed between glyphosate 
exposure and multiple myeloma. 
Sorahan (2015)
12 re-analyzed the AHS data reported by De Roos et al. (2005) to examine the 
reason for the disparate findings in relation to the use of a f ull data set versus the restricted data 
set. Using Poisson regression, ris k ratios were calculated wit hout excluding subjects with 
missing covariate data.  When adj usted for age and sex, the RR for ever-use of glyphosate was 
1.12 (95% CI of 0.5–2.49). Additional adjustment for lifestyle  factors and use of other pesticides 
did not have a large impact  (RR=1.24; 95% CI=0.52–2.94).  The a uthors concluded that the 
disparate findings in De Roos et al.  (2005) could be attributed to the use of a restricted dataset 
that was unrepresentative. 
Landgren et al. (2009), within the AHS study population, also investigated th e association 
between pesticide use and preval ence of monoclonal gammopathy of undetermined significance 
(MGUS). MGUS is considered a pre-clinical marker of multiple m yeloma progression.  The 
authors did not observe an associ ation with glyphosate use and MGUS using subjects from the 
AHS cohort (OR=0.50; 95% CI=0.20–1.0). No adjustment was made for exposure to other 
pesticides. In a population-based case-control study (Pahwa et al., 2012) among men in six Canadian 
provinces, a non-statistically significant elevated odds of multiple myeloma was reported in 
relation to glyphosate use (O R=1.22; 95% CI = 0.77–1.93), based upon 32 glyphosate exposed 
12 Funded by Monsanto 
Page 54 of 216
	 
 
  
 
 
 
 
 
 
 multiple myeloma cases and 133 controls.  There was no adjustme nt for exposure to other 
pesticides. In an extended ana lysis of these data, Kachuri et al. (2013), using the same Canadian 
study population, further explored m ultiple myeloma in relation  to days per year that glyphosate 
was used. Adjustment for exposur e to other pesticides was also  not performed in this study.  For 
ever-use, there was a slight non-statistically s ignificant incr eased odds ratio (OR=1.19; 95% 
CI=0.76–1.87). For light users (> 0 and ≤2 days/year), there wa s no association (OR=0.72; 95% 
CI = 0.39–1.32; 15 exposed cases); whe reas, for heavy users (>2  days/ year), there was a non-
statistically significant incr eased odds ratio (OR=2.04; 95% CI =0.98–4.23; 12 exposed cases). 
Similar results were obtaine d when proxy respondents were exclu ded from the analysis.  The low 
number of cases and controls e xposed to glyphosate, particularl y when exposed subjects were 
divided into light and heavy user s, was a limitation of the stu dy.  It would be expected that effect 
estimates would be reduced if adjustment for co-exposure to oth er pesticides had been 
performed.  
In a hospital-based case-control study conducted by Orsi et al. (2009) in France, 56 multiple 
myleoma cases and 313 age- and sex -matched controls were identi fied.  A non-statistically 
significant elevated risk wa s observed (OR=2.4; 95% CI=0.8–7.3;  5 exposed cases and 18 
exposed controls). The wide CI range can primarily be attribut ed to the low number of exposed 
cases, which reduces the relia bility of the results to demonstr ate a true association.  Additionally, 
the study did not adjust for exposure to multiple pesticides. Chang and Delzell (2016) conducte d a meta-analysis exploring glyphosate exposure and multiple 
myeloma using data from the 6 s tudies described above (Brown et al. , 1993; De Roos et al ., 
2005; Sorahan, 2015; Pahwa et al., 2012; Kachuri et al., 2013; Orsi et al ., 2009). Meta-risk 
ratios were obtained using data f rom each of the 4 independent study populations, such that if a 
study population was already represe nted in the analysis by one  study, then the same population 
analyzed by another stud y would not be included (e.g. , Sorahan, 2015 and De Roos et al. , 2005 
could not be used simultaneously in a meta-analysis).  The comb ined meta-risk ratio based on 
data from prioritized studies (Brown et al. , 1993; Kachuri et al. , 2013; Orsi et al. , 2009; and 
Sorahan, 2015) was 1.4 (95% CI=1.0-1.9) using random-effects an d fixed-effects models and the 
I
2 value = 0.0% indicating consistency across data sets.  There w as relatively no impact on the 
meta-risk ratio and associated 95 % CI when secondary analyses w ere conducted using 
alternative estimates for a study population (e.g. , substituting the data from Sorahan, 2015 for De 
Roos et al., 2005). 
(3) Hodgkin Lymphoma 
In a Canadian case-control study, Karunanayake et al., (2012) evaluated Hodgkin lymphoma 
(HL) and observed no association with glyphosate exposure follo wing adjustment for age, 
province of residence, and medical  history variables (OR=0.99; 95% CI=0.62-1.56; 38 cases).  
No adjustment was made for e xposure to other pesticides. 
Page 55 of 216
	 
 
  
 
 
 
 
  
 In a hospital-based case-control study conducted by Orsi et al. (2009) in France, authors 
identified 87 HL cases and 265 age-and sex-matched controls.  There was a non-statistically 
significant elevated odds rati o observed (OR=1.7; 95% CI=0.6–5. 0; 6 exposed cases and 15 
exposed controls). The wide CI range can primarily be attribut ed to the low number of exposed 
cases. Also, as noted earlier, this study did not adjust for e xposure to multiple pesticides. 
Chang and Delzell (2016) conducte d a meta-analysis exploring glyphosate exposure and HL 
using data from both of these stu dies.  A meta-risk ratio of 1. 1 (95% CI=0.7-1.6) was obtained 
with a I
2 value of 0.0%, indicating consiste ncy across the data sets. 
HL was also evaluated in the re cently published analysis of the  AHS cohort (Andreotti et al. , 
2017) and no association was obser ved with glyphosate use; howe ver, the number of cases 
available for this analysis was limited.   
(4) Non-Hodgkin Lymphoma 
NHL has about 60 subtypes classified by the WHO, which may have  etiological differences 
(Morton et al. , 2014). There are analyses availa ble for particular subtypes of NHL; however, 
these are particularly limited by the small sample sizes.  As a  result, this evaluation only presents 
results for total NHL with the exception of the recently publis hed analysis of the AHS cohort 
(Andreotti et al.,  2017) where sample sizes were not limited for all subtypes. 
There were six studies availabl e that investigated the association between glyphosate exposure 
and NHL, which was the most fo r any type of cancer.  As discussed in Section 3.4, these studies 
encompass a combination of strengths and limitations.  These st udies are therefore discussed in 
more detail in this section as compared to discussions of other  cancer types in order to highlight 
the strengths and identify the  limitations for each study. 
De Roos et al . (2005) was the only prospective cohort study available; there fore, subjects were 
enrolled prior to developing can cer outcomes.  Disease status w as determined through state 
cancer registries. Exposure information was obtained from a large number of licensed pesticide applicators and no proxies were us ed.  Exposure was evaluated a s ever/never use, cumulative 
lifetime exposure, and intensity-w eighted cumulative exposure. Due to the study design, the 
potential for many biases were reduced.  Additionally, the stud y adjusted and/or considered 
numerous factors, including use  of other pesticides.  Median fo llow-up time was approximately 7 
years.; however, as discussed in Section 3.3.1, study participants provided exposure information prior to enrollment and this in formation was incorporated into the cumulative lifetime and 
intensity-weighted cumulative e xposure metrics.  As a result, t he amount of time exposed was 
longer than just the follow-up time since enrollment.  For appl icators with the full data set, the 
RR for ever/never use was 1.2 (95% CI=0.7–1.9; 92 cases) with o nly adjustment for age.  In the 
fully adjusted model excluding subjects with missing covariate data, the RR was similar 
following adjustment for age, demographic and lifestyle factors , and exposure to other pesticides 
(RR=1.1; 95% CI=0.7-1.9). Effect e stimates obtained using cumu lative lifetime exposure and 
intensity-weighted cumulative exposure were below 1 (RR = 0.6-0 .9 when comparing to the 
lowest tertile). The recently publ ished analysis of the AHS co hort with a longer follow-up 
Page 56 of 216
	 
 
  
 
 
 
 
 
 
 period of approximately 17.5 years (Andreotti et al., 2017) also reported no association between 
glyphosate exposure and NHL overall or any of its subtypes. 
De Roos et al.  (2003) used pooled data from three case-controls studies evalu ating NHL in white 
males from Nebraska, Kansas, and in Iowa and Minnesota (Cantor et al. , 1992; Hoar et al. , 1986; 
Zahm et al., 1990; Appendix B). Exposure information was obtained from exp osed individuals 
or their next of kin (i.e., proxy respondents) if the subjects were dead or incapacitated; however, 
techniques varied acr oss the three studie s.  There is potential  for selection bias due to exclusion 
of observations with missing cova riate data, but only if the la ck of the covariate data was 
associated with glyphosate exposure.  The effect estimates for the association between 
glyphosate exposure and NHL was  significant (OR=2.1; 95% CI=1.1 –4.0) in the logistic 
regression analyses ad justing for co-exposure to other pesticides.  However, utilizi ng alternative 
hierarchical regression technique s to adjust for co-exposure to other pesticide exposures, the 
odds ratio was still elevated, but the increase was not statistically significant (OR=1.6; 95% CI=0.90–2.8). 
Eriksson et al.  (2008) is a Swedish case-contro l study that used detailed expo sure information 
from exposed individuals (i.e. , no use of proxy respondents), but only minimal demographic 
information was provided on subjects (age and sex) and a table with subject characteristics (e.g., 
smoking status, alcohol intake, phys ical activity, education) w as not provided.  Cases were 
identified through physicians and v erified histopathologically.  Glyphosate exposure, which was 
reported in 29 cases and 18 c ontrols between 1999 and 2003, pro duced a statistically significant 
increased OR in the univariate analysis (OR=2.02; 95% CI=1.10–3 .71); however, in the 
multivariate analysis adjustments were conducted for co-exposur e to different agents including 
MCPA, “2,4,5-Y and/or 2,4-D”, mer curial seed dressing, arsenic,  creosote, and tar and the OR 
reduced to 1.51 (95% CI=0.77–2.94) and w as not statistically significant.  Additional analyses 
were conducted to investigate th e impact of various exposure times.  When exposure was for 
more than 10 cumulative days ( the median number of days among e xposed controls), the OR was 
2.36 (95% CI=1.04–5.37; 17 exposed cas es) and for exposure less  than 10 cumulative days, the 
OR was 1.69 (95% CI=0.7–4.07; 12 exposed cases).  By dividing t he exposed cases and controls 
using this exposure metric, wid er CIs were observed due to smal ler sample sizes, which reduces 
the reliability of the results t o demonstrate a true associatio n.  Additionally, these analyses did 
not account for co-exposure to o ther pesticides.  Similarly, wider CIs were also observed when 
exposed cases and controls were  divided by a longer exposure me tric.  ORs of 1.11 (95% 
CI=0.24-5.08) and 2.26 (95% CI=1.16- 4.40) were obtained for 1-10 years and >10 years, 
respectively. It was not clear whether this analysis adjusted for co-exposure to other pesticides 
based on the statistical methods de scription and the subjects f or each exposure group were not 
reported. This finding, while limited to a single study, sugge sts that cohort studies without 
sufficient follow-up time or othe r case-control studies which d id not stratify by time since first 
exposure may be less sensitive in detecting risk.  
Hardell et al.  (2002) used pooled data from two case-control studies in Swede n (Hardell and 
Eriksson, 1999; Nordstrom et al., 1998; Appendix B) that examin ed hairy cell leukemia, a 
subtype of NHL, and NHL (not inc luding hairy cell leukemia).  E xposure information was 
collected from individuals or proxy respondents based on a work ing history with specific 
questions on exposures to different  chemicals.  Cases were iden tified from regional cancer 
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 registries and verified histopa thologically.  In the univariate  analysis, risk of NHL associated 
with glyphosate exposure was found to be significantly increased (OR=3.04; 95% CI=1.08– 
8.52), but when study site, vital st atus, and co-exposure to ot her pesticides were considered in 
the multivariate analysis, the OR noticeably attenuated and was  found to be non-statistically 
significant (OR=1.85; 95% CI=0.55–6.20). The wide range of the  CI resulting from the small 
sample size (only 8 glyphosate- exposed cases and 8 glyphosate-c ontrols). 
McDuffie et al.  (2001) is a multicenter population-based study among men of si x Canadian 
provinces. This case-control study utilized a well-conducted exposure assessment and cases 
were ascertained from cancer r egistries or hospitals in six provinces with histopathological 
verification for 84% of the samples.  There are concerns with c ontrol selection.  There was low 
control participation (48%) and di fferent sources were used for selecting controls depending on 
the province of residence. Effect  estimates were obtained usin g a considerable number of 
exposed cases and controls (51 cases and 133 controls); however , the study did not assess co-
exposure to other pesticides. There was a non-statistically si gnificant increased risk of NHL 
from glyphosate exposure when a djusting for age and province (O R=1.26; 95% CI=0.87–1.80) 
and when adjusting for age, provin ce and medical variables (OR= 1.20; 95% CI=0.83–1.74). 
Medical variables found to be sta tistically significant include d history of measles, mumps, 
previous cancer, skin-prick all ergy tests, allergy desensitization shots, and a positive family 
history of cancer in a first-de gree relative.  It would be expected that effect estimates would 
attenuate if adjustment for co-e xposure to other pesticides had  been performed.  Additional 
analyses were conducted to inves tigate differences in exposure time.  When exposure was for 
more than 2 days/year, the O R was 2.12 (95% CI=1.20-3.73; 23 exposed cases and 36 exposed 
controls) compared to unexposed s ubjects and for exposure more than 0 and ≤ 2 days/year, the 
OR was 1.00 (95% CI=0.63–1.57; 28 exposed cases and 97 exposed controls) compared to 
unexposed subjects. 
Orsi et al.  (2009) is a French hospital-base d case-control study that obta ined exposure 
information from subjects (no pr oxies used) using a detailed qu estionnaire with lifelong 
residential and occupational hi stories followed by a discussion  with a trained interviewer who 
was blinded to case status. N o issues regarding exposure or ou tcome assessment were identified; 
however, there is potential for selection bias given the study utilized hospital-based controls 
(primarily from orthopedic and r hematological departments) that may not be representative of 
the general population that gave r ise to the cases.  The study evaluated several potential 
confounders; however, it did not ass ess co-exposure to other pe sticides.  There was no 
association observed between NHL and glyphosate use (OR=1.0; 95 % CI=0.5-2.2; 12 exposed 
cases and 24 exposed controls). The  low number of cases and co ntrols exposed to glyphosate 
and lack of adjustment for exposure to multiple pesticides were  limitations of the study.   
Schinasi and Leon (2014) conducted a meta-analysis exploring oc cupational glyphosate exposure 
and NHL using data from six of the above mentioned studies (McD uffie et al ., 2001; Hardell et 
al., 2002; De Roos et al ., 2003; De Roos et al ., 2005; Eriksson et al., 2008; and Orsi et al., 
2009). Since the authors identi fied a variety of sources of heterogeneity between publications, 
they decided a priori to calculat e meta-risk ratio estimates an d 95% CIs using random effect 
models, allowing between study heterogeneity to contribute to the variance.  I2 values were 
reported as a measure of incons istency in results.  For glyphos ate, the meta-risk ratio was 1.5 
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 with a 95% CI of 1.1–2.0 and the I2 value was 32.7% indicating relatively low levels of 
heterogeneity among these studies.  This study combined multipl e smaller studies that on their 
own had limitations, includi ng small sample sizes.  
The 2015 IARC evaluation noted tha t fully adjusted effect estim ates in two of the Swedish 
studies (Hardell et al., 2002 and Eriksson et al ., 2008) were not used in the analysis conducted 
by Schinasi and Leon (2014). Conse quently, the IARC Working Gr oup conducted a 
reexamination of the results of  these studies (IARC 2015).  For  an association between 
glyphosate exposure and NHL, the I ARC estimated a meta-risk rat io of 1.3 (95% CI=1.03–1.65, 
I2 =0%; p=0.589 for heterogeneity). 
Chang and Delzell (2016) conducte d their own meta-analysis exploring glyphosate exposure and 
NHL using six independent studies (De Roos et al., 2003; De Roos et al.,  2005; Eriksson et al., 
2008; Hardell et al.,  2002; McDuffie et al., 2001; and Orsi et al.,  2009). A meta-risk ratio of 1.3 
(95% CI=1.0-1.6) was obtained with an I2 value of 0.0%. In a secondary a nalysis, the De Roos et 
al. (2003) OR using hierarchical regression was replaced by the lo gistic regression OR.  This 
change had no impact on the meta-ri sk ratio and associated conf idence interval (meta-risk 
ratio=1.3; 95% CI=1.0-1.6). In ano ther secondary analysis, the OR from McDuffie et al.  (2001) 
was replaced by the OR from Hohenadel et al.  (2011), which evaluated the same study 
population (minus four previously m isclassified NHL cases).  Th is analysis also yielded similar 
results (meta-risk ratio=1.3;  95% CI=1.0-1.7).  A final analysi s was performed with the 
replacements for both secondary analyses [i.e. , logistic regression OR from De Roos et al.  (2003) 
and OR from Hohenadel et al.  (2011)]. The results w ere relatively the same as the other meta-
analyses (meta-risk ratio= 1.4; 95% CI=1.0-1.8).  Chang and Delz ell (2016) also tested for 
publication bias using Egger’s lin ear regression approach to ev aluating funnel plot asymmetry, 
and found no significant asymmetry i ndicating little evidence o f publication bias; however, given 
the small sample size (n=6), t his analysis would lack power and  the results are not considered 
meaningful. 
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 Table 3.4. Summary of Findings : Non-Solid Tumor Cancer Studies. 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Leukemia 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.0 (0.5-1.9) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.9 (0.8-4.5) 
1.0 (0.4-2.9) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
1.9 (0.8-4.7) 
0.7 (0.2-2.1) Age, demographic and lif estyle factors, and 
other pesticidesb 
Brown et al. (1990) Case-Control USA: Iowa and 
Minnesota Ever/never 0.9 (0.5-1.6) Vital status, age, tobacco use, family history 
of lymphopoietic cancer, high occupations, 
and high risk exposures 
Multiple Myeloma 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 2.6 (0.7-9.4) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
1.1 (0.4-3.5) 
1.9 (0.6-6.3) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
1.2 (0.4-3.8) 
2.1 (0.6-7.0) Age, demographic and lif estyle factors, and 
other pesticidesb 
Brown et al.  (1993) Case-Control USA: Iowa Ever/never 1.7 (0.8-3.6) Age and  vital status 
Kachuri et al. (2013) 
(extended analysis of 
Pahwa 2012) Case-Control Canada Ever/never 1.19 (0.76-1.87) Age, province of resid ence, smoking status, 
selected medical conditions, family history 
of cancer, and use of a proxy respondent 
Days per year of use: 
0 to ≤2 days/year 
>2 days/year 0.72 (0.39-1.32) 2.04 (0.98-4.23) Age, province of resid ence, smoking status, 
selected medical conditions, family history 
of cancer, and use of a proxy respondent 
Pahwa et al. (2012) Case-Control Canada Ever/never 1.22 (0.77-1.93) Age group, province of residence, and 
statistically significant medical history 
variables 
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   Table 3.4. Summary of Findings : Non-Solid Tumor Cancer Studies. 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Orsi et al. (2009) Case-Control France Ever/ne ver 2.4 (0.8-7.3) Age, centre , and socioeconomic category 
Sorahan (2015) 
Reanalysis of De Roos 
et al.  (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.12 (0.5-2.49) Age and sex 
1.24 (0.52-2.94) Age sex, lifestyle factors, and other 
pesticides 
Monoclonal Gammopathy of Undetermined Significance (MGUS) 
Landgren et al. (2009) Nested Case-Control USA: Iowa and 
North Carolina Ever/never 0.5 (0.2-1.0) Age and education 
Hodgkin Lymphoma (HL) 
Karunanayake et al. 
(2012) Case-Control Canada Ever/ never 0.99 (0.62-1.56) Age group, province of residence, and 
statistically significant medical history 
variables 
Orsi et al. (2009) Case-Control France Ever/ne ver 1.7 (0.6-5.0) Age, centre , and socioeconomic category 
Non-Hodgkin Lymphoma (NHL) 
De Roos et al. (2005) Prospective Cohort USA: Iowa and 
North Carolina Ever/never 1.1 (0.7-1.9) Age, demographic and lif estyle factors, and 
other pesticidesb 
Cumulative Exposure Days 
(by tertile cut points): 
1-20 
21-56 
57-2,678 1.0 
0.7 (0.4-1.4) 
0.9 (0.5-1.6) Age, demographic and lif estyle factors, and 
other pesticidesb 
Intensity-Weighted C umulative Exposure 
Days 
(by tertile cut points): 
0.1-79.5 
79.6-337.1 
337.2-18,241 1.0 
0.6 (0.3-1.1) 0.8 (0.5-1.4) Age, demographic and lif estyle factors, and 
other pesticides
b 
De Roos et al. (2003) Case-Control USA: Iowa, 
Nebraska, 
Minnesota, and 
Kansas Ever/never 1.6 (0.9-2.8) Age, stu dy site, and use of other pest icides 
Eriksson et al. (2008) Case-Control Sweden Ever/never Multivariate: 
1.51 (0.77-2.94) Age, sex, year of dia gnosis or enrollment, 
and exposure to other pesticides 
Days per year of use: 
≤ 10 days 
>10 days 1.69 (0.70-4.07) 
2.36 (1.04-5.37) Age, sex, and year  of diagnosis or 
enrollment 
Years of use: 
1-10 years 
>10 years 1.11 (0.24-5.08) 2.26 (1.16-4.40) Unknown 
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  Table 3.4. Summary of Findings : Non-Solid Tumor Cancer Studies. 
Study Study Design Study Location Exposure Metric Adjusted Effect Estimate: 
RR or OR (95% CI)a Covariate Adjustments in Analyses 
Hardell et al. (2002) Case-Control Sweden Ever/never Multivariate: 
1.85 (0.55-6.20) Study, study area, vit al status, and exposure 
to other pesticides 
McDuffie et al.  (2001) Case-Control Canada Ever/never 1.20 (0.83-1.74) Age, province of residence, and statistically 
significant medical variables 
Days per year of use: 
>0 and ≤ 2 days 
>2 days 1.00 (0.63-1.57) 
2.12 (1.20 -3.73) Age and province of residence 
Orsi et al.  (2009) Case-Control France Ever/ never 1.0 (0.5-2.2) Age, centr e, and socioec onomic category 
a Some studies report multiple quantitative risk measurements. This table reports the most hi ghly adjusted qua ntitative measur ements.
	
b De Roos et al. (2005) excluded subjects missing c ovariate data for demographic  and lifestyle factors and exposure to other pesticides; theref ore, the number of subjects included
	
in each analysis varies.
	
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 3.6 Discussion 
A total of 63 individual studies  were identified in the systematic review.  The data from 7 of 
these studies were used in pooled analyses by other studies; therefore, they were not subjected to 
detailed evaluation. Overall , 3 studies, 19 studies, and 34 studies were assigned high, moderate, 
or low rankings, respectively. A ll of the high and moderate quality studies were considered 
informative with regard to the  carcinogenic potential of glypho sate.  Additionally, the recently 
published analysis of the  AHS cohort (Andreotti et al. , 2017) was also considere d as part of this 
evaluation. 
There was no evidence of an association between glyphosate expo sure and solid tumors, 
leukemia, or HL.  These conclusi ons are consistent with those r ecently conducted by IARC, 
EFSA, and JMPR who also concluded t here is no evidence of an as sociation for these tumors at 
this time.  The data should be  considered limited though with o nly one or two studies available 
for almost all of the cancer t ypes investigated.  The remainder  of this discussion focuses on 
multiple myeloma and NHL.  Study elements for the available stu dies and their potential to 
impact effect estimates are examined; however, the discussion is applicable in most cases to all 
of the epidemiological studi es used in this evaluation. 
Multiple Myeloma 
Four studies were available ev aluating the association between glyphosate exposure and risk of 
multiple myeloma in the initial evaluation presented to the SAP  in December 2016 (Brown et al., 
1993; De Roos et al ., 2005; Orsi et al., 2009; Pahwa et al., 2012).  Since that time, a recent 
analysis of the AHS cohort ha s been published (Andreotti et al. , 2017), which included 
evaluation of multiple myeloma.  One reanalysis (Sorahan, 2015)  and one extended analysis 
(Kachuri et al., 2013) were also included in the e valuation.  The effect estimates for ever/never 
use ranged from 1.19 to 2.6 although none were found to be stat istically significant.  Only one 
study (De Roos et al ., 2005) adjusted for co-exposures to other pestic ides; therefo re, potential 
confounding was not addressed in t he other studies.  There was an indication of a possible 
exposure-response relationship; however, this was the only study that evaluated the exposure-
response relationship for multiple myeloma.  Reanalysis of the full dataset by Sorahan (2015) 
raised concerns about whether the restricted dataset used for t hese analyses was representative of 
the whole cohort.  Furthermore, in the recent analysis of the A HS cohort (Andreotti et al. , 2017) 
with a longer follow-up period and almost 5 times more exposed cases, there was no evidence of 
an association between glyphosate exposure and risk of multiple  myeloma.  There was a single 
study of MGUS, a precursor to multiple myeloma, which showed de creased risk with exposure 
to glyphosate; however, the study d id not adjust for exposure t o other pesticides.  Overall, the 
available evidence does not link glyphosate exposure to multipl e myeloma. 
NHL 
Six studies were available eval uating the association between g lyphosate exposure and risk of 
NHL in the initial evaluation pr esented to the SAP in December 2016.  Since that time, a recent 
analysis of the AHS cohort ha s been published (Andreotti et al. , 2017), which included 
evaluation of NHL. Effect estimates for ever/never use ranged from 1.0-1.85 in adjusted 
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 analyses with none reaching statis tical significance (Figure 3. 2).  Two of these studies did not 
adjust for co-exposures to other pesticides (McDuffie et al., 2001; Orsi et al., 2009). Many of 
the evaluated studies were limited by small sample sizes, which  resulted in large confidence 
intervals and reduced the relia bility of the results to demonst rate a true association.  Meta-
analyses were performed by IARC (2015) and Chang and Delzell (2 016) using these results for 
the ever/never use metric.  Both a nalyses reported similar meta -risk ratios ranging from 1.3-1.5, 
depending on the effect estimates a nd studies included in the a nalyses.  Any of the meta-analysis 
estimates that were statistically significant were all borderli ne with the lower limit of the 95% CI 
just slightly over 1. For example, the lower 95% confidence li mit reported by IARC (2015) was 
1.03 and the lower 95% confidence li mit displayed in Figure 3.2 generated by the agency is 1.01.  
It should also be noted that publi cation bias may play a role i n this evaluation given there is a 
tendency to only publish positive results and potential concern s regarding glyphosate have only 
been raised in recent years. 
With respect to meta-analyses , caution should be taken when int erpreting results.  Meta-analyses 
are a systematic way to combine  data from several studies to es timate a summary effect.  
Analyses were performed with 6 studies, which many would consid er small for performing meta-
analyses. Rarely will meta-analyses synthesize data from studi es with identical study designs 
and methods.  In the meta-analyses  performed by IARC (2015) and  Chang and Delzell (2016), 
inclusion was primarily based on w hether a study addressed the broader question regarding the 
association between glyphosate exposure and risk of NHL.  For m eaningful results, careful 
consideration of whether studies are similar and should be comb ined in the analysis.  
Furthermore, the bias and conf ounding issues inherent for each individual study are carried over 
into the meta-analyses.  Across the NHL studies, study characte ristics varied, such as overall 
study design (i.e., cohort and cas e-control), source population , proxy respondent use, covariate 
adjustments, and confounding contro l.  Even if these difference s are not detected s tatistically, the 
meta-analysis estimate should be  considered in the context of t he data that are used to generate it.   
Using cumulative lifetime and intensity-weighted cumulative exp osure metrics, all effect 
estimates were less than 1 (OR  = 0.6-0.9 when comparing to the lowest tertile) in the AHS 
cohort study (De Roos et al. , 2005). Similar results were obtained in the recent analysis of the 
AHS cohort (Andreotti et al. , 2017). Two case-control studies (Eriksson et al., 2008; McDuffie 
et al., 2001) evaluated the association of glyphosate exposure and N HL stratifying exposure by 
days per year of use. These studi es obtained effect estimates greater than 1, which conflicted 
with the results in the prospect ive cohort study; however, thes e estimates from the case-control 
studies do not appear to be adjus ted for co-exposures to other pesticides.  By dividing the total 
number of exposed cases and controls by these exposure metrics in Eriksson et al. (2008), wider 
confidence intervals were observed due to small sample sizes, which reduces the reliability of the 
results to demonstrate a true association.  Furthermore, as men tioned previously (and will be 
discussed further below), there  was clearly strong potential fo r confounding from exposure to 
other pesticides. In each instance where a study adjusted for co-exposure to other pesticides, the adjusted effect estimate decrea sed in magnitude, including othe r analyses performed in one of 
these case-control studies. Consequently, lack of adjustment f or co-exposure to other pesticides 
in these analyses could parti ally explain the conflicting resul ts between the cohort and case-
control studies. 
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Figure 3.2.  Forest plot  of effect estimates (denoted as ES for  effect sizes) and associated 95% confidence 
intervals (CI) for non-Hodgkin lymphoma (NHL). 
The possible effect of confounding factors, which are related t o both the exposure of interest and 
the risk of disease, may make it difficult to interpret the results.  Control for confounding varied 
considerably across studies (Ta ble 3.2).  Studies primarily adj usted for standard variables, such 
as age, gender, and residency location. Co-exposure to other pesticides was considered for several of the NHL studies f or ever/never use (De Roos et al. , 2003; De Roos et al. , 2005; 
Eriksson et al., 2008; Hardell et al., 2002); however, analyses of e xposure-response and latency 
effects did not appear to adjust for these co-exposures.  The r ecent analysis by Andreotti et al. 
(2017) also adjusted for co-exposure to other pesticides.  
There is clearly a strong poten tial for confounding by co-expos ures to other pesticides since 
many are highly correlated and have been reported to be risk factors for NHL.  In the studies that 
did report a quantitative measure adjusted for the use of other pesticides, the risk was always found to be closer to the null than the risk calculated prior to this adjustment.  For examples, Eriksson et al. (2008) reported unadjusted and adjusted effect estimates of 2 .02 (95% CI: 1.10-
3.71) and 1.51 (95% CI: 0.77-2.94), respectively.   Comparing the magnitude of those effect sizes 
on the natural log scale, the unadjusted effect was β=0.70 (95%  CI: 0.10, 1.31) while the 
adjusted effect was β=0.41 (95% CI: -0.26, 1.08), suggesting a difference compatible with a 
degree of confounding by those herbicide co-exposures which appeared to have inflated the unadjusted effect upwards by 70% o n the natural log scale (or b y 46% on the OR scale).  This 
demonstrates the profound effect this adjustment has on effect estimates and the concern for 
residual confounding by other pesticides that cause NHL themselves.  As discussed in Section 3.2.4, other potential confounders have also been identified. With an association between 
glyphosate exposure and the outcome of interest, occupational e xposure to diesel exhaust fumes, 
solvents, livestock and other farm animals, and UV radiation ar e highly likely confounders in the 
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 NHL studies; however, none of the s tudies accounted for these p otential confounders.  These 
confounders and/or other unknown fac tors could explain the incr eased risk of NHL among 
farmers, particularly since increased risk of NHL to farmers has been previously documented and 
existed prior to the i ntroduction of glyphosate. 
Recall bias and missing data are also limitations in most of th e studies.  In epidemiologic studies, 
the quality of the exposure assessment is a major concern since  the validity of the evaluations 
depends in large part on the ability to correctly quantify and classify an indivi dual’s exposure.  
Variation in the quality of e xposure assessment, study design and methods, as well as available 
information concerning potential  confounding variables could al so explain discrepancies in study 
findings. During their lifetime, f armers are typically exposed  to multiple pesticides and often 
several may be used together posi ng a challenge for identifying  specific risk factors.  Moreover, 
there is no direct information on pe sticide exposure or absorbe d dose because analyses are based 
on self-reported pesticide use. The studies included in this e pidemiology assessment relied 
primarily on questionnaires and int erviews to describe particip ants’ past and/or current exposure 
to glyphosate. Since the questi onnaires are commonly used to a ccount for exposure and capture 
self-reporting, the results ca n be subject to misclassification  and recall bias.    
Furthermore, the use of proxy res pondents has the potential to increase recall bias and thus may 
increase exposure misclassification, especially for proxy respo ndents not directly involved in 
farming operations that may be more prone to inaccurate respons es than directly interviewed 
subjects. In some of the NHL studies, the study participants were interviewed directly to assess exposure (De Roos et al. , 2005; Eriksson et al. , 2008; McDuffie et al. , 2001; Orsi et al. , 2009), 
making proxy respondent use a non-issue for these studies.  In other studies, however, study 
participants or proxy respondents were interviewed to assess ex posure (Hardell et al. , 2002, De 
Roos et al. , 2003). De Roos et al.  (2003) did not find type of res pondent to be statistically 
significant, but Hardell et al. (2002) did not conduct analyses to evaluate the impact of pro xy 
use. In non-NHL studies, proxy analyses were conducted in a sm all subset (Kachuri et al. , 2013; 
Lee et al., 2004b; Lee et al.,  2005; Yiin et al. , 2012) and differences in effect estimates were 
often observed. In a few studies, respondent type was used as an adjustment variable when 
calculating effect estimates (Band et al. , 2011; Kachuri et al.,  2013; Lee et al. , 2005). As with 
all study design elements of case- control studies, one concern is whether or not the use of proxy 
respondents had a differential impact on the cases and controls  included in the study because any 
differential impact may result in differential exposure misclas sification.  When use of proxy 
respondents was comparable for cases and controls in the full s tudy population, it could be 
assumed that there is less con cern for potential recall bias from the use of proxy respondents.  In 
Hardell et al., (2002), the percentage of cases  and controls with proxy respondents was not fully 
reported for cases and controls though and this adds a potentia l source of uncertainty for the 
study. Moreover, when proxy respo ndents were used in a study, the percentages were usually 
reported only for the full study population and were not reported for the specific cases and controls exposed to glyphosate. T his lack of information makes  it difficult to assess the degree 
to which recall bias may have  occurred due to the use of proxy respondents.   
Previously, some have argued that the follow-up period (median = 7 years) in De Roos et al . 
(2005) is not sufficiently long to account for the latency of N HL (Portier et al., 2016); however, 
an analysis of the AHS cohort was recently published (Andreotti et al., 2017) with an extended 
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 follow-up of 17.5 years. This st udy reported no association be tween glyphosate exposure and all 
lymphohematopoietic cancers, NHL, or any of its subtypes across exposure metrics.  No 
association was observed in unlagged or lagged analyses, after adjustment for pesticides linked 
to NHL in previous AHS analyses, and after exclusion of multiple myeloma from the NHL grouping. 
It was also noted that referen ce groups differed across studies .  For example, some studies 
(McDuffie et al., 2001; Hardell et al., 2002; and Eriksson et al., 2008) eliminated cases and 
controls who had been exposed to cer tain classes of  pesticides,  which may have resulted in 
selection bias and/or recall bias that may ultimately impact the effect estimates obtained in these 
studies. In the dose-resp onse analysis by De Roos et al. (2005), the lowest exposed tertile was 
used as the reference group in an effort to reduce the potential for residual confounding by unmeasured covariates due to lac k of comparability observed bet ween the never exposed group 
and the higher exposed groups. A nalyses were also performed using the unexposed group as the 
reference. This study consist ently found no evidence of an ass ociation between glyphosate 
exposure and NHL using different e xposure metrics and reference  groups.  Similarly, there was 
no evidence of an association observed in the recent analysis o f the AHS cohort (Andreotti et al. , 
2017) with a longer follow-up period. 
There are conflicting views on how  to interpret the overall res ults for NHL.  Some believe that 
the data are indicative of a potential association between glyp hosate exposure and risk of NHL.  
This is primarily based on reported effect estimates across cas e-control studies and the associated 
meta-analyses greater than 1.  A dditionally, the analysis conducted by Eriksson et al. (2008) 
observed a slightly statisticall y significant increase for thos e with more than 10 years of exposure 
prior to diagnosis. There were al so two case-control studies t hat investigated the association of 
glyphosate exposure and NHL by stratifying exposure by days per  year of use that reported 
effect estimates greater tha n 1 for groups with the highest exp osure. 
Conversely, others have viewed the  effect estimat es as relatively small in magnitude and 
observed associations could be e xplained by chance and/or bias,  particularly since studies have 
reported farmers develop NHL at ex cess rates and this risk existed prior to the introduction of 
glyphosate. All of the effect est imates for ever/never use wer e non-statistically significant.  
Several studies reported effect e stimates approximately equal t o the null.  The widest confidence 
intervals were observed for the  highest effect estimates indica ting these effect estimate are less 
reliable. Sample sizes were limited in several of these case-c ontrol studies.  Meta-analyses were 
based on studies with varying study characteristics.  Given the  limitations and concerns 
discussed above for the individua l studies included in this eva luation, chance and/or bias cannot 
be excluded as an explanation for the relatively small increase  observed in the meta-risk ratios.  
Meanwhile, analyses performed by De Roos et al.  (2005) and Andreotti et al. (2017) reported 
effect estimates less than 1 for  cumulative lifetime exposure and intensity-weighted cumulative 
exposure and these extensive a nalyses did not detect any exposure-response relationship, which 
conflicts with the two case-control studies that indicate poten tial for an exposure-response 
relationship comparing two groups  stratified by days per year o f use.  Although increased effect 
estimates were observed in one case-control study (Eriksson et al., 2008) for subjects exposed 
more than 10 years prior to dia gnosis and in two case-control s tudies (McDuffie et al ., 2001; 
Eriksson et al ., 2008) that stratified exposur e by days per year of use, none  of these analyses 
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  appeared to adjust for exposures to other pesticides, which has  been found to be particularly 
important for these analyses and would be expected to attenuate  these estimates towards the null.  
Furthermore, none of the studies  in this evaluation of glyphosa te exposure and risk of NHL 
accounted for other potential c onfounders, such as diesel exhau st fumes, solvents, animals, and 
UV radiation. 
Based on the weight-of-evidence, t he agency cannot exclude chan ce and/or bias as an 
explanation for observed associ ations in the database.  Due to study limitations and contradictory 
results across studies of at least equal quality, a conclusion regarding the asso ciation between 
glyphosate exposure and risk of NHL cannot be determined based on the available data.  The 
agency will continue to monito r the literature for studies and any updates to the AHS will be 
considered when available. 
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 4.0 Data Evaluation of Animal Carcinogenicity Studies 
4.1 Introduction 
Cancer bioassays in animals have  historically been the primary studies available to evaluate 
cancer hazard in humans since, until recently, epidemiological evidence was limited.  The results 
of these bioassays, as well as res ults from screening assays fo r genotoxicity, are  considered in a 
weight-of-evidence approach to d etermine the potential of a chemical to induce cancer in 
humans.  Carcinogenicity studies i n two rodent species are required for the reg istration of food 
use pesticides or when the use of a pesticide is likely to resu lt in repeated human exposure over a 
considerable portion of the human lifespan (40 CFR Part 158.500 ).  Rodent carcinogenicity 
studies identified from the data  collection phase of the system atic review were evaluated for 
study quality and acceptable studies were evaluated in the cont ext of the 2005 EPA Guidelines 
for Carcinogen Risk Assessment as described in Sections 4.2 and  4.3 below, respectively.  This 
included studies using glyphosat e salts, which dissociate quick ly in aqueous environments to the 
glyphosate acid and the corres ponding cation.  The cations woul d not be expected to impact the 
toxicity results compared to studi es where animals are treated with glyphosate acid alone.       
4.2 Consideration of Study Quality fo r Animal Carcinogenicity Studi es 
The agency has published test  guidelines on how to conduct carc inogenicity studies (OCSPP 
870.4200) and combined chronic/carci nogenicity studies (OCSPP 8 70.4300) in rodents which 
have been harmonized with OECD guidelines (Test Nos. 451 and 453).  Test substances are 
typically administered in anima l carcinogenicity studies by the oral route for food use pesticides.  
The studies are generally conducted in mice and rats with expos ure durations of 18-24 months 
for mice and 24 months for rats, which represent exposures of t he majority of the expected 
lifespan in these animals.  Gui deline carcinogenicity studies a re designed to test three or more 
doses in both sexes (with at leas t 50 animals/sex/dose) with ad equate dose spacing to 
characterize tumor dose-respons e relationships.  Key considerat ions when evaluating 
carcinogenicity studies for cance r hazard assessment include id entification of target organs of 
carcinogenicity, increased incid ence of tumors or proportion of  malignant neoplasms, and 
reduction in the time to appearance of tumors relative to the c oncurrent control group (OECD 
TG 451). 
There are a number of criteria the agency uses when evaluating the technical adequacy of animal 
carcinogenicity studies. A prim ary criterion is the determinat ion of the adequacy of dosing.  The 
2005 EPA Guidelines for Carcinoge n Risk Assessment recommends t hat the highest dose level 
selected should elicit signs of toxicity without substantially altering the normal life span due to 
effects other than tumors; or w ithout inducing in appropriate to xicokinetics (e.g., overwhelming 
absorption or detoxification mech anisms); however, the high dose need not exceed 1,000 
mg/kg/day (i.e., limit dose) (OCSPP 870.4200; OCSPP 870.4300). Additional criteria to judge 
the technical adequacy and accep tability of animal carcinogenic ity studies are provided in the 
test guidelines as well as other published sources (NTP, 1984; OSTP, 1985; Chhabra et al., 
1990). As stated in the 2005 EPA G uidelines for Carcinogen Ris k Assessment, studies that are 
judged to be wholly inadequate in pr otocol, conduct or results, should be discarded from 
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      analysis. Studies the agency cons ider acceptable are further evaluated for potential tumor 
effects. 
Following study quality evaluation, a total of 8 chronic/carcin ogenicity studies in the rat and 6 
carcinogenicity studies in the m ouse were considered acceptable  for use in the current evaluation 
for the active ingredient glyphos ate and were subsequently evaluated in the context of the 2005 
EPA Guidelines for Carcinogen R isk Assessment as described in S ection 4.3.  A number of 
studies were judged to be inade quate in protocol, conduct or re porting and were not considered 
in the analysis of glyphosate. T hese studies and the justifica tion for not including them in the 
analysis are listed below: 
1.		A two-year chronic oral toxicit y study in Albino rats by Reyna (1974)13. The study 
was considered inadequate to a ssess carcinogenicity due to insufficient reporting on 
the histopathology findings in t he control and treatment groups. Approximately 70 
animals were unaccounted for across the study.  
2.		A two-year drinking water study in  Wistar rats with a formulate d product (13.6% 
ammonium salt) by Chruscielska et al. , (2000). In addition to defi ciencies including 
inadequate reporting of water  consumption and body weight data, this study was 
conducted with a glyphosate formulated product and not the acti ve ingredient 
glyphosate, which is the focus of  this review. Glyphosate formulations contain 
various components other than glyphosate and it has been hypoth esized these 
components are more toxic than g lyphosate alone.  The agency is collaborating with 
NTP to systematically investigate the mechanism(s) of toxicity for glyphosate and 
glyphosate formulations. This project is discussed in more deta il in Section 7.0 of 
this document. 
3.		An initiation-promotion study (George et al. , 2010) in male Swiss mice that tested a 
commercial formulation of glyphos ate (41%) on the skin.  Study deficiencies 
included small number (20) of a nimals, tested only males, and l ack of 
histopathological examination. 
4.		A carcinogenicity study in S wiss albino mice (Kumar, 2001)14. This study was not 
included due to the presence of a  viral infection within the colony, which confounded 
the interpretation of the study fi ndings. Malignant lymphomas w ere reported in this 
study in all dose groups. However, lymphomas are one of the mo st common types of 
spontaneous neoplastic lesi ons in aging mice (Brayton et al., 2012). Murine 
leukemia viruses (MuLVs) are also a common cause of lymphoma in  many different 
strains of mice (Ward, 2006). For example, Tadesse-Heath et al. (2000) reported 
50% lymphoma (mostly B-cell orig in) incidence in a colony of Sw iss mice infected 
with MuLVs. Although the lymphoma incidences in Kumar (2001) were within or 
near normal background variation, it is not clear whether or no t the viral infection 
may have contributed to the lymphoma incidence reported or the lower survival seen 
at the high dose in this study. 
13 MRID 00062507. 
14 MRID 49987403. In Greim et al. (2015), the same study is cited as Feinchemie Schwebda (2001).
	
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 5.		A two year feeding study in Sprague-Dawley rats (Excel, 1997) w as not included. 
The agency does not have access to this study to perform an ind ependent assessment 
of its conduct and; however, Greim et al. (2015) stated that th e study “is considered 
unreliable for carcinogenicity eva luation” and there were “several deviations from 
the OECD Test Guideline 453”. 
4.3  Assessment of Animal Ca rcinogenicity Studies 
The agency considers many factors when interpreting the results  of carcinogenicity studies.  
The 2005 EPA Guidelines for Carcinogen Risk Assessment are inte nded as a guidance only and 
does not provide a checklist for determining whether tumor find ings are related to treatment.   
These guidelines emphasize the importance of weighing multiple lines of evidence in reaching 
conclusions regarding human carci nogenic potential of chemicals .  Evaluation of observed 
tumor findings takes into c onsideration both biological and sta tistical significance.  There are 
several factors in the 2005 EPA  Guidelines for Carcinogen Risk Assessment used in the weight-
of-evidence evaluation of indivi dual studies.  For this evaluat ion, the interpretation of the 
evidence related to tumor fi ndings is described below.       
Dose Selection 
Doses should be selected based on relevant toxicological inform ation.  Caution is taken in 
administering an excessivel y high dose that would confound the interpretation of the results to 
humans.  As mentioned above, the 2005 EPA Guidelines for Carcin ogen Risk Assessment 
recommends that the highest dos e level selected should elicit signs of toxicity without 
substantially alteri ng the normal life span due to effects other than tumors; or without inducing 
inappropriate toxicokinetics (e.g., overwhelming absorption or detoxification mechanisms); 
however, the high dose is not recommended to exceed 1,000 mg/kg /day (OCSPP 870.4200; 
OCSPP 870.4300). Doses should provide relevant dose-response d ata for evaluating human 
hazard for human health risk assessment.  In the case of glypho sate, the low (oral) systemic 
toxicity and limited pharmacokinetic  (PK) data for this chemica l make it difficult to define a 
maximum tolerated dose (MTD) for the cancer bioassays.  A large  number of the 
carcinogenicity studies conducte d with glyphosate approach or exceed the limit dose.  The 2005 
EPA Guidelines for Carcinogen Risk Assessment state that “weigh ing of the evidence includes 
addressing not only the likeli hood of human carcinogenic effect s of the agent but also the 
conditions under which such effects may be expressed”.  As such, the agency puts less weight 
on observations of increased incid ence of tumors that only occu r near or above the limit dose. 
Statistical analyses to evaluate dose response and tumor incidences 
The main aim of statistical evalu ation is to determine whether exposure to the test agent is 
associated with an increase in t umor development, rather than d ue to chance alone.  Tumors 
were selected for statistical analyses in the current evaluatio n if the study report identified 
tumors as statistically significant and/or have been identified by the reviewer as potentially biologically significant based on the presence of an increasing  monotonic dose-response and/or 
relative increases from concurre nt controls. For toxicological  studies submitted to the agency 
for pesticide registration, inc luding animal carcinogenicity st udies, detailed reviews are 
performed, which summarize stud y findings and identify effects,  such as tumors, for evaluation. 
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  Statistical analyses should be performed on each tumor type sep arately.  The incidence of 
benign and malignant lesions of t he same cell type, usually within a single tissue or organ, are 
considered separately, but may be  combined when scientifically defensible (McConnell et al., 
1986). Trend tests and pairwise co mparison tests are the recom mended tests for determining 
whether chance, rather than a t reatment-related effect, is a pl ausible explanation for an apparent 
increase in tumor incidence .  The 2005 Guidelin es for Carcinoge n Risk Assessment states that:  
“A trend test such as the Cochra n-Armitage test (Snedecor and C ochran, 1967) asks whether the 
results in all dose groups togeth er increase as dose increases.   A pairwise comparison test such 
as the Fisher exact test (Fishe r, 1950) asks whether an inciden ce in one dose group is increased 
over that of the control group. By convention, for both tests a statically significant comparison 
is one for which p is less than 0.05 that the increa sed incidence is due to chanc e.  Significance 
in either kind of test is suffici ent to reject the hypothesis that chance accounts for the result.” 
In the current evaluation, anima ls sacrificed for interim evalu ations or died prior to the interim 
sacrifices were not included in the statistical evaluations to avoid dilution of a potential 
carcinogenic effect. Additionally, survival was evaluated acro ss dose groups and no significant 
mortality differences were obser ved in any of the studies.  As a result, there was no need to 
incorporate survival adjustmen ts into the analyses (e.g., Peto prevalence test).  The Cochran-
Armitage Test for Trend (Snedecor and Cochran, 1967; one-sided)  was used for trend analysis.  
For pairwise comparisons, the F isher Exact Tes t (Fisher, 1950; one-sided) was used to 
determine if incidences observe d in treated groups were differe nt from concurrent controls.  
Furthermore, the 2005 EPA Guidelines for Carcinogen Risk Assessment state that 
“considerations of multiple comparisons should also be taken in to account”.  Multiple 
comparison methods control the fami lywise error rate, such that the probability of Type I error 
(incorrect rejection of the null  hypothesis or “false positive” ) for the pairwise comparisons in 
the family does not exceed the al pha level.  In the current eva luation, the Benjamini-Hochberg 
correction method was used to adjust for multiple comparisons (Benjamini and Hochberg, 1995). 
For the current evaluation, stati stical significance observed i n either test is judged in the context 
of all of the available eviden ce.  Statistically significant re sponses may or may not be 
biologically significant and vi ce versa (Hsu and Stedeford, 201 0; EPA, 2005).  If a trend was 
found to be statistically signifi cant, a closer examination of the tumor incidence was taken to 
determine whether the data dem onstrate a monotonic dose-response where an increase in tumor 
incidence is expected with co rresponding increase in dose.  Therefore, statistically significant 
results with fluctuating tumor i ncidence across doses are not w eighed as heavily as those 
displaying a monotonic dose-respons e.  If a pair-wise compariso n was found to be statistically 
significant, a closer examinati on of the tumor incidence and other lines of evidence was taken 
to determine whether the respons e was biologically significant.   Factors considered in 
determining the biological rele vance of a response are discusse d below.  
All statistical analyses were r eanalyzed for the purposes of this evaluation to ensure consistent 
methods were applied (M. Perron; 12-DEC-2017; TXR#0057690).   
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 Historical Control Data 
As indicated in the 2005 EPA Guid elines for Carcinogen Risk Ass essment (Section 2.2.2.1.3), 
the standard for determining sta tistical significance of tumor incidence comes from a comparison 
of tumors in dosed animals with those in concurrent control ani mals. Additional insight into the 
statistical and/or biological significance of a response can co me from the consideration of 
historical control data (Tarone, 1982; Haseman, 1995; EPA, 2005 ).  Historical control data can 
add to the analysis, particula rly by enabling id entification of  uncommon tumor types or high 
spontaneous incidence of a tumor  in a given animal strain.  Gen erally speaking, statistically 
significant increases in tumo rs should not be discounted simply  because incidence rates in the 
treated groups are with in the range of historical controls or b ecause incidence rates in the 
concurrent controls are somew hat lower than average.    
Historical control data are also useful to determine if concurr ent control tumor incidences are 
consistent with previously reported tumor rates (Haseman, 1995).  Historical control data 
available to the agency from th e performing laboratory for the same species and strain for a study 
were considered in the current evaluation.  These data were primarily generated within 3 years and in limited cases within 5 year s of the study date.  Given t he large number of age-related 
tumor outcomes in long-term rodent bioassays, and thus the large number of potential statistical tests run, caution is taken when interpreting results that have marginal statistical significance or in which incidence ra tes in concurrent controls are unusually l ow in comparison with historical 
controls since there may be an a rtificial inflation of the diff erences between concurrent controls 
and treated groups. Consequently, in the current evaluation, u nusually low incidence in 
concurrent controls was noted w hen applicable and considered as  part of the weight-of-evidence 
for the tumor findings.  Identif ication of common or uncommon s ituations prompts further 
thought about the meaning of the r esponse in the current study in context with other observations 
in animal studies and with other evidence about the carcinogenic potential of the agent. 
Evidence of supporting preneoplastic lesi ons or related non-neoplastic lesions 
Carcinogenicity rodent studies a re designed to examine the prod uction of tumors as well as 
preneoplastic lesions and other indications of chronic toxicity  that may provide evidence of 
treatment-related effects and ins ights into the way the test ag ent produces tumors (EPA, 2005).  
As such, the presence or lack of supporting preneoplastic or ot her related non-neoplastic 
changes were noted in the current evaluation of each study and considered in the weight-of-
evidence to aid in the determin ation of biological significance  since these lesions would not be 
expected for age-related tumors in carcinogenicity with continu ous treatment.  In the current 
evaluation, the agency investigated  lesions in organs where tum ors were observed and 
demonstrated biological signi ficance based on the presence of a n increasing monotonic dose-
response and/or relative increa ses from concurrent controls.  
Additional Considerations 
Other observations can strengthe n or lessen the significance of  tumor findings in carcinogenicity 
studies. Such factors include: unc ommon tumor types; tumors a t multiple sites; tumors in 
multiple species, strains, or both sexes; progression of lesions from preneoplastic to benign to 
malignant; reduced latency of ne oplastic lesions (i.e., time to  tumor); presence of metastases; 
unusual magnitude of tumor res ponse; and proportion of malignan t tumors (EPA, 2005).  The 
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   agency considers all of the above  factors when determining the significance of tumor findings in 
animal carcinogenicity studies.  
4.4 Summary of Animal Carcinogenicity Studies 
A total of 8 chronic t oxicity/carcinogenici ty studies in the ra t15 and 6 carcinogenicity studies in 
the mouse were considered acceptable and evaluated in the weigh t-of-evidence analysis for 
glyphosate. This includes all of  the studies that were part of  the 2015 CARC evaluation plus an 
additional 4 studies identified f rom the systematic review.  In  the 2015 CARC evaluation, for 
some of the studies considered, the CARC relied on summary data that was provided in the 
supplement to the Greim et al. (2015) review article. Due t o the ongoing data collection ef fort 
and the acquiring of studies not previously submitted, the agen cy no longer needs to rely on the 
Greim et al. (2015) review article for the study data generated in relevan t studies, allowing for a 
more complete and independent a nalysis.  It should be noted tha t studies have been cited 
differently in this evalua tion as compared to Greim et al . (2015) so these alternative citations 
have been noted for applicable studies. 
The carcinogenicity studies c onducted in the rat and mouse that were considered for the analysis 
are discussed in Sections 4.5 and 4.6, respectively. In these sections, short study summaries are 
presented which include infor mation on the study design (includ ing test material, strain of animal 
used, and doses and route of administration) as well as study f indings including effects on 
survival, general toxicity observed, relevant non-neoplastic le sions, and the incidence and 
characterization of any tumor fi ndings.  The characterization of the tumor response(s) is based on 
the considerations previousl y discussed in Section 4.3 for interpreting the significance of tumor 
findings in animal carcinogenici ty studies.  The rat and mouse carcinogenicity studies are all 
summarized in Table 4.11 and Table 4.18, respectively.   
4.5 Rat Carcinogenicity Studies with Glyphosate 
4.5.1 Lankas, 1981 (MRID 00093879)16 
In a chronic toxicity/carcinogenicity study, groups of Sprague-Dawley rats (50/sex/dose) were 
fed diets containing glyphosate (98.7%, pure) at dietary doses of 0, 3/3, 10/11, and 31/34 
mg/kg/day (M/F) for 26 months. 
There were no treatment-relate d effects on survival at any dose  level.  The highest dose tested of 
approximately 31 mg/kg/day was not considered a maximum tolerab le dose to assess the 
carcinogenic potential of glyphos ate.  Consequently, a second study (Stout and Ruecker, 1990) 
was conducted at higher doses, whi ch is summarized in the Secti on 4.5.3. 
A statistically significant tre nd was reported for the testicul ar interstitial tum ors; however, closer 
examination of the tumor inciden ce indicates that the data do n ot demonstrate a monotonic dose 
response with greater incidence  observed at the low-dose as com pared at the mid-dose.  The 
15 Note: the original draft of this Issue Paper included 9 studie s in rats; however, one stu dy (Burnett, 1979) was 
removed since the study was conducted with a contaminant of gly phosate, not the active ingredient glyphosate. 
16 In Greim et al.  (2015), the same study is c ited as Monsanto (1981). 
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     incidence at the high dose was f ound to be statistically signif icant as compared to the concurrent 
controls (raw and adjusted p-values). 
Table 4.1. Testicular Interstit ial Cell Tumors in Male Sprague -Dawley Rats (Lankas, 1981) 
Cochran-Armitage Trend Test & F isher’s Exact Test Results. 
0 mg/kg/day 3.05 mg/kg/day 10.3 mg/kg/day 31.49 mg/kg/day 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 0/47a 
(0) 
0.011** 
0.032* 3/49 
(6) 
0.129 
0.172 1/47 
(2) 
0.500 0.500 6/50 
(12) 
0.016* 0.032* 
Note: Trend test results denoted  at control ; * denotes signific ance at p=0.05; ** denotes s ignificance at p=0.01. 
a. Number of tumor-bearing animals/Number of animals examined, excluding those that die d or were sacrificed 
prior to study week 52 (interim sacrifice). 
The study report provided historic al control information for 5 studies of similar duration (24-29 
months) run concurrently withi n 9 months of the termination of the study in the same laboratory.  
The historical control range for  this tumor type was 3.4%-6.7% (mean = 4.5%) when considering 
all animals. When only considering animals that survived to ter minal sacrifice, the historical 
control range was 6.2%-27.3% (mean = 9.6%).  These data indicat e that the incidence of 
testicular cell tumors in concu rrent controls (0%) appears to b e unusually low for this tumor 
type. Furthermore, the inciden ce at all doses, including the h igh dose, was within the historical 
control range when evaluating ani mals at terminal sacrifice.  T here were no supporting 
preneoplastic or other related non -neoplastic changes observed. 
4.5.2 Stout and Ruecker, 1990 (MRID 41643801)17 
In a chronic toxicity/carcinogenicity study, groups of Sprague-Dawley rats (60/sex/dose) were 
fed diets containing glyphosate (96.5%, pure) at dietary doses of 0, 89/113, 362/457 or 940/1183 
mg/kg/day M/F) for 24 months. T he highest dose tested in this study approaches or exceeds the 
highest dose recommended in the  test guidelines on how to condu ct carcinogenicity studies 
(OCSPP 870.4200 and OCSPP 870.4300).  Tum or findings at these high doses are given less 
weight. 
There was no significant increa se in mortality.  Three types of tumors were evaluated in this 
study: pancreatic cell adenomas, hepatocellular adenomas, and t hyroid C-cell adenomas in 
males.  A discussion of each tumor type by organ is presented b elow: 
1.		Pancreas: Tumor incidences of panc reatic islet cell tumors in m ale rats are presented in 
Tables 4.2. The incidence of panc reatic islet cell tumors lack ed monotonic dose-
responses and trend analyses were  not statistica lly significant .  There was also no 
statistical significance of the pa irwise comparisons.  Historical control data were 
provided for 7 studies conducted i n the same laboratory from 19 83-1989 (within 1-4 
years of when Stout and Ruecker (1990) was performed).  The his torical control range for 
the adenomas was 1.8%-8.3% (mean = 5.3%).  These data are prese nted in Table 4.3 and 
indicate that the incidence of  adenomas in concurrent controls (2%) was at the lower limit 
17 In Greim et al.  (2015), the same study is  cited as Monsanto (1990). 
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  of the historical range. There  were no supporting preneoplastic or other related non-
neoplastic changes observed and no evidence of progression from  adenomas to 
carcinomas.   
Table 4.2. Pancreatic Islet Ce ll Tumors in Male  Sprague-Dawley  Rats (Stout and Ruecker, 1990) 
Cochran-Armitage Trend Test & F isher’s Exact Test Results. 
Tumor Type 0 mg/kg/day 89 mg/kg/day 362 mg/kg/day 940 mg/kg/day 
Adenoma Incidence 1/43
a 8/45 5/49 7/48b 
(%) (2) (18) (10) (15) 
Raw p-value = 0.176 0.018* 0.135 0.042* 
Adjusted p-value = 0.176 0.071 0.176 0.083 
Carcinoma 
Incidence 1/43c 0/45 0/49 0/48 
(%) (2) (0) (0) (0) 
Raw p-value = -d -d -d -d 
Adjusted p-value = -d -d -d -d 
Combined 
Incidence 2/43 8/45 5/49 7/48 
(%) (5) (18) (10) (15) 
Raw p-value = 0.242 0.052 0.275 0.108 
Adjusted p-value =  0.275 0.209 0.275 0.215 
Note: Trend test results denoted  at control ; * denotes signific ance at p=0.05.   
a.Number of tumor-bearing animals/ Number of animals examined, ex cluding those that died or were 
sacrificed prior to study wee k 55 (interim sacrifice). 
b. First adenoma in the study was observed at week 81 in the 940 m g/kg/day group. 
c. First carcinoma in the study was  observed at week 105 in the co ntrols. 
d. Trend p-value not reported since tumor incidence decreased with  increasing dose. 
Table 4.3. Historical  Control Data — Pan creatic Islet Cell Ade nomas in Male Sprague- Dawley Rats (MRID No. 41728701). 
Study No. 1 2 3 4 5 6 7 Mean 
Study Year 07/83 02/85 10/85 6/85 9/88 1/89 3/89 -
Tumor Incidence 2/68 5/59 4/69 1/57 5/60 3/60 3/59 -
Percentage (%) 2.9% 8.5% 5.8% 1.8% 8.3% 5.0% 5.1% 5.3% 
2.		Liver: Tumor incidences of liver  tumors in male rats are presen ted in Tables 4.4.  There 
was a statistically significant dose trend for liver adenomas; however, the trend was not 
statistically significant with an adjustment for multiple compa risons.  Closer examination 
of the incidence indicates a rel atively flat response at the lo w- and mid-dose with only an 
increase observed at the high-dose (940 mg/kg/day); however, the incidence of liver adenomas at the high-dose was not statistically significant whe n compared to the 
concurrent controls (raw or adjusted p-values).  Carcinomas and  combined 
adenomas/carcinomas lacked statis tical significance in trend an d pairwise comparisons 
(Table 4.4). Historical contro l data were provided for 7 studi es conducted in the same 
laboratory from 1983-1989 (within 1 -4 years of when Stout and R uecker (1990) was 
performed).  The historical cont rol range was 1.4%-18.3% (mean = 9.2%) for the 
adenomas and 0%-6.7% for carcinomas (mean = 2.6%).  These data are provided in 
Table 4.5 and indicate that the ob served incidences at all dose  levels were within the 
historical control ranges. Excep t for a single animal at the m id-dose late in the study (89 
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 weeks), no hyperplasia, preneopl astic foci or other non-neoplas tic lesions were observed.  
Furthermore, there was no evide nce of progression from adenomas to carcinomas.   
Table 4.4. Hepatocellu lar Tumors in Male Sprague-Dawley Rats ( Stout and Ruecker, 1990) 
Cochran-Armitage Trend Test & F isher’s Exact Test Results 
Tumor Type 0 mg/kg/day 89 mg/kg/day 362 mg/kg/day 940 mg/kg/day 
Adenoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value =  2/44a 
(5) 
0.022* 
0.089 2/45 
(4) 
0.700 
0.700 3/49 
(6) 
0.551 0.700 7/48
b 
(15) 
0.101 0.202 
Carcinoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 3/44 
(7) 
-
d 
-d 2/45 
(4) 
-d 
-d 1/49 
(2) 
-d 
-d 2/48c 
(4) 
-d 
-d 
Combined 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 5/44 
(11) 
0.078 0.312 4/45 
(9) 
0.769 0.808 4/49 
(8) 
0.808 0.808 9/48 
(19) 
0.245 0.489 
Note: Trend test results denoted  at control; * denotes signific ance at p=0.05.   
a. Number of tumor-bearing animals/ Number of animals examined, exc luding those that died or were 
sacrificed prior to study wee k 55 (interim sacrifice). 
b. First adenoma in the study was observed at week 88 in the 940 m g/kg/day group. 
c. First carcinoma in the study was observed at week 85 in the 940  mg/kg/day group. 
d. Trend p-value not reported since tumor incidence decreased with  increasing dose. 
Table 4.5. Historical Control Data — Hepatocellular Tumors in Male Sprague- Dawley Rats (MRID No. 41728701). 
S t u d y N o . 1 2 3 4 5 6 7 M e a n 
Study Year 07/83 02/85 10/85 6/85 9/88 1/89 3/89 -
Adenomas 
Tumor Incidence 5/60 11/68 1/70 3/59 11/60 5/60 4/60 -
Percentage (%) 8.3% 16.2% 1.4% 5.1% 18.3% 8.3% 6.7% 9.2% 
Carcinomas 
Tumor Incidence 4/60 0/68 1/70 2/59 3/60 1/60 0/60 -
Percentage (%) 6.7% 0% 1.4% 3.4% 5% 1.7% 0% 2.6% 
3.		Thyroid: Tumor incidences of thyr oid tumors in male and female rats are presented in 
Tables 4.6 and 4.7, respectively. For males, no statistically significant trends were 
observed for adenomas, carcinomas , or combined adenomas/carcino mas.  For females, a 
statistically significant tre nd was observed for adenomas and combined 
adenomas/carcinomas; however, t he trend was not  statistically significant with 
adjustment for multiple comparis ons.  There was no statistical significance in pairwise 
analyses. Historical control data were provided for 7 studies conducted in the same 
laboratory from 1983-1989 (within 1 -4 years of when Stout and R uecker (1990) was 
performed).  The historical cont rol range was 3.3%-10% (mean = 6.1%) for the adenomas 
and 0%-2.9% for carcinomas (mean = 0.9%).  These data are provi ded in Table 4.8.  
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   Non-neoplastic lesions (thyroid C -cell hyperplasia) were observ ed; however, there was a 
lack of a monotonic dose-response for these histopathological f indings and no dose-
related increase in severity t o support tumor findings (Table 4.9).  There was also no 
evidence of progression from adenomas to carcinomas. 
Table 4.6. Thyroid C-Cell Tumors in Male Sprague-Dawley Rats ( Stout and Ruecker, 1990) 
Cochran-Armitage Trend Test & F isher’s Exact Test Results 
Tumor Type 0 mg/kg/day 89 mg/kg/day 362 mg/kg/day 940 mg/kg/day 
Adenoma 
Incidence 2/54a, b 4/55 8/58 7/58 
(%) (4) (7) (14) (12) 
Raw p-value = 0.079 0.348 0.060 0.099 
Adjusted p-value = 0.132 0.348 0.132 0.132 
Carcinoma 
Incidence 0/54 2/55c 0/58 1/58 
(%) (0) (4) (0) (2) 
Raw p-value = 0.457 0.252 1.000 0.518 
Adjusted p-value = 0.518 0.518 1.000 0.518 
Combined 
Incidence 2/54 6/55 8/58 8/58 
(%) (4) (11) (14) (14) 
Raw p-value = 0.087 0.141 0.060 0.060 
Adjusted p-value = 0.116 0.141 0.116 0.116 
Note: Trend test results  denoted at control . 
a.Number of tumor-bearing animals/ Number of animals examined, ex cluding those that died or were 
sacrificed prior to study wee k 55 (interim sacrifice). 
b. First adenoma in the study was observed at week 54 in the controls.  
c. First carcinoma in the study was observed at week 93 in the 89 mg/kg/day group. 
Table 4.7. Thyroid C-Cell Tumors in Female Sprague Dawley Rats Cochran-Armitage Trend Test & Fisher’s Exact Test Results (Stou t and Ruecker, 1990). 
Tumor Type 0 mg/kg/day 113 mg/kg/day 457 mg/kg/day 1183 mg/kg/d ay 
Adenoma Incidence 2/57
a 2/60 6/59b 6/55 
(%) (4) (3) (10) (11) 
Raw p-value = 0.040* 0.710 0.147 0.124 
Adjusted p-value = 0.159 0.710 0.196 0.196 
Carcinoma 
Incidence 0/57 0/60 1/59c 0/55 
(%) (0) (0) (2) (0) 
Raw p-value = 0.494 1.000 0.509 1.000 
Adjusted p-value = 0.509 1.000 0.509 1.000 
Adenoma/Carcinoma 
Incidence 2/57 2/60 7/59 6/55 
(%) (4) (3) (12) (11) 
Raw p-value = 0.042* 0.710 0.090 0.124 
Adjusted p-value = 0.166 0.710 0.166 0.166 
Note: Trend test results denoted  at control ; * denotes signific ant at p=0.05. 
a. Number of tumor-bearing animals/ Number of animals examined, exc luding those that died or were 
sacrificed prior to study wee k 55 (interim sacrifice). 
b. First adenoma in the study was observed at week 72 in the controls. 
c. First carcinoma in the study was observed at week 93 in the 457  mg/kg/day group. 
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   Table 4.8. Historical Control Data — Thyroid C-Cell Tumors in Female Sprague- Dawley Rats (MRID No. 41728701). 
S t u d y N o . 1 2 3  4  5 6 7 M e a n 
Study Year 07/83 02/85 10/85 6/85 9/88 1/89 3/89 -
Adenomas 
Tumor Incidence 2/60 3/69 7/70 3/59 5/59 5/60 2/60 -
Percentage (%) 3.3% 4.3% 10.0% 5.1% 8.5% 8.3% 3.3% 6.1% 
Carcinomas 
Tumor Incidence 1/60 2/69 0/70 1/59 0/59 0/60 0/60 -
Percentage (%) 1.7% 2.9% 0% 1.7% 0% 0% 0% 0.9% 
Table 4.9. Thyroid Non-Neoplasti c Lesions (Stout  and Ruecker, 1 990) 
Males 
Dose 0 mg/kg/day 89 mg/kg/day 362 mg/kg/day 940 mg/kg/day 
Total Incidences of thyroid 
C-cell hyperplasia and 
severity scores 5/60 
(8%) 
Diffuse (moderate) – 1 
Multi-focal (minimal) – 3 
Focal (mild) – 1 1/60 
(2%) 
Focal (mild) – 1 6/60 
(10%) 
Focal (minimal) – 4 
Multi-focal (minimal) – 1 
Multi-Focal (mild) – 1 5/60 
(8%) 
Focal (minimal) – 2 
Focal (mild) – 1 
Multi-focal (mild) – 1 
Multi-focal (moderate) – 1 
Females 
0 mg/kg/day 113 mg/kg/day 457 mg/kg/day 1183 mg/kg/day 
Thyroid C-cell hyperplasia 
and severity scores 10/60 
(17%) 
Diffuse (moderate) – 1 
Focal (mild) – 1 
Focal (minimal) – 1 
Focal (mild) – 1 
Focal (moderate) – 1 
Multi-focal (minimal) – 3 
Multi-focal (moderate) – 1 
Diffuse (moderate) – 1 5/60 
(8%) 
Focal (mild) – 3 
Focal (minimal) – 1 
Multi-focal (minimal) – 1 9/60 
(15%) 
Focal (minimal) – 4
 Multi-focal (minimal) – 2 
Multi-focal (mild) – 3 5/60 
(8%) 
Focal (mild) – 1 
Focal (minimal) – 1 
Multi-focal (mild) – 2 
Diffuse (moderate) – 1 
*Data taken from pages 1071-2 114 of the study report. 
4.5.3 Atkinson et al. , 1993a (MRID 49631701)18 
In a combined chronic toxicity /carcinogenicity study, glyphosat e (98.9% pure) was administered 
to 50 Sprague-Dawley rats/sex/dose in the diet at doses of 0, 1 1/12, 112/109, 320/347, and 
1147/1134 mg/kg/day for 104 weeks (M/F) for 104 weeks. An addi tional 35 rats/sex/dose were 
included for 1-year interim sacrifice. 
18 Note: In Greim et al. (2015), the same study is cited as Cheminova (1993a). 
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     No adverse effects on survival were seen in either sex across t he doses tested.  There were no 
changes in histopathological f indings observed.  There were no treatment-related increases in 
tumor incidences in the study.   
4.5.4 Brammer, 2001 (MRID 49704601)19 
In a combined chronic toxicity /carcinogenicity study, glyphosat e acid (97.6% pure) was 
administered to groups of Wistar  rats in the diet.  Groups of 5 2 rats/sex received diets containing 
doses of 0, 121/145, 361/437 or 1214/1498 mg/kg/day for 24 months, in males/females, 
respectively.  The highest dose tested in this study exceeds th e highest dose recommended in the 
test guidelines on how to conduct ca rcinogenicity studies (OCSP P 870.4200 and OCSPP 
870.4300). 
A statistically significant higher survival (p=0.02) was observ ed in males at the highest dose 
tested at the end of 104 weeks rela tive to concurrent controls,  and a statistically significant trend 
for improved survival was obser ved in treated males (p=0.03). The inter-current (early) deaths 
were 37/52, 36/52, 35/52, and 26/52 for t he control, low-, mid- , and high-dose groups, 
respectively. The termina l deaths were 16/52, 17/52, 18/52, and 26/52 for the control, low-, mid- 
and high-dose groups, respectively. There were no treatment-rel ated non-neoplastic lesions in 
any organs of either sex at a ny dose level tested.  As shown in  Table 4.10, a statistically 
significant trend in the incidences of liver adenomas was obser ved in male rats; however, a 
monotonic dose-response was not  observed upon closer examinatio n of the incidence data.  
Tumor incidences appear to fluct uate with increases observed at the low- and high-dose and no 
tumors observed in the control a nd mid-dose.  Statistical signi ficance with raw (unadjusted) p-
values was observed for the tum or incidence at the high-dose (1 214 mg/kg/day) when compared 
to concurrent controls; however, it was not statistically signi ficant with an adjustment for 
multiple comparisons (p= 0.055).  The improved survival in the high-dose group may help 
explain a modestly higher incidence of an age-related backgroun d tumor like liver adenomas and 
this corresponds with the lack of  associated lesions observed i n the study.     
Table 4.10. Liver Aden omas in Male Wistar Rats (Brammer, 2001) 
Cochran-Armitage Trend Test and  Fisher’s Exact Test Results. 
0 mg/kg/day 121 mg/kg/day 361 mg/kg/day 1214 mg/kg/day 
Adenoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value =  0/44a 
(0) 
0.010* 
0.029* 2/48 
(4) 
0.269 0.269 0/48 
(0) 
1.000 1.000 5/49 
(10) 
0.037* 
0.055 
Note: Trend test results denoted at control; * denotes signific ance at p=0.05; ** denote s significance at p=0.01 
a. Number of tumor-bearing animals/Number of animals examined, excluding those that died or were 
sacrificed prior to study wee k 52 (interim sacrifice). 
4.5.5 Pavkov and Wyand 1987 (MRIDs 40214007, 41209905, 41209907) 
Glyphosate trimesium salt (sulfo sate, 56.2% pure) was tested in  a 2-year chronic 
feeding/carcinogenicity study in m ale and female Sprague-Dawley  (Crl:CD[SD]BR) rats.  Sixty 
19 Note: In Greim et al. (2015), the same study is cited as Syngenta (2001). 
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     animals/sex were tested in c ontrol group 1 (basal diet, no vehi cle), 80/sex were tested in control 
group 2 (basal diet plus propylene g1ycol at 1% w/w vehicle) an d in the low and mid-dose 
groups, and 90/sex were tested in the high dose group.  The following dose levels were tested: 0, 
4.2/5.4, 21.2/27 or 41.8/55.7 mg/kg/day i n males and females re spectively.  
Treatment had no effect on survival.   There were no changes in histopathological findings 
observed. There were no treatment-related increases in tumor i ncidences in the study.   
4.5.6 Suresh, 1996 (MRID 49987401)20 
In a combined chronic toxicity /carcinogenicity study, glyphosate (96.0-96.8% pure) was 
administered to groups of Wistar  rats in the diet.  Groups of 5 0 rats/sex/group received diets 
containing 0, 6.3/8.6, 59.4/88.5, a nd 595.2/886 mg/kg/day glyphosate for 24 months in males and 
females respectively.  The highest  dose tested in females in th is study approaches the highest 
dose recommended in the test guidelines on how to conduct carci nogenicity studies (OCSPP 
870.4200 and OCSPP 870.4300).      
No adverse effects on survival were observed in either sex acro ss the doses tested.  There were 
no changes in histopathological findings observed.  There were no treatment-related increases in 
tumor incidence observed in the study.   
4.5.7 Enemoto, 1997 (MRID 50017103-50017105)21 
In a combined chronic toxicit y and carcinogenicity study, groups of 50 Sprague-Dawley 
rats/sex/group received d aily dietary doses of 0, 104/115, 354/ 393 and 1127/1247 mg/kg 
bw/day glyphosate for males and f emales, respectively.  In addi tion, 10 rats/sex /group were 
included for interim sacrif ices at 26, 52, and 78 weeks.  The h ighest dose tested in this study 
exceeds the highest dose recommended in the test guidelines on how to conduct 
carcinogenicity studies (OCSPP 870.4200 and OCSPP 870.4300).   There were no changes in mortali ty at any of the doses tested. There were no changes in 
histopathological findings obser ved.  There were no treatment-r elated increases in tumor 
incidence observed in the study. 
4.5.8 Wood et al. , 2009a (MRID 49957404)
22 
In a combined chronic toxicity /carcinogenicity study, glyphosat e (95.7% pure) was administered 
to groups of Wistar rats in the  diet. Groups of 51 rats/sex/gro up received diets containing 0, 95.0, 
316.9, and 1229.7 mg/kg/day glyphosate f or males and female, re spectively.  The highest dose 
tested in this study exceeds the  highest dose recommended in th e test guidelines on how to 
conduct carcinogenicity st udies (OCSPP 870.4200 and OCSPP 870.4300).  
20 Note: In Greim et al. (2015), the same study is cited as Feinchemie Schwebda (1996). 
21 Note: In Greim et al. (2015), the same study is cited as Arysta Life Sciences (1997b). 
22 Note: In Greim et al. (2015), the same study is cited as NuFarm (2009b). 
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 No adverse effects on survival were seen in either sex across t he doses tested.  There were no 
treatment-related preneoplastic  or related non-neoplastic lesio ns in either sex at any dose level.   
In female rats, mammary gland t umors were noted.  Tumor inciden ces for mammary gland 
adenomas, adenocarcinomas, and com bined adenomas/adenocarcinoma s in female mice are 
presented in Table 4.11. Statisti cally significant trends were observed for the adenocarcinoma 
and combined analyses; however, statistical sign ificance was only seen for the combined 
analyses following adjustment for multiple comparisons.  There was no statistical significance 
observed in pairwise comparisons. 
Table 4.11 Mammary Gland Tumor I ncidences in Female Rats (Wood et al. , 2009a) 
Fisher’s Exact Test and Cochran -Armitage Trend Test Results 
Tumor Type 0 mg/kg/day 95.0 mg/kg/day 316.9 mg/kg/day 1229.7 mg/kg/day 
Adenoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 0/48a 
(0) 
0.062 
0.124 0/51 
(0) 
1.000 1.000 0/50 
(0) 
1.000 1.000 2/50 
(4) 
0.258 0.258 
Adenocarcinoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 2/48 
(4) 
0.043* 
0.172 3/51 
(6) 
0.529 0.705 1/50 
(2) 
0.886 0.886 6/50 
(12) 
0.148 0.296 
Combined Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 2/48 
(4) 
0.007** 
0.028* 3/51 
(6) 
0.529 0.705 1/50 
(2) 
0.886 0.886 8/50 
(16) 
0.053 0.105 
Note: Trend test results d enoted at control; * denotes si gnificance at p=0.05; ** denot es significant at p=0.01. 
a. Number of tumor-bearing animals/Number of animals examined, excluding those that die d or were sacrificed 
prior to study week 52 (interim sacrifice). 
4.5.9 Summary of Rat Data 
In 4 of the 8 rat studies conduc ted with glyphosate, no tumors were identified for evaluation.  Of 
the remaining 4 rat studies, a sta tistically significant trend was observed for tumor incidences in 
the testes, liver, or mammary gland following adjustment for mu ltiple comparisons.  A 
statistically significant pairwise comparison was only observed  following adjustment for 
multiple comparisons for testicular tumors at the highest dose tested (31 mg/kg/day) in one 
individual study. In some cases, the tumor incidence across do ses did not demonstrate a 
monotonic dose response. There w as no evidence of corroboratin g pre-neoplastic or related non-
neoplastic lesions or evidence  of tumor progression (progressio n from pre-neoplastic to 
malignancy) to support biological s ignificance of tumor finding s.  In a limited number of cases, 
the agency considered historical  control data to inform the rel evance of a tumor increase, which 
indicated concurrent controls were unusually low or the observed incidences were within the 
historical control range  in most instances.   
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   Table 4.12. Summary of Rat Carcinogenicity Studies 
Study Dose Range Pre-Neoplastic or Related 
Non-Neoplastic Lesions Tumors Incidences, Statistical Significance, and Related Commen ts 
Lankas (1981) 
Sprague-Dawley rats 98.7% Technical in diet 
0, 3/3, 10/11, and 31/34 mg/kg/day [M/F] None observed Statistically significant trend observed for testicular interst itial cell tumors; 
however, did not observe monotoni c dose-response with higher in cidence at 
low-dose than mid-dose.  Inciden ces were 0/47 in controls, 3/49  at low-dose, 
1/47 at mid-dose, and 6/50 at h igh-dose. Increased incidence a t high-dose 
statistically significant, but unusually low control incidence (based on 
terminal sacrifice historical c ontrol data in study report) inf lated increase at 
high-dose. 
Pancreatic tumors lacked statis tically significant trend. Tumo r incidence for 
pancreatic adenomas in  males were 1/43 in controls, 8/45 at the  low-dose, 
5/49 at the mid-dose, and 7/48 at the high-dose.  Concurrent co ntrol incidence 
for this tumor type was at the lower bound of the historical co ntrol range for 
performing laboratory. Negative trend observed for carcinomas.  Combined 
adenoma/carcinoma incidence similar except low-dose was 2/43. No 
statistically significant pairwise comparisons, including the h ighest dose 
tested which is approaching/ exceeding 1,000 mg/kg/day. 
No statistically significant tre nds or pairwise comparisons for  hepatocellular 
Stout and Ruecker (1990) 96.5% Technical in diet 0, 89/113, 362/457 and 940/ 1183 mg/kg/day [M/F] for None observed tumors following adjustment for multiple comparisons.  Negative  trend 
observed for carcinomas.  The highest dose tested approached/ex ceeded 1,000 
Sprague-Dawley rats 24 months mg/kg/day.  All incidences withi n historical control range for performing 
laboratory. 
No statistically significant trend for thyroid C-cell tumors in  males.  For 
females, statistically significant trend for combined adenomas/ carcinomas 
following adjustment for multipl e comparisons. Incidences for combined 
adenomas/carcinomas were 2/57 in  controls, 2/60 at the low-dose , 7/59 at the 
mid-dose, and 6/55 at the high-do se.  No statistically signific ant pairwise 
comparisons, including the hi ghest dose tested which is 
approaching/exceeding 1,000 mg/kg/day. 
Atkinson et al.  (1993a) 
Sprague-Dawley rats 98.9% Technical in diet 
0, 11/12, 112/109, 320/347, and 1147/1134 mg/kg/day 
for 104 weeks (M/F) None observed There were no tumors identified for evaluation, including the h ighest dose 
tested which exceeded 1,000 mg/kg/day.  
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 Table 4.12. Summary of Rat Carcinogenicity Studies 
Study Dose Range Pre-Neoplastic or Related 
Non-Neoplastic Lesions Tumors Incidences, Statistical Significance, and Related Commen ts 
Brammer (2001) 
Wistar rats 97.6% Technical in diet 
0, 121/145, 361/437 and 1214 /1498 mg/kg/day [M/F] None observed Statistically significant trend in liver adenomas in males. No n-monotonic 
dose-response with incidences at  0/44 in controls, 2/48 at the low-dose, 0/48 
at the mid-dose, and 5/49 at th e high-dose.  No statistically s ignificant 
pairwise comparisons following adjustment for multiple comparisons, 
including the highest dose test ed which exceeded 1,000 mg/kg/da y.  
Pavkov and Wyand (1987) 
Sprague-Dawley rats 56.2% Technical (Trimesi um salt; Sulfosate) 
0, 4.2/5.4, 21.2/27 and 41.8/55.7 mg/kg/day [M/F] None observed There were no tumo rs identified for evaluation.  
Suresh (1996) 
Wistar rats 96.0-96.8% Technical in diet 
0, 6.3/8.6, 59.4/88.5, and 595.2/886 mg/kg/day [M/F] None observed There were no tumors identified for evaluation, including the h ighest dose 
tested which exceeded  1,000 mg/kg/day. 
Enemoto (1997) 
Sprague-Dawley rats 94.61-97.56% Technical in diet 
0, 104/115, 354/393 and 1127 /1247 mg/kg/day [M/F] None observed There were no tumors identified for evaluation, including the h ighest dose 
tested which exceeded  1,000 mg/kg/day. 
Wood et al.  (2009a ) 
Wistar rats 95.7% Technical in diet 0, 86/105, 285/349 or 1077/1382 mg/kg/day [M/F] None observed Statistically significant trends were observed for the combined mammary 
gland adenoma/adenocarcinoma analyses following adjustment for multiple 
comparisons.  Incidences were 2/48 in controls, 3/51 at the low -dose, 1/50 at 
the mid-dose, and 8/50 at the high-dose. No statistically sign ificant pairwise 
comparisons, including the highest dose tested which exceed 1,0 00 
mg/kg/day. 
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    4.6 Mouse Carcinogenicity Studies with Glyphosate 
4.6.1 Reyna and Gordon, 1973 (MRID 00061113) 
In an 18-month carcinogenicity study, groups of 50 Swiss white mice/sex/dose were fed 
glyphosate at dietary levels of  approximately 17 mg/kg/day and 50 mg/kg/day.  There was no 
effect on survival at any of t he doses tested.  There were no c hanges in histopathological findings 
observed. There were no treatment-related increases in tumor i ncidence observed in the study.  
Although only ten mice/sex/dose we re examined for histopatholog ical changes, there were no 
statistically significant incr eases in tumors observed in the s tudy; therefore, this deficiency 
would not impact the overall conclusion regarding tumor findings.     
4.6.2 Knezevich and Hogan, 1983 (MRID 00130406)23 
Groups of 50 male and female CD-1 mice received glyphosate (99. 78%, pure) at dietary doses of 
0, 161/195, 835/968, 4945/6069 mg/kg/day for males and females,  respectively for 24 months. 
The highest dose tested in thi s study far exceeds the highest d ose recommended in the test 
guidelines on how to conduct carc inogenicity studies (OCSPP 870.4200 and OCSPP 870.4300).  
Furthermore, the mid-dose test ed in this study was approaching 1,000 mg/kg/day.  Tumor 
findings at these high doses are given less weight.  No effect on survival was observed.  A low 
incidence of renal tubule adenomas, which are considered rare, were noted in males.  The 
incidences of renal tubule ade nomas following initial evaluatio n of the study were reported as 
follows: 0/49 in the controls;  0/49 at the lo w-dose; 1/50 at th e mid-dose; and 3/50 at the high 
dose (TXR# 0004370). In 1985, the registr ant directed a re-eva luation of the original renal 
sections by a consulting patholog ist.  This re-evaluation ident ified a small renal tubule adenoma 
in one control male mouse, which was not diagnosed as such in t he original pathology report.  In 
1986, at the request of the agency, additional renal sections ( 3 sections/kidney/mouse spaced at 
150 micron intervals) were evalu ated in all control and all gly phosate-treated male mice in order 
to determine if additional tumors were present.  The additional  pathological and statistical 
evaluations concluded that the r enal tumors in male mice were not compound-related. 
Subsequently, the agency requested a Pathology Work Group (PWG)  evaluate the kidney 
sections. The PWG examined all sections of the kidney, includi ng the additional renal sections, 
and were blinded to treatment gr oup.  The renal tubular-cell le sions diagnosed by the PWG are 
presented below in Table 4.13 with r esults from statistical ana lyses.  The PWG noted that 
because differentiation betwee n tubular-cell adenoma and tubula r-cell carcinoma is not always 
clearly apparent and because both lesions are derived from the same cell type, it is appropriate to 
combine the incidences from these two tumor types for purposes of evaluation and statistical 
analysis. The PWG unanimously conc luded that these lesions are not compound-related based on 
the following considerations: 1) renal tubular cell tumors are spontaneous lesions for which there 
is a paucity of historical contro l data for this mouse stock; 2 ) there was no statis tical significance 
in a pairwise comparison of treat ed groups with the concurrent controls and there was no 
evidence of a statistically significant linear trend; 3) multip le renal tumors were not found in any 
23 Note: In Greim et al. (2015), the same study is cited as Monsanto (1983). 
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 animal; and 4) compound-related n ephrotoxic lesions, including pre-neoplastic changes, were not 
present in male mice i n this study (TXR# 0005590). 
Table 4.13.  Renal Tubular Cell Tumors in Male CD-1 Mice (Kneze vich and Hogan, 1983) 
Cochran-Armitage Trend Test & F isher’s Exact Test Results. 
Tumor Type 0 mg/kg/day 161 mg/kg/day 835 mg/kg/day 4945 mg/kg/d ay 
Adenoma Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 1/49 
(2) 
0.442 
1.000 0/49 
(0) 
1.000 1.000 0/50 
(0) 
1.000 1.000 1/50 
(2) 
0.758 1.000 
Carcinoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 0/49 
(0) 
0.063 0.190 0/49 
(0) 
1.000 1.000 1/50 
(2) 
0.505 0.505 2/50 
(4) 
0.253 0.379 
Combined 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 1/49 
(2) 
0.065 0.259 0/49 
(0) 
1.000 1.000 1/50 
(2) 
0.758 1.000 3/50 
(6) 
0.316 0.633 
Note: Trend test results  denoted at control . 
Historical control data fro m 14 studies conducted between 1977 and 1981 (within <1 to 3 years 
of when Knezevich and Hogan (1983)  was performed) at the perfor ming laboratory (Table 4.14) 
indicated that the mouse renal tubular adenomas ranged from 0 t o 3.3% and the incidence in the 
current study was within the hi storical contro l range (TXR# 0007252). 
Table 4.14. Historical Control Data- Kidney tumors in CD-1 Mice  (TXR #0007252). 
Study Period 6/78 -
7/80 12/77 -
4/80 12/77 -
3/80 10/78 -
4/81 11/78 -
4/81 11/77 -
4/80 10/77 -
4/80 
No. Examined 57 54 61 51 53 59 60 60 60 60 60 60 60 60 
Tubular Adenoma 0 1 0 0 0 0 0 0 0 2 0 0 0 0 
Histopathological examinations not ed chronic interstitial nephr itis and tubular ep ithelial changes 
(basophilia and hypertrophy) in the k idneys of male rats in the  study (Table 4.15).  The increased 
incidence of chronic interstitial nephritis in males lacked a d ose-response.  The incidence in 
controls of bilateral interstitia l nephritis was higher than lo w-dose group and approximately the 
same as the mid-dose group.  Unilateral chronic in terstitial ne phritis was only seen in 1 animal in 
the low- and high-dose groups. Furthermore, chronic interstitial nephritis is not  considered to be 
a precursor lesion for tubular ne oplasms.  A monotonic dose-res ponse was not observed for the 
epithelial basophilia and hypertrophy, such that the incidence fluctuated with dose and the lowest 
incidence was observed at the h ighest dose tested.  There was no increase in supporting 
preneoplastic or related non-neopl astic renal tubular lesions ( e.g., tubular epithelial 
necrosis/regeneration, hyperpla sia) observed in male mice.   
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     Table 4.15. Kidney Histopathological Alterations in Male CD-1 M ice (Knezevich and Hogan, 1983) 
Males 
Dose 0 mg/kg/day 161 mg/kg/day 835 mg/kg/day 4945 mg/kg/day 
Bilateral Chronic 
Interstitial Nephritis 5/49 
(10%) 1/49 
(2%) 7/50 
(14%) 11/50 
(22%) 
Unilateral Chronic Interstitial Nephritis 0/49 
(0%) 1/49 
(2%) 0/49 
(0%) 1/50 
(2%) 
Proximal Tubule Epithelial Basophilia 
and Hypertrophy 15/49 
(31%) 10/49 
(20%) 15/50 
(30%) 7/50 
(14%) 
*Data taken from page 305 and 306, and the study pathology repo rt; incidences were moderate diffuse 
4.6.3 Atkinson, 1993b (MRID 49631702)24 
In a carcinogenicity study, glyphosate (>97% pure) was administ ered to groups of 50 CD-1 
mice/sex/dose in the diet for 104 weeks at doses of 0, 98/102, 297/298, 988/1000 mg/kg/day for 
males and females, respectivel y.  No interim sacrifices were performed. 
There was no effect on survival in the study.  There were no preneoplastic lesions or related non-
neoplastic lesions observed. As shown in Table 4.16, hemangios arcomas were found in 4/45 
(9%) of high-dose male mice (1000 mg/kg/day) compared to none in the concurrent controls or 
other treated groups. Hemangios arcomas are commonly observed i n mice (generally more 
common in males for CD-1 strain)  as both spontaneous and treatm ent-related tumors arising 
from endothelial cells.  As vascul ar tumors, they can occur at different sites, with liver and 
spleen tending to be the most co mmon sites in mice.  In the hig h-dose mice with 
hemangiosarcomas, one had the tumors present in the liver and s pleen, one had the tumor present 
in the liver only, one had the tu mors present in the liver, spl een, and prostate, and one had the 
tumor present in the spleen onl y.  A statistically significant trend was observed.  Closer 
examination of the incidence indi cates a relatively flat respon se at the low- and mid-dose with 
only an increase observed at the high-dose; however, the incidence of hemangiosarcomas at the 
high-dose was not statistically s ignificant when compared to th e concurrent controls. 
Table 4.16. Hema ngiosarcomas in Male CD-1 Mice (Atkinson, 1993 b) 
Cochran-Armitage Trend Test and  Fisher’s Exact Test Results. 
Dose (mg/kg/day) 0 100 300 1000 
Hemangiosarcoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value = 0/47a 
(0) 
0.003** 
0.006** 0/46 
(0) 
1.000 1.000 0/50 
(0) 
1.000 1.000 4/45 
(9) 
0.053 0.053 
Note: Trend test results denoted at control; * denotes signific ance at p=0.05; ** denote s significance at p=0.01 
a= Number of tumor bearing animals/Number of animals examined, excluding those that died before week 52. 
24 Note: In Greim et al. (2015), the same study is cited as Cheminova (1993b). 
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    4.6.4 Wood et al. , 2009b (MRID 49957402)25 
In a feeding study, CD-1 mice (50/sex/dose) received glyphosate  (95.7%) for 80 weeks at dietary 
dose levels of 0, 71.4/97.9, 234.2/299.5, or 810/1081.2 mg/kg/d ay for males and females, 
respectively. The highest dose tested in this study approaches  or exceeds the highest dose 
recommended in the test guidelines on how to conduct carcinogenicity studies (OCSPP 870.4200 
and OCSPP 870.4300).   
There was no effect on survival in the study.  In male mice at the high dose, there were increases 
in the incidences of lung adenocar cinomas and malignant lymphom as.  A discussion of each 
tumor type is presented below: 
1.		Lung: Tumor incidence for lung a denomas, adenocarcinomas, and combined 
adenomas/adenocarcinomas are presented in Table 4.17.  A statis tically significant trend 
was only noted for the adenocarci nomas; however, the trend was not statistically 
significant with adjustment for multiple comparisons.  Closer examination of the tumor 
incidence indicates t he dose-response was relatively flat at the low- and mid-dose with 
only an increase observed at the high-dose and the incidence of  lung adenocarcinomas at 
the high-dose (810 mg/kg/day) was  not statistica lly significant  when compared to the 
concurrent controls. There wer e no treatment-related preneopla stic or related non-
neoplastic lesions observed. 
2.		Malignant lymphoma: Tumor incidence for malignant lymphoma are also presented in 
Table 4.18. A statistically significant trend was observed and  the incidence at the high-
dose (810 mg/kg/day) was statistic ally significantly elevated a s compared to concurrent 
controls with the raw (unadjust ed) p-value; however, with an ad justment for multiple 
comparisons, the increased incid ence at the high-dose was not statistically significant (p= 
0.059). Historical control data have been submitted (MRIDs 504 64501and 50464601) 
from the same testing laboratory for 10 studies of similar dura tion.  These data were 
generated within approxim ately 5 years of the Wood et al.  (2009b) study. The historical 
control range was 0%-32% (m ean = 8.7%).  All observed incidences of this tumor type 
were within the historical control range. 
25 Note: In Greim et al. (2015), the same  study is cited as NuFarm (2009 a). 
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    Table 4.17.  Lung Tumors in Male CD-1 Mice (Wood et al. , 2009b) 
Fisher’s Exact Test and Cochran -Armitage Trend Test Results. 
Dose (mg/kg/day) 0 71.4 234.2 810 
Lung Adenoma 
Incidence 9/44 7/46 9/48 4/45 
(%) (20) (15) (19) (9) 
Raw p-value = -b -b -b -b 
Adjusted p-value = -b -b -b -b 
Lung 
Adenocarcinoma 5/44a 5/46 7/48 11/45 
 (%) (11) (11) (15) (24) 
Raw p-value = 0.026* 0.659 0.443 0.091 
Adjusted p-value = 0.103 0.659 0.590 0.182 
Lung Combined 
Incidence 14/44 12/46 16/48 15/45 
(%) (32) (26) (33) (33) 
Raw p-value = 0.328 0.797 0.527 0.529 
Adjusted p-value = 0.706 0.797 0.706 0.706 
Note: Trend test results denoted at control ; * denotes signific ance at p=0.05;** denotes significance at p=0.01
	
a= Number of tumor bearing animals/Number of animals examined, excluding those that died before week 
52 (interim sacrifice). 
b = Trend and pairwise p-values not reported since tumor incide nce decreased with  increasing dose. 
Table 4.18.  Malignant Lymphoma s in Male CD-1 Mice (Wood et al. , 2009b) 
Fisher’s Exact Test and Cochran -Armitage Trend Test Results. 
Dose (mg/kg/day) 0 71.4 234.2 810 
Malignant 
Lymphoma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value 
= 0/44 
(0) 
0.006** 
0.025* 1/46 
(2) 
0.511 
0.511 2/48 
(4) 
0.269 0.359 5/45 
(11) 
0.029* 
0.059 
Note: Trend test results denoted at control; * denotes significance at p=0.05; ** denotes significance at 
p=0.01 a= Number of tumor bearing animals/Number of animals examined, excluding those that died before week 
52 (interim sacrifice). 
4.6.5 Sugimoto, 1997 (MRID 50017108 - 50017109)26 
In a carcinogenicity study, glyphosate (purity 97.56 and 94.61%; two lots) was administered 
to groups of 50 male and 50 female Specific-Pathogen-Free (SPF)  ICR (Crj: CD-1) 
mice/dose in the diet at dose levels of 0, 165/153.2, 838.1/786.8, or 4348/4116 mg/kg/day 
for males and females, respect ively, for 18 months.  The highes t dose tested in this study far 
exceeds the highest dose recommended in the test guidelines on how to conduct 
carcinogenicity studies (OCSPP 870.4200 and OCSPP 870.4300).  F urthermore, the mid-
dose tested in this study was approaching 1,000 mg/kg/day.  Tumor findings at these high 
doses are given less weight. 
26Note: In Greim et al. (2015), the same s tudy is cited as Arysta Life Sciences (1997b) 
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  There were no treatment-related effects on mortality or surviva l.  There were no changes in 
histopathological f indings observed.   
Hemangiomas in female mice were found to occur at different sites.  The tumor incidences are 
presented in Table 4.19. A statis tically significant trend was observed.  Tumor incidence at the 
high-dose, which was approximate ly 4 times the recommended high -dose in test guidelines 
(4116 mg/kg/day), was statistically significant as compared to concurrent controls.  
Table 4.19. Hemangioma Inc idences (Sugimoto, 1997) 
Fisher’s Exact Test and Cochran -Armitage Trend Test Results 
Tumor Type 0 mg/kg/day 153.2 mg/kg/day 786.8 mg/kg/day 4116 mg/ kg/day 
Hemangioma 
Incidence 
(%) 
Raw p-value = 
Adjusted p-value 
= 0/48 
(0) 
0.002** 
0.005** 0/47 
(0) 
1.000 1.000 2/45 
(4) 
0.231 0.231 5/45 
(11) 
0.024* 0.035* 
Note: Trend test results d enoted at control; * denotes si gnificance at p=0.05; ** denotes significance at p=0.01. 
a= Number of tumor bearing animals/Number of animals examined, excluding those that died before week 
52 (interim sacrifice). 
4.6.6 Pavkov and Turnier, 1987 (MRIDs 40214006, 41209907) 
Glyphosate trimesium salt (sulfo sate, 56.2% pure) was tested in  a 2-year chronic 
feeding/carcinogenicity study in m ale and female CD-1 mice.  Si xty animals/sex were tested in 
control group 1 (basal diet, no ve hicle), 80/sex were tested in  control group 2 (basal diet plus 
propylene glycol at 1% w/w vehicle) and in the low- and mid-dose groups, and 90/sex were 
tested in the high-dose group. T he following dose levels were tested:  0, 11.7/16, 118/159, and 
991/1341 mg/kg/day for males and f emales, respectively.   
No adverse effects on survival were seen in either sex across t he doses tested.  There were no 
changes in histopathological f indings observed.  There were no treatment-related increases in 
tumor incidence observed in the study.   
4.6.7 Summary of Mouse Data 
No tumors were identified for  evaluation in 2 of the 6 mouse carcinogenicity studies.  In the 
remaining 4 mouse studies, 3 observe d a statistically significa nt trend in tumor incidences 
in the hemangiosarcomas, malignant lymphomas, or hemangiomas fo llowing adjustment for 
multiple comparisons.  In one individual study, a statistically significant pairwise 
comparison was only observed following adjustment for multiple comparisons for hemangiomas at the highest dose tested, which was more than 4X the limit dose.  There was 
no evidence of corroborating pre- neoplastic or related non-neop lastic lesions or evidence of 
tumor progression (progression fro m pre-neoplastic to malignanc y) to support biological 
significance of tumor findings .  In a limited number of cases, historical control data were 
available which the observed tum or incidences were within the h istorical control range. 
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 Table 4.20. Summary of Mouse Carcinogenicity Studies 
Study Dose Range Pre-Neoplastic or Related 
Non-Neoplastic Lesions Tumors Incidences, Statistical Significance, and Related Commen ts 
Reyna and Gordon (1973) 
Swiss white mice 0, 17 or 50 mg/kg/day for 18 months None observed There were no tumo rs identified for evaluation.  
Knezevich and Hogan (1983) 
CD-1 mice 99.78% Technical in diet 
0, 161/195, 835/968, 4945/6069 mg/kg/day for 
[M/F] for 24 months. Chronic interstitial nephritis lacked dose-response and not 
considered relevant to renal tumors.  Tubular epithelial changes in kidney were approximately the same in controls, low- and mid-doses and then decreased at high-
dose. No statistical significance in trend or pairwise comparisons, including the 
mid- and high-doses which approached or exceeded 1,000 mg/kg/da y. 
Incidence of adenomas within his torical control range for perfo rming 
laboratory. 
Atkinson et al.  (1993b). 
CD-1 mice 97.5 - 100.2% Technical in diet 
0, 98/102, 297/298, 988/1000 mg/kg/day for 104 
weeks (M/F) None observed Statistically significant trend for hemangiosarcomas that were only 
observed in 4/45 (9%) high-dose male mice.  Increased incidence  was not 
statistically significant from the concurrent controls at all d oses, including 
the highest dose tested which i s approximately 1 ,000 mg/kg/day. 
Wood et al.  (2009b ) 
CD-1 mice 95.7% Technical in diet 
0, 71.4/97.9, 234.2/299.5, or 810/1081.2 
mg/kg/day [M/F] for 80 weeks None observed No statistically significance in  trend or pairwise comparisons following 
adjustment for multiple comparisons.  Negative trend observed f or 
adenomas. 
Statistically significant trend f or malignant lym phoma with inc idences of 
0/44 in controls, 1/46 at the low -dose, 2/48 at the mid-dose, a nd 5/45 at the 
high-dose. No statistically significant pairwise results follo wing 
adjustment for multiple comparisons, including the highest dose  tested 
which was approaching 1,000 mg/ kg/day.  All observed incidences  within 
historical control range for  performing laboratory. 
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    Table 4.20. Summary of Mouse Carcinogenicity Studies 
Study Dose Range Pre-Neoplastic or Related 
Non-Neoplastic Lesions Tumors Incidences, Statistical Significance, and Related Commen ts 
Sugimoto (1997) 
CD-1 mice 94.61 – 97.56% Technical in diet 
0, 165/153.2, 838.1/786.8, or 4348/4116 
mg/kg/day [M/F] for 18 months None observed Statistically significant trend f or hemangiomas in female mice following 
adjustment for multiple comparisons with incidences of 0/48 in controls, 
0/47 at the low-dose, 2/45 at the mid-dose, and 5/45 at the hig h-dose.  
Increased incidence at high-dose statistically significant foll owing 
adjustment for multiple comparisons.  Highest dose tested was m ore than 
4X the lim it dose. 
Pavkov and Turnier (1987) 
CD-1 mice 56.2% Technical (Trimesi um salt; Sulfosate) 
0, 11.7/16, 118/159, and 991/1341 mg/kg/day 
[M/F] for 24 months. None observed There were no tumors identified for evaluation, including the h ighest dose 
tested which approached/exceeded 1,000 mg/kg/day. 
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  4.7 Absorption, Distribution, Metabolism, Excretion (ADME) 
The 2005 EPA Guidelines for Carcinogen Risk Assessment also permit analysis of other key 
data that may provide valuable i nsights into the likelihood of human cancer risk from exposure 
to a chemical, such as informa tion regarding the absorption, distribution, metabolism, and 
excretion (ADME) of a test chem ical.  EPA’s Harmonized Test Gui delines for pesticides include 
a series of studies for character izing a chemical’s metabolism and pharmacokinetics.  As 
described in the test guide line (OCSPP 870.7485), testing of the disposition of a t est substance is 
designed to obtain adequate in formation on its: absorption, distribution, biotransformation 
(metabolism), and excretion, whic h can all collectively aid in understanding the chemical’s 
mechanism of toxicity.  Basic  pharmacokinetic/toxicokinetic par ameters determined from these 
studies can also provide information on the potential for accum ulation of the test substance in 
tissues and/or organs and the potential for induction of biotra nsformation as a result of exposure 
to the test substance. These data can be used to assess the ad equacy and relevance of the 
extrapolation of animal toxicit y data (particularly chronic toxicity and/or carcinogenicity data) to 
estimate human risk.   
Oral exposure is considered the p rimary route of concern for gl yphosate. The maximum 
absorption from the GI tract for glyphosate was estimated to be  ~30% with one study showing up 
to 40% based upon radiolabel detect ed in the urine.  In general, the amounts of glyphosate 
detected in tissues wer e negligible indicat ing low tissue retention following dosing.  Parent 
glyphosate is the principal form excreted in urine and feces.  The primary route of excretion 
following oral administration of glyphosate is the feces, as ve rified by the intravenous dosing 
and bile cannulation e xperiments.  Within the dose ranges tested, elimination was essentially 
complete by 24 hours indicating tha t glyphosate does not bioacc umulate. 
Multiple studies examined the pharmacokinetics of a single dose  of radiolabeled glyphosate 
ranging from 5.6 – 400 mg/kg. Across th ese studies, time to reach peak plasma concentrations 
(Tmax) appeared to increase with inc reasing dose; however, the repor ted range of T max (1-5.5 
hours) suggests only a slight shi ft in absorption kinetics occu rs despite large increases in dose.  
In the one study that tested two doses (NTP, 1992), data graphi cally show that peak blood levels 
were only roughly 3-fold with a 10-fo ld increase between the tw o doses.  Reported area under 
the curve (AUC) values indicate d conflicting resu lts regarding whether linear or non-linear 
absorption kinetics was occurring at higher doses. 
In general, EPA and OECD guideli ne ADME studies are designed for a different purpose and do 
not provide the information needed t o adequately determine whet her linear kinetics is still 
occurring at high doses of glyphosate.  These studies are often  limited to one or two doses and do 
not include time course data.  A  well-conducted pharmacokinetic study testing multiple doses is 
needed to conclusively make this determination. 
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 4.8 Discussion 
Glyphosate has been extensively t ested in rodents to evaluate i ts carcinogenic potential.  A total 
of 14 rodent carcinogenicity studies were considered to be adeq uate for this analysis.  Eight 
studies were conducted in the r at and 6 studies were conducted in the mouse.  When a potential 
tumor signal was identified in a  study, the agency considered s everal factors.  Consistent with the 
EPA’s 2005 Guidelines for Carcinog en Risk Assessment, the agency evaluated the tumor 
responses for both statistical  and biological significance by c onsidering factors such as historical 
control data; rarity of tumor types; tumors at multiple sites; tumors in multiple species, strains, or 
both sexes; progression of lesions from preneoplastic to benign  to malignant; reduced latency of 
neoplastic lesions (i.e., time to tumor); presence of metastase s; unusual magnitude of tumor 
response; proportion of malignant t umors; and dose-related incr eases.  When these factors were 
considered together, the agenc y made a determination of whether  or not the observed tumor was 
related to treatment with glyphosat e.  A weight of the evidence  approach was used to determine 
the carcinogenic potential  of glyphosate in rodents.  
In 4 of the 8 rat studies conduc ted with glyphosate, no tumors were identified for evaluation.  Of 
the remaining 4 rat studies, tumor incidences were evaluated in  detail for testicular, pancreatic, 
hepatocellular, thyroid C-cell, and mammary gland tumors.  In 2  of the 6 mouse studies, no 
tumors were identified for e valuation.  In the remaining 4 mous e studies, tumor incidences were 
evaluated in detail for hemangios arcomas, malignant lymphoma, h emangiomas, lung, and kidney 
tumors.  Below are the weight of evidence evaluations for each tumor type. 
Testicular Tumors 
In Table 4.1, a statistically si gnificant trend was observed for testicular interst itial cell tumors 
(adjusted p-value = 0.032) and pairwise significance was observ ed at the highest dose tested of 
31 mg/kg/day (adjusted p-value  = 0.032) in male Sprague-Dawley rats (Lankas, 1981).  Closer 
examination of the tumor inciden ce indicated that the data do n ot demonstrate a monotonic dose 
response with greater incidence  observed at the low-dose as compared at the mid-dose.  There 
was a lack of preneoplastic or related non-neoplastic lesions to support a treatment-related effect.  
It was also noted that the incide nce of testicular cell tumors in concurrent controls (0%) appears 
to be unusually low for this tumor type as compared to historic al controls from the performing 
laboratory. These data also indicat ed that the incidence at the highest dose tested was outside the 
historical control range when a ll animals were considered, but within the terminal historical 
control range for the performi ng laboratory.  Testicular inters titial cell tumors are relatively 
common in Sprague-Dawley rats an d this tumor type is difficult to distinguish from simple 
hyperplasia. Testicular tumors were not seen in the other 7 ra t studies, many of which tested up 
to or beyond the limit dose (1000 m g/kg/day).  More specifically, of the 4 other studies 
performed in Sprague-Dawley rat s (Stout and Ruecker, 1990; Atkinson et al. , 1993a; Pavkov and 
Wyand, 1987; Enemoto, 1997), 3 were tested at doses 30X higher or more than the highest dose 
tested in Lankas (1981) and no tes ticular tumors were observed.  Furthermore, there were no 
testicular tumors observed in the 6 mouse bioassays.   
Pancreatic Tumors 
In Table 4.2, no statistically sig nificant trends were observed  for pancreatic islet cell tumors in 
male Sprague-Dawley rats (Sto ut and Ruecker, 1990).  Raw p-valu es were statistically 
Page 94 of 216
	 
 
  
 
 
 significant for adenomas at the low and high dose for pairwise comparisons; however, these were 
not statistically significant following adjustment for multiple  comparisons.  Closer examination 
of the tumor incidence indicate d that the data do not demonstrate a monotonic dose response 
with greater inciden ce observed at the low-dose as compared at the mid-dose and high-dose. 
There was a lack of preneoplas tic or related non- neoplastic les ions to support a tr eatment-related 
effect. Historical control data from the performing laboratory for pancreatic adenomas indicated 
that the incidence in concurrent controls was at the lower limi t of the historical control range.  
There was no evidence of progression to malignancy.  Notably, c arcinomas demonstrated a 
negative trend with decr easing tumor inciden ce with increasing dose.  Pancreatic tumors were 
not observed in the other 7 rat s tudies, including 4 other stud ies performed in Sprague-Dawley 
rats (Atkinson et al. , 1993a; Pavkov and Wyand, 1987; Enemoto, 1997; Lankas, 1981). 
Furthermore, pancreatic tumors were not observed in the 6 mouse  bioassays. 
Hepatocellular Tumors 
Hepatocellular tumors were ev aluated in 2 rat carcinogenicity s tudies (Stout and Ruecker, 1990; 
Brammer, 2001). In Table 4.4, the raw  p-value for trend was st atistically significant for 
adenomas in male Sprague-Dawle y rats (Stout and Ruecker, 1990); however, it was not 
statistically significant following adjustment for multiple com parisons.  There were no 
statistically significant pairwise comparisons.  Historical con trol data from the performing 
laboratory indicated t hat the incidence of hepatocellular tumor s was within the h istorical control 
range at all doses. Closer exam ination of the tumor incidence indicated that the data fluctuated 
with no tumors observed in concur rent controls or the mid-dose and increases seen at the low-
dose and high-dose. In Table 4.10, a statistically significant trend was observed for adenomas in 
male Wistar rats (adjusted p-value = 0.029) (Brammer, 2001).  For pairwise comparisons, the 
raw p-value was statistically significant at the highest dose t ested (1214 mg/kg/day); however, it 
was not statistically significan t following adjustment for multiple comparisons.  There was a lack 
of preneoplastic or related non- neoplastic lesions to support a treatment-related effect in both 
studies. There was no evidence  of progression to malignancy.  In particular, carcinomas 
demonstrated a negative trend w ith decreasing tumor incidence w ith increasing dose.  
Hepatocellular tumors were not obs erved in the other 6 rat stud ies, including 4 other studies in 
Sprague-Dawley rats (Atkinson et al. , 1993a; Pavkov and Wyand, 1987; Enemoto, 1997; 
Lankas, 1981) and 2 other studies in Wistar rats (Suresh, 1996; Wood et al.  2009a) the same rat 
strains. Furthermore, hepatoce llular tumors were not observed in the 6 mouse bioassays. 
Thyroid Tumors 
In Table 4.6, there were no statistically significant trends or pairwise comparisons were observed 
for thyroid C-cell tumors in mal e Sprague-Dawley rats (Stout and Ruecker, 1990).  In Table 4.7, 
a statistically significant tre nd for adenomas and combined ade nomas/carcinomas was observed 
with raw p-values in female Spra gue-Dawley rats (Stout and Ruec ker, 1990); however, the 
trends were not statis tically significant with adjustment for m ultiple comparisons.  There were no 
statistically significant pairwi se comparisons observed at any dose.  There was a lack of 
preneoplastic or related non-neoplastic lesions to support a tr eatment-related effect.  There was 
no evidence of progression to ma lignancy.  Thyroid tumors were not observed in the other 7 rat 
studies, including 4 other studies performed in Sprague-Dawley rats (Atkinson et al. , 1993a; 
Pavkov and Wyand, 1987; Enemoto, 1997; Lankas, 1981).  Furtherm ore, thyroid tumors were 
not observed in the 6 mouse bioassays. 
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 Mammary Gland Tumors 
In Table 4.11, raw trend p-values  were statistically significan t for mammary gland 
adenocarcinomas and combined ade nomas/adenocarcinomas in female Wistar rats (Wood et al. , 
2009a); however, only the combined p-value for trend remained s tatistically significant 
following adjustment for multiple comparison (adjusted p-value = 0.028).  There were no 
statistically significant pairwise comparisons.  There was a lack of preneoplastic or related non-
neoplastic lesions to support a treatment-related effect.  Mamm ary gland tumors were not 
observed in the other 7 rat stu dies, including 2 other studies performed in Wistar rats (Brammer, 
2001; Suresh, 1996). Furthermore, mammary gland tumors were no t observed in the 6 mouse 
bioassays. 
Kidney Tumors 
In Table 4.13, there were no statistically significant trend ob served for renal tubular cell tumors 
in male CD-1 mice (Knezevic h and Hogan, 1983).  This study test ed up to almost 5000 
mg/kg/day. Historical control da ta from the performing laboratory indicated tha t the incidence 
of adenomas was within the historical control range.  There was  a lack of preneoplastic or related 
non-neoplastic lesions to suppor t a treatment-related effect.  There was no evidence of 
progression to malignancy.  Kidney tumors were not observed in the other 5 mouse studies, 
including 4 other studies perf ormed in CD-1 mice (Atkinson et al. , 1993b; Wood et al. , 2009b; 
Sugimoto, 1997; Pavkov and Turni er, 1987).  Furthermore, kidney tumors were not observed in 
the 8 rat bioassays. 
Hemangiosarcomas 
In Table 4.16, a statistically s ignificant trend was observed f or hemangiosarcomas in male CD-1 
mice (adjusted p-value = 0.006) (Atkinson et al. , 1993b). There were no stat istically significant 
pairwise comparisons. There was a lack of prene oplastic or rel ated non-neoplastic lesions to 
support a treatment-related eff ect.  There was no evidence of p rogression to malignancy.  
Hemangiosarcomas are commonly obse rved in mice (generally more common in males for CD-1 
strain) as both spontaneous and tre atment-related tumors arisin g from endothelial cells.  
Hemangiosarcomas were not obser ved in the other 5 mouse studies , including 4 other studies 
performed in CD-1 mice (Knezevich and Hogan, 1983; Wood et al. , 2009b; Sugimoto, 1997; 
Pavkov and Turnier, 1987). Furthermore, hemangiosarcomas were not observed in the 8 rat 
bioassays. 
Lung Tumors 
In Table 4.17, the raw p-value for trend was observed for lung adenocarcinomas; however, the 
trend was not statistic ally significant following adjustment fo r multiple comparisons in male CD-
1 mice (Wood et al. , 2009b). There were no statistical ly significant pairwise com parisons.  
Tumor incidences at all doses w ere within the historical contro l range for the performing 
laboratory. There was a lack of  preneoplastic o r related non-neoplastic lesions to support a 
treatment-related effect.  Lung t umors were not observed in the other 5 mouse studies, including 
4 other studies performed in CD- 1 mice (Knezevich and Hogan, 19 83; Atkinson et al., 1993b; 
Sugimoto, 1997; Pavkov and Turni er, 1987).  Furthermore, lung t umors were not observed in the 
8 rat bioassays. 
Page 96 of 216
	 
 
  
 
 
 
 
 
 Malignant Lymphoma 
In Table 4.18, statistically significant trend was observed in male CD-1 mice (adjusted p-value = 
0.025) (Wood et al. , 2009b). For pairwise comparisons, the raw p-value for the hi ghest dose 
tested was statistically signifi cant; however, it was not stati stically significant following 
adjustment for multiple comparisons.  Malignant lymphoma was no t observed in the other 5 
mouse studies, including 4 other studies performed in CD-1 mice  (Knezevich and Hogan, 1983; 
Atkinson et al. , 1993b; Sugimoto, 1997; Pavkov and T urnier, 1987).  Furthermor e, malignant 
lymphoma was not observed i n the 8 rat bioassays. 
Hemangiomas In Table 4.19, a statis tically significant trend was observed i n female CD-1 mice (adjusted p-
value = 0.005) (Sugimoto, 1997).  For pairwise comparisons, the  incidence at the highest dose 
tested was statistically significant (adjusted p-value = 0.035) .  The highest dose tested in this 
study was more than 4X the limit dose.  Hemangiomas were not observed in the other 5 mouse 
studies, including 4 other studies  performed in CD-1 mice (Knez evich and Hogan, 1983; 
Atkinson et al. , 1993b; Wood et al., 2009b; Pavkov and Turnier, 1987). Furthermore, 
hemangiomas were not observe d in the 8 rat bioassays.   
Based on the weight-of-evidence ev aluations, the agency has con cluded that none of the tumors 
evaluated in individual rat a nd mouse carcinogenicity studies a re treatment-related due to lack of 
pairwise statistical significan ce, lack of a monotonic dose response, absence of preneoplastic or 
related non-neoplastic lesions, no evidence of tumor progression, and/or historical control information (when available).  T umors seen in individual rat an d mouse studies were also not 
reproduced in other studies, including those conducted in the s ame animal species and strain at 
similar or higher doses.  
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 5.0 Data Evaluation of Genetic Toxicity 
5.1 Introduction 
Genotoxicity is a broad term f or any damage to the genetic mate rial, whether the damage is 
transient or permanent.  Transie nt damage refers to unintended modifications to the structure of 
DNA, which may or may not undergo successful repair.  Permanent  damage refers to heritable 
changes in the DNA sequence, known as mutations.  Types of mutations include: 1) changes in 
single base pairs, partial, single or multiple genes, or chromo somes, 2) breaks in chromosomes 
that result in transmissible  deletion, duplica tion or rearrange ment of chromosome segments, and 
3) mitotic recombination (OECD, 2015).  In somatic cells, DNA-r eactive chemicals can cause 
cancer if the mutations occur w ithin regulatory genes that control cell growth, cell division and 
differentiation, such as proto-onc ogenes, tumor suppressor gene s and/or DNA damage response 
genes (OECD, 2015). Additionally, DNA damage may signal the ce ll to undergo apop tosis (cell 
death) rather than cell divisi on and, therefore, the damage is not “fixed” as a mutation and is not 
passed along to daughter cells. 
Evaluation of genotoxicity data e ntails a weight-of-evidence ap proach that includes 
consideration of the various type s of genetic damage that can o ccur. Since no single genotoxicity 
assay evaluates the many types  of genetic alterations that can be induced by a chemical, one 
must employ a battery of genotoxi city tests to adequately cover  all the genetic endpoints 
important for regulatory decisi ons.  EPA, like other regulatory  agencies, considers genotoxicity 
information as part of the weight  of evidence when assessing th e potential of a chemical to 
induce cancer in humans. Under FIFR A, OPP requires genotoxicity  tests of the technical grade 
active ingredient for the registration of both food and non-foo d use pesticides.  The current 
genotoxicity test battery (40 C FR Part 158.500) for pesticide r egistration consists of: 
1)		Bacterial reverse mutation tes t (typically c onducted in bacteri a strains Salmonella 
typhimurium  and Escherichia coli ), 
2)		in vitro  mammalian (forward) gene mutation and in vitro  mammalian chromosomal 
aberration test, and 
3)		in vivo  test for micronucleus induction (mammalian erythrocyte micronu cleus test) 
or in vivo  chromosomal aberration test (mammalian bone marrow chromosomal 
aberration test). 
In cases where equivocal or inconsistent results are obtained f or the same endpoint in different 
test systems, additional testi ng may be required.  Test Guideli nes on how to conduct the 
genotoxicity tests have bee n published by the agency and have b een harmonized with the 
Organization for Economic Cooperation and Development (OECD, 2015; Cimino 2006).  These 
guidelines identify specific te st species, genetic endpoints, t est conditions, exposure durations as 
well information on how to report data and interp ret the result s.  The test guidelines provide a 
level of consistency and predicta bility for regulatory complian ce and regulatory decision making.  
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 5.2 Scope of the Assessment Considerations for Study Quality Evalua tion 
Previous genotoxicity assessments  conducted as part of the CARC  reviews for glyphosate in 
1991 and 2015, considered only studies conducted with glyphosate technical and included only 
studies that provided adequate cha racterization of the test mat erial ( i.e. purity information 
provided). In the current analy sis, a fit-for-purpose systematic review process was conducted to 
identify relevant genotoxicity da ta from regulatory studies and  published literature from open 
sources (published and unpublishe d) for both glyphosate technic al and glyphosate-based 
formulations. Studies conducte d with glyphosate formulations th at were identified and 
considered relevant for genotoxicity evaluation are summarized in table form in Appendix F.  As 
described in Section 7.0 of this  document, glyphosate formulati ons are hypothesized to be more 
toxic than glyphosate alone. The  agency is collaborating with NTP to systematically investigate 
the mechanism(s) of toxicity f or glyphosate and glyphosate formulations.  However, the focus of 
this section is the genotoxic  potential of glyphos ate technical.   
As described previously in Sect ion 2.1.3, the list of studies identified in this process were also 
cross-referenced with genotoxic ity review articles for glyphosa te from the open literature [Kier 
and Kirkland (2013), and Williams et al.  (2000)], as well as recent inte rnational evaluations of 
glyphosate (IARC 2015, EFSA 2015, JMPR 2016).  The current anal ysis also includes studies 
conducted by other registrants th at were not previously availab le to the agency. S ixteen studies 
for glyphosate technical that w ere included in Kier and Kirklan d (2013) were not available to the 
agency; therefore, data and study s ummaries provided in the review articles were relied upon in 
the current review and are ident ified in the data tables with a  footnote. The Kier and Kirkland 
(2013) article serves as the orig inal publication for these stu dies and provided relevant 
information on study design and conditions as well as summary data.  The data set includes in 
vitro  and in vivo  studies conducted in mammalian s ystems, with the exception of standard 
bacterial test strains, whic h have a long history of detecting chemicals that are mutagenic in 
humans. Studies conducted in non-ma mmalian species (e.g. worms,  fish, reptiles, plants), were 
excluded because they were consider ed to be not relevant for in forming genotoxic risk in 
humans.  Several epidemiological s tudies that evaluated biomark ers for genotoxicity were not 
included in this evaluation because these studies were assigned  a low quality ranking as 
described in Section 3.3. 
When evaluating the quality of  the published and unpublished data for inclusion in the analysis, 
the agency considered the repor ting quality (how well a study w as reported), the study design 
and how well the study was conducted. Critical elements in stu dy design and interpretation for 
genotoxicity tests are described in the various EPA and OECD te st guidelines.  Elements such as 
test conditions (e.g. solubilit y, pH, osmolarity, and cytotoxicity) and study design (e.g. number 
of test organisms, doses selected, use of positive and negative  controls; blinded evaluation) were 
used to evaluate the qual ity of published and non-published studies.  In cases where 
inappropriate testing conditions or study design clearly had an  impact on the outcome the study, 
the study was excluded from the analysis.  For example, early s tudies by Majeska (1982) were 
excluded from the analysis since  it was clearly demonstrated th at altered pH by the test chemical 
can result in false positive responses in several of in vitro  genotoxicity tes ts (Majeska, 
1985d,e,f). In other cases, particul arly with the published literature studies, where test 
conditions and/or study design diffe red from what is generally considered as acceptable 
Page 99 of 216
	 
 
  
   
 
 
 
 
 
  
 
 
 
 following in the EPA or OECD guidelines, the differences are no ted, but the studies were not 
excluded from analysis unless the condition made the study unre liable.  Summaries of relevant 
genotoxicity studies can b e found in TXR# 0057499.  Studies tha t were excluded from the 
analysis are listed in Appendix G. 
The studies evaluating the geneti c toxicity of the active ingre dient glyphosate are presented in 
the following sections accordi ng to the type of genetic endpoin ts evaluated:  mutations, 
chromosomal aberrations and other assays evaluating DNA damage. In vitro and in vivo  assays 
are discussed separately according to the genetic endpoint.  Fo r the purpose of this analysis, 
glyphosate and its salts are cons idered together when evaluating the genotoxic potential of the 
active ingredient glyphosate.   
5.3 Tests for Gene Mutations for Glyphosate Technical 
5.3.1 Bacterial Mutagenicity Assays 
Bacteria have traditionally been e mployed as a primary test organism for the detection of 
chemical mutagens.  The bacterial reverse mutation assay is routinely performed in the test 
strains of Salmonella typhimurium  and Escherichia coli.  These test strains are mutant strains 
that are deficient for the synt hesis of an essential amino acid .  The assay detects mutations that 
revert the test strains back to wild type for amino acid synthesis and the revertants are identified by their ability to grow in culture  medium deficient of the specific amino acid(s).  This 
mutagenicity test identifies poi nt mutations, which includes ba se substitutions and deletions and 
insertions of up to a few base pair s (OECD 471).  The tests are  typically conducted in the 
presence and absence of an exogenous source of metabolic activa tion (e.g., S9 microsomal 
fraction of activated liver homoge nates) to identify potential mutagenic metabolites. 
Glyphosate has been extensively evaluated for its potential to induce mutations in bacteria.  Most 
of the studies considered consis t of the full battery of bacter ial strains ( i.e. the recommend strains 
in EPA and OECD Test Guidelines) and were evaluated at appropriate test concentrations (up to cytotoxic or assay limit concentrations).  
EPA identified 27 studies that tested glyphosate technical in b acterial mutagenicity assays by 
means of the standard plate i ncorporation method or the pre-inc ubation modification of the 
standard assay. Glyphosate was negative in the presence and absence of metabolic activation in 
all the studies. The results of  the bacterial reversion mutati on assays evaluating glyphosate 
technical are presented in Table 5.1 
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    Table 5.1. In vitro  Test for Gene Mutations in Bacteria: Glyphosate Technical. 
Test/ Test System Concentrations Purity Results Reference Comments 
Endpoint 
Bacterial Reverse S. typhimurium 156-5000 μg/plate  95.68% Negative ± S9 Akanuma (1995) 
Mutation TA1535, 
TA1537, TA98 and TA100 and 
WP uvrA ± S9 [MRID 50017102] 
Bacterial Reverse S. typhimurium 100-5000 μg/plate in 95.6% Negative ± S9 Callander (1996) 
Mutation TA535, TA1537, 
TA98 and 
TA100 and E. coli WP2P and 
WP2P uvrA ± S9 DMSO glyphosate 
acid [MRID 44320617] 
Bacterial Reverse S. typhimurium 100-5000 μg/plate in 60% Negative ± S9 Callander (1999)
1 
Mutation TA 1535, 
TA1537, TA98 
and TA100 and 
E. coli WP2P 
and WP2P uvrA 
± S9 water potassium glyphosate salt 
Bacterial Reverse S. typhimurium 25-2000 μg in Not provided Negativ e ± S9 Chruscielska et al. (2000) 
Mutation TA97a, TA98, TA100 and 
TA102, ± S9 aqueous solution 
Bacterial Reverse S. typhimurium 10-1000 µg/plate 98.4% Negative ± S9 Flowers and Kier (1978) 
Mutation TA98, TA100, 
TA1535, 
TA1537 
± S9 [MRID 00078620] 
Bacterial Reverse S. typhimurium 31.6-3160 µg/plate  98.8% Negative ± S9 Flügge (2009a)
1 
Mutation TA98, TA100, 
TA102, TA1535, TA1537 ± S9 
Bacterial Reverse S. typhimurium 31.6-3160 µg/plate  96.4% Negative ± S9 Flügge (2010b)
1 
Mutation TA98, TA100, 
TA102, TA1535, 
TA1537 ± S9 technical 
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    Table 5.1. In vitro  Test for Gene Mutations in Bacteria: Glyphosate Technical. 
Test/ Test System Concentrations Purity Results Reference Comments 
Endpoint 
Bacterial Reverse S. typhimurium 310-5000 μg/plate 98.6% Negative ± S9 Jensen (1991a) 
Mutation TA1535, (+S9); 160-2500 [MRID 49961502] 
TA1537, TA98 
and TA100 μg/plate (−S9) 
Bacterial Reverse S. typhimurium 1-1000 μg/plate 98.05% Negative ± S9 Miyaji (2008)1 
Mutation TA98, TA100, TA102, TA1535, 
TA1537 ± S9 
Bacterial Reverse S. typhimurium 5000 μg/plate Not report ed Negative ± S9 Moriya et al.  (1983) 
Mutation TA98, TA100, 
TA1535, 
TA1537, 
TA1538 ± S9 
Bacterial Reverse S. typhimurium 33-10,000 μg/plate 99% Negative ± S9 NTP (1992)  Hamster and rat S9 
Mutation TA1535, TA97, 
TA98 and 
TA100 ± S9 
Bacterial Reverse S. typhimurium 1-5000 µg/plate 61.27 % Negative ± S9 Ranzani (2000)
1 
Mutation TA98, TA100, 
TA1535 and 
TA97a ± S9 Glyphosate 
isopropyl -
amine salt 
Bacterial Reverse S. typhimurium 648-5000 µg/plate  98.01% Negative ± S9 Ribeiro do Val (2007) 
Mutation TA98, TA100, 
TA102, TA1535, 
TA1537 ± S9 [MRID 50000903] 
Bacterial Reverse S. typhimurium 31.6-5000 µg/plate 96.0% Negative ± S9 Schreib (2010)1 
Mutation TA98, TA100, 
TA1535, 
TA1537 and E. 
Coli WP2 uvrA ± 
S9 technical 
Page 102 of 216
	 
 
  
 
   
 
 
    
  
   
 
 
        
   
   
 
 
     
   
   
 
 
        
   
   
 
 
  
    Table 5.1. In vitro  Test for Gene Mutations in Bacteria: Glyphosate Technical. 
Test/ Test System Concentrations Purity Results 
Endpoint Reference Comments 
Bacterial Reverse 
Mutation S. typhimurium TA1535, 
TA1537, TA1538, TA98, 
TA100 and E. 
coli WP2  hcr ± 
S9 10-5000 μg/plate  98.4% Negative ± S9 Shirasu et al . (1978)  
[MRID 00078619] Published in Li & 
Long, 1988 
Bacterial Reverse 
Mutation S. typhimurium TA98, TA100, TA1535, 
TA1537 and E. 
coli WP uvrA ± 
S9 3-5000 µg/plate 
(plate-incorporation), 33-5000 µg/plate 
(pre-incubation test) 95.1% Negative ± S9 Sokolowski (2007a) 
[MRID 49957406] 
Bacterial Reverse 
Mutation S. typhimurium TA98, TA100, 
TA1535, TA1537 and E. 
coli WP uvrA ± 
S9 3-5000 µg/plate 
(plate–incorporation) 
33 – 5000 µg/plate (pre-incubation test) 97.7% Negative ± S9 Sokolowski (2007b) 
[MRID 49957407] 
Bacterial Reverse 
Mutation S. typhimurium TA98, TA100, 
TA1535, 
TA1537 and E. 
coli WP uvrA ± 
S9 3-5000 µg/plate (plate–incorporation) 
33-5000 µg/plate 
(pre-incubation test) 95.0% Negative ± S9 Sokolowski (2007c) 
[MRID 49957408] 
Bacterial Reverse 
Mutation S. typhimurium TA98, TA100, 
TA1535, 
TA1537 and E. 
coli WP uvrA ± 
S9 3-5000 µg/plate 96.66% 
technical Negative ± S9 Sokolowski (2009a)
1 
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 Table 5.1. In vitro  Test for Gene Mutations in Bacteria: Glyphosate Technical. 
Test/ Test System Concentrations Purity Results 
Endpoint Reference Comments 
Bacterial Reverse 
Mutation S. typhimurium TA98, TA100, 
TA1535, TA1537 and E. 
coli WP2 uvrA 
pKM 101 and WP2 pKM 101 ± 
S9 3-5000 µg/plate  96.3% 
glyphosate acid Negative ± S9 Sokolowski (2009b) 
[MRID 49961801] 
Bacterial Reverse Mutation S. typhimurium TA98, TA100, 
TA1535, 
TA1537 and E. 
coli WP uvrA ± 
S9 3-5000 µg/plate  97.16 % Negative ± S9 Sokolowski (2010) [MRID 50000902] 
Bacterial Reverse Mutation S. typhimurium TA98, TA100, TA1535, 
TA1537, 
TA1538  ± S9 1-1000 µg/plate 96.0% Negative ± S9 Suresh (1993a)
1 
Bacterial Reverse Mutation S. typhimurium TA98, TA100, 
TA1535, 
TA1537 and E. 
coli WP uvrA ± 
S9 0-5000 µg/plate  95.3% Negative ± S9 Thompson (1996) [MRID 49957409] 
Bacterial Reverse Mutation S. typhimurium TA98, TA100, TA102, TA1535, 
TA1537 ± S9 31.6-5000 µg/plate  98.2% Negative ± S9 Wallner (2010)
1 
Bacterial Reverse 
Mutation S. typhimurium TA98 and 
TA100 ± S9 25 µg/plate Not reported Negative ± S9 Wilderman and Nazar 
(1982) Rat S9 and plant cell-free homogenates were 
used for metabolic 
activation 
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        Table 5.1. In vitro  Test for Gene Mutations in Bacteria: Glyphosate Technical. 
Test/ Test System Concentrations Purity Results 
Endpoint Reference Comments 
Bacterial Reverse 
Mutation S. typhimurium TA1535, 
TA1537, TA1538, TA98 
and TA100 ± S9 0.12-10 mg/plate –S9 0.56-15 mg/plate +S9 90% glyphosate 
trimesium salt Negative ± S9 Majeska et al. (1982a) 
[MRID 00126612] 
Bacterial Reverse Mutation S. typhimurium TA1535, 
TA1537, TA98 
and TA100 ± S9 0.005-50 μL/mL  55.6% glyphosate 
trimesium salt Negative ± S9 Majeska (1985a) 
[MRID 00155527] 
1 Study was cited in Kier and Kirkland (2013).  Supplementary inf ormation about the study was provided online including test gui deline, test material purity, 
control chemicals and summary data tables. 
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  5.3.2 In vitro Tests for Gene Mutations in Mammalian Cells 
In vitro  gene mutation studies in mammalian cells are conducted in cell  lines with reporter genes 
for forward mutations. The most  common reporter genes are the endogenous thymidine kinase 
(TK) gene, endogenous hypoxanthine- guanine phosphoribosyl transferase (HPRT) gene and the 
xanthine-guanine phosphoribosyl t ransferase transgene (XPRT).  Mutations that occur within 
these reporter genes result in m utant cells that are resistant to the cytotoxic effect of the 
pyrimidine analogue trifluorothymidine (for TK) or the purine a nalogue 6-thioguanine (for 
HPRT and XPRT) (OPPTS 870.5330). S uitable cell lines for this assay include L5178Y mouse 
lymphoma cells, Chinese hamster ovary (CHO) cells, hamster AS52 and V79 lung fibroblasts and human TK6 lymphoblastoi d cells.  Similar to other in vitro  assays, chemicals are tested both 
in the presence and absence of S9 metabolic activation.   
A total of four studies were conducted for (forward) mutations in mammalian cells (Table 5.3).  
Three studies were conducted w ith a high purity concentration o f glyphosate technical (≥95.6%) 
and the remaining study was perf ormed with glyphosate trimesium  salt.  In four of the assays, 
mouse lymphoma L5178Y TK
+/- cells were the target organism and one was conducted in CHO 
cells with the HPRT endpoint. G lyphosate technical and the gly phosate trimesium salt were 
negative in the mouse lymphoma cell assays (Jensen, 1991b; Clay , 1996; Majesak, 1985b) when 
tested up to the current guidel ine limit concentration and glyp hosate was negative in CHO/HPRT 
cells when tested up to cytotoxic concentrations (Li, 1983a).  
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 Table 5.2. In vitro  Mammalian Gene Mutation A ssays: Glyphosate Technical. 
Test/Endpoint Test System Concentrations/ 
Conditions Test Material Purity Results Reference Comments 
Gene Mutations in 
Mammalian Cells Mouse lymphoma L5178Y TK
+/-cells ± S9 296-1000 µg/mL 95.6% Negative Clay (1996)1 Relative survival was 90% (-S9) and 57% 
(+S9) at top concentration 
Gene Mutations in 
Mammalian Cells Mouse lymphoma L5178Y TK
+/-cells ± S9 520–4200 µg/mL 
(+S9); 610–5000 
µg/mL (-S9) 98.6% Negative Jensen (1991b) 
[MRID 49961504] Reported no significant reduction in cloning 
efficiency at any 
concentration.    
Gene Mutations in 
Mammalian Cells Chinese hamster ovary (CHO) cells, HPRT locus ± S9 500–25000 µg/mL (+S9); 500-22500 µg/mL (-S9) 98.7% Negative Li (1983a); 
[MRID 00132681]  Tested S9 from 1-10% Cytotoxic at 22.5 mg/mL (-S9, and with 1,2 and 
10% S9) and at 17.5 
mg/ml (10% S9) 
Gene Mutations in Mammalian Cells Mouse lymphoma L5178Y TK
+/-cells ± S9 1-5 µl/mL 55.6% Glyphosate 
trimesium salt Negative Majeska (1985b) 
[MRID 00155530] Negative with pH adjusted 
1 Study was cited in Kier and Kirkland (2013).  Supplementary inf ormation about the study was provided online including test gui deline, test material purity, 
control chemicals and summary data tables. 
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 5.4 In vitro Tests for Chromosomal Abnormalities 
Cytogenetic assays are tests tha t can detect chemicals that cau se structural chromosomal damage 
(clastogenicity) or affect the segregation of chromosomes during cell division and alter 
chromosome number (aneuploidy).  Generally, there are two types  of in vitro  cytogenetic assays 
that identify chemicals inducing chromosomal abnormalities: chr omosomal aberration assays 
and micronucleus assays. Although chromosomal damage observed i n these assays are not 
considered heritable mutations, chemicals that can induce these  types of chromosomal damage 
can also induce transmissible mu tations to daughter cells indicating their role in cancer (Yauk et 
al., 2015; OECD 2015). In addition, assa ys such as (fluorescence in situ  hybridization (FISH)) 
can provide additional mechanis tic information on the formation  of chromosomal abnormalities. 
It is important to note that factor s such as cytotoxicity, solubility of the test s ubstance, changes in 
pH or osmolality play a significan t role in the outcome of the assay.  Like other in vitro  assays, 
compounds are generally tested in t he presence or absence of S9  metabolic activation to 
determine if metabolism affect s the genotoxic activity of the p arent compound and to determine 
if potential genotoxic me tabolites are formed.  
5.4.1 In vitro Mammalian Chromosomal Aberration Test 
Chromosomal aberration assays detect both structural chromosoma l and numerical aberrations. 
Structural chromosomal aberrations are of two types: chromatid and chromosome and include breaks, deletions and rearrangements (OPPTS 870.5375, OECD 2015 ).  Numerical chromosomal 
aberrations generally result from the loss of an entire chromos ome mostly due to damage in the 
spindle fiber resulting in aneuploidy. The types of cells that are most commonly used in 
chromosomal aberration assays include established cell lines su ch as Chinese hamster lung 
(CHL) and CHO cells or primary cell cultures such as human or o ther mammalian peripheral 
blood lymphocytes.  In this assay, cells are typically sampled at a time equivalent to the length of 
approximately 1.5 cell cycles from the start of treatment.  Pri or to harvesting, cells are treated 
with Colcemid
® or colchicine to arrest cells a t the first metaphase stage of the cell cycle 
following the beginning of exposure to the test article.  Once harvested, the cells are stained and 
metaphase cells are evaluated microscopically for various types  of chromosome aberrations. 
(OECD TG 473). Data should be pres ented in a way that indicates  the percentage of affected 
cells in the population of cells  scored (e.g., % cells with aberrations or # aberrant cells/100 cells). 
Gaps should not be included in the analysis; they are scored but gaps alone in the absence of any 
additional chromosomal aberratio ns (e.g., a fragment or a ring chromosome) are not sufficient to 
define a cell as aberrant. 
Glyphosate technical was evaluate d in eight chromosomal aberrat ions tests to determine its 
potential to induce clastogenic effects in vitro . The findings are presen ted in Table 5.3.  Six of 
the eight studies were negativ e.  The two positive studies were both from the same laboratory 
where, Lioi et al. reported an increase in chromos omal aberrations at glyphosate  concentrations 
of 8.5μM and above in bovine lymphocytes (Lioi et al. , 1998b) and at all c oncentrations of 
glyphosate tested (7-170 μM) in human lymphocytes (Lioi et al. , 1998a) following a 72-hour 
exposure period. No chromosomal aberrations were observed as a  result of exposure to 
glyphosate in one study using CHO cells (Majeska, 1985c) and in  two studies with CHL cells 
Page 108 of 216
	 
 
  
 
 
  
 
 
 (Matsumoto, 1995; and Wright, 1996).  Sivikova and Dianovsky (2006) reported no statistically 
significant increases in chromosomal aberrations in bovine lymphocytes treated with glyphosate 
(62% pure) at concentrati ons up 1120 μM following 24-hour expos ure. (Sivikova and 
Dianovsky, 2006). In studies conducted with human lymphocytes treated with glyphosate 
(≥95%) for 24-96 hours at concentr ations, no increase in chromo somal aberrations were seen at 
concentrations as high as 6000 μM (Fox, 1998; and Manas et al., 2009). 
5.4.2 In vitro Mammalian Micronucleus Test 
The in vitro  micronucleus test can detect t he induction of micronuclei in the cytoplasm of cells in 
the interphase stage of the cel l cycle.  Micronuclei form from acentric chromosome fragments 
(i.e., chromosome fragments lack ing a centromere) or when whole  chromosomes are unable to 
migrate to the cellular poles  during anaphase prior to cell div ision. (OECD 487).  Thus, the 
micronucleus assay can detect both structural an d numerical chr omosomal changes. It should be 
noted, however, that additional work is required to distinguish  whether induced micronuclei have 
arisen from a clastogenic versus an aneugenic mechanism, e.g., staining micronucle i to detect the 
presence of kinetochore protei ns.  The assay is typically perfo rmed with cell lines or primary cell 
cultures of human or rodent orig in.  The assay can be conducted with the addition of 
cytochalasin B which inhibits c ytokinesis resulting in the form ation of binucleated cells.  The 
presence of binucleated cells, indicates that cells have underg one one round of mitosis, a 
necessary prerequisite for  micronucleus formation.  
Six studies evaluated glyphosate technical for its potential to  induce micronuclei in vitro  (Table 
5.4). Four of the six studies were positive and the remaining t wo studies were equivocal. In a 
study by Koller et al. (2012), TR146 cells (derived from a human neck metastasis of buccal 
epithelial origin) were tre ated for 20 minutes with up to 20 mg /L (~0.12 mM) glyphosate (95%), 
the authors reported a statistically significant increase in bi nucleated cells wit h micronuclei at 15 
(~0.09 mM) and 20 (~0.12 mM) mg/L, and also indicated significa nt apoptosis and necrosis at 
20 mg/L.  The short exposure pe riod in this study was unusually  short (20 minutes) and was 
conducted in a tumor cell line  that had not been well character ized in regards t o its degree of 
chromosomal instability and DNA damage and repair capacity.  In  another study, Roustan et al. 
(2014) reported positive findings  +S9 only in CHO cells treated  with glyphosate (unknown 
purity) at 10- 100 μg/mL with littl e evidence of a dose response over that concentration range.  
Two other studies evaluated glyphos ate technical in human lymph ocytes (Mladinic et al., 2009a, 
2009b). These studies used an expos ure protocol that is differ ent from the OECD 
recommendations for the in vitro  micronucleus assay.  OECD recommends that whole blood or 
isolated lymphocytes are culture d in the presence of a mitogen (e.g. phytohemagglutinin; PHA) 
prior to exposure of a test ch emical in order to detect micronuclei formed via an aneugenic 
mechanism.  However, in these tw o studies, blood cells were exp osed to glyphosate for 4 hours, 
washed, and then treated with PHA to stimulate cell division. B oth studies reported a statistically 
significant increase in micronucle ated cells at 580 μg/mL (~3.4  mM), but not at lower 
concentrations, following 4-hour exposures in the presence of S 9.  The frequency of 
micronucleated cells (+S9)  ranged from 11.3 to 28.7 in one stud y (Mladinic et al., 2009a) and 
33.3 to 65.2 in the other study (Mladinic et al., 2009b) over the 1000-fold concentration range. 
No statistically significant inc reases in micronucleated cells were seen in either study in the 
absence of S9 activation. Whe n cells were evaluated with vital stains, cells treated with 580 
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 μg/mL showed a significant (p<0.05 ) increase in the percentage of cells undergoing apoptosis 
and necrosis compared to the negative controls.   
Piesova et al.  (2004, 2005) conducted two in vitro  micronucleus studies using glyphosate 
technical (62%) up to 560 µM in bovine lymphocytes.  In the 200 4 study, bovine lymphocytes 
from two donors were treate d for 24 or 48 hours w ithout S9 meta bolic activation, and for 2 hours 
(with and without S9 activatio n) or 48 hours (-S9) in the 2005 study.  Both studies yielded 
similar results following 48-hour  exposure to glyphosate.  In b oth cases, the authors reported a 
weak induction of micronuclei i n one donor at 280 μM and at 560 μM in the second donor.  The 
induction was approximately 2-f old (p < 0.05), but with no clear dose response. No effects on 
micronuclei induction were seen at the 2- or 24-hour time point s; however, with these early time 
points it is unlikely that one  cell division has occurred durin g or after treatment.    
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	Table 5.3. In vitro Tests for Chromosome Aberrations in Mammalian Cells- Glyphosate Technical 
Test/Endpoint Test System Concentrations/ Test Material Results Reference Comments 
Conditions Purity 
In vitro 
Chromosomal Aberration Chinese hamster ovary (CHO) cells 4-10 µl/mL, ± S9 55.6% Glyphosate trimesium salt Negative Majeska (1985c) [MRID 00155530] pH adjusted (7.4-7.6) 
In vitro Chinese Hamster lung ±S9: 0, 250, 500, 1000 95.68% Negative Matsumoto (1995) Decline in pH noted at 
Chromosomal (CHL) cells and 2000 µg/mL; 24 [MRID 50017106] 500 and 1000 µg/mL.  
Aberration and 48 h treatment - S9; 6 h treatment ±S9 
harvest 24 h 
In vitro Chinese hamster lung -S9: 24 & 48-hr 95.3% Negative Wright (1996) Excessive decrease in 
Chromosomal (CHL) cells exposure: 0-1250 [MRID 49957410] pH >1250 µg/mL 
Aberration µg/mL; 
+S9: 0-1250 µg/mL 
In vitro Chromosomal 
Aberration Bovine lymphocytes -S9 only: 0, 7, 85 and 
170 μM; 
72 h exposure ≥98% Positive 
(all concs.) Lioi et al.  (1998b) 
In vitro Bovine lymphocytes ±S9: 0, 28, 56, 140, 62.0% Negative Sivikova and Decreased MI and PI at 
Chromosomal 280, 560 and 1120 Dianovsky (2006) ≥ 560 µM 
Aberration µM; 
24 h exposure 
In vitro 
Chromosomal Aberration Human lymphocytes ±S9: 100-1250 µg/mL cultures analyzed;  68 & 92 h 95.6% Negative Fox (1998) 
[MRID 49961803] Excessive decrease in pH >1250 µg/mL 
In vitro 
Chromosomal 
Aberration Human lymphocytes -S9 only: 0, 5.0,  
8.5, 17.0 and 51.1 μM; 
72 h exposure ≥98% Positive 
≥ 8.5 μM Lioi et al.  (1998a) No significant ↓ in MI observed. 
In vitro 
Chromosomal 
Aberration Human lymphocytes -S9: 0, 200, 1200 and 
6000 μM; 48 h 
exposure 96.0% Negative Manas et al. (2009) No toxicity observed up 
to 6000 µM 
1 Study was cited in Kier and Kirkland (2013).  Supplementary inf ormation about the study was provided online including test gui deline, test material purity, 
control chemicals and summary data tables.  
CA= chromosomal aberrations, MI= mitotic index, PI= proliferati on index. 
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 . Table 5.4. In vitro Tests for Micronuclei Induction in Mammalian Cells- Glyphosate Technical 
Test/ Test System Concentrations/ Test Material Results Reference Comments 
Endpoint Conditions Purity 
In vitro Cytokinesis Block 
Micronucleus 
Assay (with FISH 
analysis) TR146 cells 
(human-derived buccal carcinoma 
cell line) 
10, 15 and 20 mg/L; 
20-minute exposure. 95% Positive 
Statistically significant 
(p<0.05) increase in MN 
at 15 and 20 mg/L. Koller et al. 
(2012) Apoptosis and necrosis reported at 20 mg/L 
Also reported ↑ in NB 
and NPB 
In vitro Cytokinesis 
Block 
Micronucleus Test CHO-K1 cells 5 - 100 µg/mL, ±S9 Not stated Negative –S9 
Positive +S9 at 10-100 
µg/mL Roustan et al. , 
(2014) No clear dose response 
In vitro Bovine lymphocytes 0, 28, 56, 140, 280 62% 24 h: Negative  Piesova, 2004 No dose-response No 
Cytokinesis (2 donors) and 560 μM significant decrease in 
Block 
Micronucleus 
Test 24 & 48 h exposure 48 h: Equivocal 
↑ MN at 280 μM only 
(donor A) ↑ MN at 560 μM only (donor B)  CBPI observed.  
In vitro Bovine lymphocytes 0, 28, 56, 140, 280 62%  2 h: Negative  Piesova, 2005 No dose-response; No 
Cytokinesis (2 donors) and 560 μM; 2 h significant decrease in 
Block (±S9) and 48 h (-S9) 48 h: Equivocal CBPI observed.  
Micronucleus exposure Metabolic activation 
Test ↑ MN at 280 μM only (donor A) and at 560 μM only (donor B) had no effect on MN formation after 2 h exposure. 
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   . Table 5.4. In vitro Tests for Micronuclei Induction in Mammalian Cells- Glyphosate Technical 
Test/ Test System Concentrations/ Test Material Results Reference Comments 
Endpoint Conditions Purity 
In vitro Human lymphocytes 4h treatment ±S9; 98.0% Negative –S9 Mladinic et al. Cells were exposed to 
Cytokinesis (treated with 0.5, 2.91, 3.50, 92.8 (2009a) glyphosate and washed 
Block cytochalasin B) and 580 µg/mL; Positive +S9, ↑ MN at prior to treatment with 
Micronucleus 
Assay (with FISH 
analysis) harvested 72 h 580 µg/mL, but not at 
0.5-92.8 µg/mL 
Also observed ↑ in NB 
at 580 µg/mL (±S9); ↑ 
NPB at 580 µg/mL 
(+S9) PHA. Authors did not report being blind to 
treatment.  
In vitro Human lymphocytes 4h treatment ±S9; 98% Negative –S9 Mladinic et al. Cells were exposed to 
Cytokinesis (treated with 0.5, 2.91, 3.50, 92.8 (2009b) glyphosate and washed 
Block 
Micronucleus 
Assay 
(with FISH analysis) cytochalasin B) and 580 µg/mL Positive +S9  
 ↑ MN at 580 µg/mL, 
but not at 0.5 -92.8 
µg/mL 
↑ apoptosis and necrosis 
at 580 µg/mL (-S9); 
↑ apoptosis at ≥ 2.91 
µg/mL and necrosis at 580 µg/mL (+S9) 
↑ in NB at 580 µg/mL 
(±S9) and NPB at 580 
µg/mL (+S9) prior to treatment with 
PHA. 
Authors did not report 
being blind to treatment.  
. 
CBPI= cytokinesis block proliferation index, FISH= fluorescent in situ hybridization; MN= micronuclei; NB= nuclear buds; NPB= nucleoplasmic bridges.
	
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 5.5 In Vivo  Genetic Toxicology Tests   
5.5.1 In Vivo  Assays for Chromosomal Abnormalities 
5.5.1.1 Mammalian Bone Marrow Chromosomal Aberration Assays 
The in vivo  mammalian bone marrow chromosomal assay detects the ability of a chemical to 
cause structural chromosomal damage in cells in the bone marrow .  The assay is typically 
conducted in rodents (mouse or rat) and detects both chromosome -type and chromatid-type 
aberrations. Chromatid-type abe rrations are expressed when a single chromatid break occurs 
and/or a reunion between chromatid s, and chromosome-type aberra tions result from damage 
expressed in both sister chro matids (OPPTS 870.5385).  In this test, animals are exposed 
(typically via oral route or int raperitoneal injection) and sac rificed at sequential intervals.  Prior 
to sacrifice, animals are treat ed with a spindle inhibitor such  as colchicine or Colcemid® to arrest 
cells at metaphase. Chromosome preparations from the bone marro w are stained and scored for 
chromosomal aberrations. (O PPTS 870.5385). Generally, the optim al time to detect 
chromosomal aberrations in the bone marrow is 24 hours after tr eatment.  
Three in vivo  mammalian bone marrow chromosomal assays were conducted with g lyphosate 
technical for regulatory purposes  and all were negative (Table 5.8).  In the first study, Sprague 
Dawley rats were administere d glyphosate (9 8%) at 0 or 1000 mg/ kg and the bone marrow was 
sampled at 6, 12 or 24 hours after dosing.  No significant incr ease in bone marrow chromosomal 
aberrations were observed ( Li, 1983b).  In the second study, Sw iss albino mice were treated 
twice by oral gavage (24 hours apart) with 0 or 5000 mg/kg glyphosate technical (96.8%) 
resulting in no significant inc rease in bone marrow chromosomal  aberrations (Suresh, 1994). In a 
third study conducted with glyphosat e trimesium salt, no increa se in chromosomal aberrations 
were seen in the bone marrow of  rats treated by oral gavage wit h up to 188 mg/kg (Majeska, 
1982c). 
5.5.1.2 Rodent Dominant Lethal Test 
Dominant lethal mutations cause  embryonic or fetal death.  The induction of a dominant lethal 
mutation after exposure to a che mical indicates that the test chemical has affected the germinal 
tissue (sperm at some point in d evelopment, from stem cell to spermatocyte).  Dominant lethal 
effects are considered to result from chromosomal damage (struc tural or numerical), but may 
also reflect gene mutations or s ystemic toxicity (OPPTS 870.5450, OECD 2016).  In this test, 
male rodents are treated with the  test material and mated with (untreated) virg in females.  The 
female animals are sacrificed a t an appropriate time and the ut eri are examined to determine the 
number of implants, and live a nd dead embryos.  Two dominant le thal studies w ere identified.   
One study was conducted in the rat (Suresh, 1992) where male ra ts were dosed by oral gavage 
with glyphosate up to 5000 mg/kg.  The other study (Rodney, 198 0) was conducted in male mice 
treated with up to 2000 mg/kg glyphos ate (98.7%) by oral gavage.  No significant increase in 
dominant lethal mutations wer e observed in either study (Table 5.5).   
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 5.5.1.3 In Vivo  Mammalian Erythrocyte Micronucleus Assays 
The mammalian micronucleus test is the most commonly conducted in vivo  test to detect 
clastogenic or aneugenic chemi cals.  The test identifies chemic als that induce micronuclei in 
proerythrocytes (pr ogenitor cells) by assessing micronucleus fr equency in immature erythrocytes 
(polychromatic erythrocytes, PCEs) sampled from the bone marrow  or from the peripheral blood 
(reticulocytes). This test is typically conducted in mice or r ats.  When bone marrow 
erythroblasts develop into erythrocytes, the main nucleus is extruded following the final cell 
division (erythrocytes are the only mammalian cell that does no t contain a nucleus). Any 
micronuclei formed after the final cell division may remain in the cytoplasm following extrusion 
of the main nucleus.  The visua lization of micronuclei is facil itated by the lac k of a nucleus in 
these cells (OPPTS 870.5395, OECD 474). Micronuclei can origin ate from acentric 
chromosomes, lagging chromosome fragments, or whole chromosomes ; thus, micronuclei are 
biomarkers of both altered chromosome structure or chromosome n umber. The assay is based on 
an increase in the f requency of micronucleated erythrocytes in treated animals, in either 
peripheral blood samples or bone marrow samples (OPPTS 870.5395 ).  Additional mechanistic 
information on the formation of chromosomal abnormalities can b e obtained from the 
incorporation of centromeric and t elomeric fluorescent probes (FISH) assay.  According to EPA 
test guidelines, a single dose of  the test substance may be used in this test if the dose is the 
maximum tolerated dose (MTD), a dose that produces some indicat ion of bone marrow 
cytotoxicity (e.g., a reduction in the proportion of immature erythrocytes (PCEs) to total erythrocytes by >50%) or a maximum limit dose of 5000 mg/kg.  T he routes of administration 
for this test are typically oral  or intraperitoneal injection a nd generally in volve a single 
administration.   
Glyphosate technical has been ext ensively evaluated for micronu clei induction in in vivo  studies. 
Fourteen studies wer e conducted for regul atory purposes, four w ere identified from the open 
literature, and one study was conducted by the U.S. National Toxicology Program (NTP).  This 
included nine studies with admin istration of glyp hosate by the intraperitoneal (i.p.) route and 10 
studies by the oral route. The findings are presented in Table  5.10.  Of the nine i.p. studies, 
seven (Costa, 2008; Chruscielska et al. , 2000; Durward, 2006; Gava, 2000; Marques, 1999; Rank 
et al. , 1993 and Zaccaria, 1996) were negative.  These studies tested  doses as high as 2016 
mg/kg (single and double administration) with sampling times at  24- and 48-hours post-dose.  
Two positive findings were reported when glyphosate technical was administered by i.p.  
Bolognesi et al.  (1997) reported a significant in crease in micronuclei in the b one marrow of male 
Swiss CD mice 24 hours after i.p. treatment with 300 mg/kg glyp hosate technical (99.9%).  The 
dose in this study was administe red as ½ dose (150 mg/kg) injec tions 24 hours apart to 3 male 
mice.  Manas et al.  (2009) evaluated glyphosate technical (96%) in BALB/c male and  female 
mice (5/sex/dose) administered 50, 100 or 200 mg/kg by two i.p.  injections, 24 hours apart.  The 
results showed a significant inc rease in micronuc leated erythro cytes at 200 mg/kg, but not at 50 
or 100 mg/kg.  It should be noted that doses that resulted in the positive responses in these two studies were above the reporte d i.p. LD50 value (130 mg/kg) for  glyphosate in mice (NTP 1992).    
Glyphosate technical was also eva luated in nine micronucleus as says with administration by the 
oral route in mice and one in the  rat.  Eight of the nine oral studies in the mouse were negative 
for micronuclei induction.  The s ingle positive response was se en in female mice treated with 
Page 115 of 216
	 
 
  
 
  two 5000 mg/kg doses (limit dose) , 24 hours apart with bone mar row sampling at 24-hours post-
dose (Suresh, 1993b). No increase wa s observed at lower doses (50 and 500 mg/kg) in females 
or at any dose in males.  The eight  negative oral studies in mi ce included single dose 
administrations of 5000 mg/kg and bone marrow analysis at 24, 48, and/or 72 hours (Jensen, 
1991c; Fox and Mackay, 1996) and one or  two administrations of glyphosate technical with top 
doses between 30 and 2000 mg/kg (H onarvar, 2005; Honarvar, 2008 ; Jones, 1999; and Zoriki-
Hosmi, 2007). It should be noted that evaluations at 48 and 72 hours post dose may be too late to 
detect chemically-induced micronucleated PCEs in the bone marro w as these cells may have 
already migrated into the peri pheral blood.  No significant in crease in micronucleated 
erythrocytes were seen in male or female mice following 13-week s of dietary (feed) 
administration of glyphosate tec hnical at doses up to 3393 mg/k g/day (NTP, 1992).  In the single 
study that evaluated micronuclei induction in rats, glyphosate technical did not induce significant 
induce micronuclei in CD1 rats treated by oral gavage at doses up to 2000 mg/kg (Flügge, 
2009b). When glyphosate trimesium salt was evaluated, no increase in micronuclei induction was seen in mice treated orally up to 1100 and 800 mg/kg in males and females, respectively (Majeska, 1987). 
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  Table 5.5. In Vivo  Tests for Chromosomal Aberrations in Mammals- Glyphosate Techn ical. 
Test/Endpoint Test System Route of Doses Test Results Reference 
Administration Material 
Purity Comments 
Bone Marrow 
Chromosomal 
Aberration Test Sprague Dawley rats  
(males and females) Intraperitoneal injection; 
sampled at 6, 12 and 24 h after 
treatment 0, 1000 mg/kg (6/sex/dose/samp 
ling time) 98% Negative Li (1983b) 
[MRID 00132683] No toxicity observed. A separate study 
using 
14C-glyphosate 
showed that 
glyphosate reaches 
BM 0.5 h after dosing with ½ life 
elimination at 7.6 h. 
Peak BM value was 
400 ppm, 
corresponding to 2000 ppm plasma value. 
Bone Marrow 
Chromosomal 
Aberration Test Sprague Dawley rats  
(males and females) 
Vehicle: distilled water Oral gavage, 
sampling after 6, 
12, 24, 48 h and 5 d 
0, 21, 63 and 
188 mg/kg 58.5% 
Glyphosate 
trimesium salt Negative Majeska (1982c) 
[MRID 00132176] 
Bone Marrow 
Chromosomal 
Aberration Test Swiss Albino mice 
(males and females) 
Vehicle: peanut oil Oral gavage 
(2 treatments, 24 
h apart); sampling after 24 
h (last treatment) 0, 5000 mg/kg 
(5/sex/dose) 96.8% Negative Suresh (1994) 
[MRID 49987408] Significant (p<0.05) decrease in bw of 
females at high dose.  
Rodent Dominant Lethal Test CD-1 mice Each dosed male mated with 2 
females/week for 8 
weeks Oral gavage 
0, 200, 800, 
and 2000 mg/kg 98.7% Negative Rodwell (1980) 
[MRID 00046364] 
Rodent 
Dominant 
Lethal Test Wistar rat 
Each dosed male 
mated with 1 female/week for 10 
weeks Oral gavage 
0, 200, 100 and 
5000 mg/kg 96.8% Negative Suresh (1992) 
[MRID 49987404 ] 
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 Table 5.6. In Vivo Tests for Micronuclei Induction in Mammals-  Glyphosate Technical. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material 
Purity 
Bone Marrow Swiss CD1 mice Intraperitoneal 0, 300 mg/kg 99.9% Positive Bolognesi et al. Material and methods 
Micronucleus (males only) injection; 2 (3/dose) (1997) indicate 3 
Test injections of half the dosage of 300 mg/kg 24 h apart; 
sampling at 6 and 
24 h Stat significant increase in 
MN at 24 h animals/dose; 
however, Table 1 of article indicates 4 
animals were 
evaluated.  
Bone Marrow Balb C mice Intraperitoneal 0, 50, 100, and 96% Positive Manas et al. No significant signs 
Micronucleus (males and females) Injection (two 200 mg/kg (2009) of toxicity observed. 
Test Vehicle: Saline injections, 24 h 
apart); sampling 
after 24 h (last treatment) (5/sex/dose) ↑MN at 200 
mg/kg, but 
not at 50 or 100 mg/kg 
Bone Marrow C3H mice Intraperitoneal 0, 300 mg/kg Not Negative  Chruscielska et 
Micronucleus (males only) Injection reported al. (2000) 
Test Vehicle: water (single treatment); 
sampling after 24, 
48 and 72 h 
Bone Marrow Swiss Albino mice Intraperitoneal 0, 15.62, 31.25, 980 g/kg Negative# Costa (2008)
1 OECD guideline 474 
Micronucleus (males and females) Injection and 62.5 mg/kg Glyphosate 
Test Vehicle: corn oil (2 treatments, 24 h apart); sampling 
after 24 h (last 
treatment) (5/sex/dose) technical #Was not tested up to limit dose and did not 
demonstrate that 
compound was tested 
up to toxic dose.  No 
mention of BM toxicity or clinical 
signs. 
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     Table 5.6. In Vivo Tests for Micronuclei Induction in Mammals-  Glyphosate Technical. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material 
Purity 
Bone Marrow Crl:CD-1TM(ICR) Intraperitoneal 0, 150, 300 and 95.7% Negative Durward (2006) Clinical signs 
Micronucleus BR mice Injection 600 mg/kg [MRID 49957411] reported at ≥ 150 
Test (males only1) 
Vehicle: PBS (single treatment); sampling after 24 and 48 h (high 
dose only) (7/dose) mg/kg. Significant ↓ 
in %PCEs reported at 24 h in 600 mg/kg 
group. ↑in MN PCEs 
observed at 600 
mg/kg (1.9± 0.7 vs. 
1.0 ± 1.2 control; p<0.05), at 24 h, but 
not 48 h, within 
historical control range. 
Bone Marrow Swiss Albino mice Intraperitoneal 0, 1008, 2016, 612.7 g/kg Negative Gava (2000)
1 LD50 was 4032 
Micronucleus (males and females) Injection and 3024 mg/kg (glyphosate mg/kg 
Test Vehicle: water (2 treatments, 24 
h apart); sampling 
after 24 h (last treatment) 5/sex/dose technical 
Nufarm) Mortality observed in 1 animal at high dose 
(only 4 m/f scored for MPCEs). 
 No effect on 
PCE/NCE. 
Bone Marrow Swiss Albino mice Intraperitoneal 0, 187.5, 375 954.9 g/kg Negative Marques (1999) LD50 was 750 mg/kg 
Micronucleus (males and females) Injection and 562.5 mg/kg (glyphosate [MRID 49957412] No significant signs 
Test Vehicle: water (2 treatments, 24 h apart); sampling after 24 h (last 
treatment) 5/sex/dose technical 
Nufarm) of toxicity observed in main study 
Bone Marrow NMRI-Bom mice Intraperitoneal 0, 150, and 200 glyphosate Negative Rank et al.  (1993) 
Micronucleus Injection (single mg/kg isopropyla 
Test treatment); sampling after 24 h (all doses) and 
48 h (150 and 200 
mg/kg) (5/sex/dose) mine (purity not specified) 
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 Table 5.6. In Vivo Tests for Micronuclei Induction in Mammals-  Glyphosate Technical. 
Test/Endpoint Test System Route of Doses Test Results 
Administration Material 
Purity Reference Comments 
Bone Marrow Micronucleus 
Test Swiss albino mice 
(males and females) Intraperitoneal Injection 
(2 treatments, 24 
h apart); sampling after 24 h (last 
treatment) 0, 68, 137, and 
206 mg/kg ( 360 g/L Negative  Zaccaria (1996) [MRID 49961501] Doses selected were reported as 
corresponding to 25, 
50 and 75% LD
50 
Bone Marrow Micronucleus 
Test CD-1 mice 
(males and females)  
Vehicle: saline Oral gavage 
(single treatment); 
sampling after 24 
and 48 h 0, 5000 mg/kg 5/sex/dose 95.6% Negative Fox and Mackay 
(1996) 
[MRID 44320619] No significant signs 
of toxicity observed 
Bone Marrow Micronucleus 
Test NMRI mice 
(males and females) 
Vehicle: PEG 400 Oral gavage 
(single treatment); 
sampling after 24 
and 48 h (high dose only) 0, 500, 1000, and 2000 mg/kg 
5 sex/dose 97.73% Negative Honarvar (2005)
1 OECD guideline 474 
No significant signs 
of toxicity observed 
Bone Marrow 
Micronucleus 
Test NMRI mice 
(males only) 
Vehicle: 0.5% 
carboxymethyl -
cellulose Oral gavage 
(single treatment); 
sampling after 24 
and 48 h (high 
dose only) 0, 500, 1000, and 2000 mg/kg 
(5/dose) 99.1% Negative Honarvar (2008) 
[MRID 49961802] No significant signs 
of toxicity observed 
Bone Marrow 
Micronucleus 
Test NMRI mice 
(males and females) 
Vehicle: 0.5% 
carboxymethyl -
cellulose Oral gavage 
(single treatment); 
sampling after 24, 
48 and 72h 0, 5000 mg/kg; 
5/sex/dose 98.6% Negative Jensen (1991c) [MRID 49961503] No significant signs of toxicity observed 
Bone Marrow 
Micronucleus Test CD-1 mice (males only
1) 
Vehicle: water Oral gavage single treatment); sampling after 24 
and 48 h 0, 2000 mg/kg 
5/dose 59.3% potassium glyphosate 
salt Negative Jones (1999)
1 OECD guideline 474 
No significant signs of toxicity observed 
Bone Marrow 
Micronucleus 
Test Swiss albino mice; 
(males and females) 
Vehicle: peanut oil Oral gavage 
(2 treatments, 24 
h apart); sampling 0, 50, 500, 5000 
mg/kg  
5/sex/dose 96.8% 
glyphosate 
acid Positive in 
females at 
5000 Suresh (1993b) 
[MRID 49987407] No significant signs of toxicity observed 
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 Table 5.6. In Vivo Tests for Micronuclei Induction in Mammals-  Glyphosate Technical. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material 
Purity 
after 24 h (last mg/kg 
treatment) only. 
Negative in 
males at all 
doses 
Bone Marrow Swiss mice Oral gavage 0, 8, 15 and 30 980.1 g/kg Negative Zoriki Hosomi OECD guideline 474 
Micronucleus (males only) (2 treatments, 24 mg/kg (2007) No significant signs 
Test Vehicle: corn oil h apart); sampling 
after 24 h (last treatment) (6/dose) [MRID 50000901] of toxicity observed 
Bone Marrow CD-1 mice Oral gavage, 
Males: 0, 700, 55.3% Negative Majeska (1987) 
Micronucleus (males and females) Sampling 24, 48 900 and 1100 Glyphosate [MRID 40214004] 
Test Vehicle:  distilled water and 72 h after treatment 
mg/kg  
Females: 0, 
400, 600 and 
800 mg/kg trimesium 
salt 
Bone Marrow B6CF3 Mice Oral (dietary). 0, 205/213, 99% Negative NTP (1992) 
Micronucleus (males and females) MN assay 410/421, 
Test conducted following 13 -
week feed study. 811/844, 1678/1690 and 3393/3393 
mg/kg (m/f)  
(10/sex/dose) 
Bone Marrow CD Rats Oral gavage 0, 500, 1000, and 98.8% Negative Flügge (2009b)
1 OECD guideline 474 
Micronucleus (males and females) (single 2000 mg/kg No significant signs 
Test Vehicle: 0.8% hydroxypropylmethyl 
cellulose treatment); 
sampling after 24 
and 48 h (high 
dose only) (5/sex/dose) of toxicity observed 
1 Study was cited in Kier and Kirkland (2013).  Supplementary inf ormation about the study was provided online including test gui deline followed, test material 
purity, control chemicals and summary data tables.
	
2Only males tested; report indicat ed that there was no differenc e between sexes seen in range finding study.
	
CA= chromosomal aberrations, MPC E= micronucleated polychromatic  erythrocytes, NCE= normochromatic erythrocytes, PCE=polychroma tic erythrocytes.
	
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 5.6 Additional Genotoxicity Assays E valuating Primary DNA Damage  
There are a number of genotoxic ity assays that evaluate primary  DNA damage, but do not 
measure the consequence of the genetic damage ( i.e., mutation or chromosomal damage).  As 
discussed in the Guidance Docu ment on Revisions to OECD Genetic  Toxicology Test 
Guidelines (OECD 2015), the endpoints measured in primary DNA d amage tests such as DNA 
adducts, comet assay, or unscheduled DNA synthesis may lead to cell death or may initiate DNA 
repair, rather than a mutati on.  These types of assays can, how ever, provide mechanistic 
information when interpreting pos itive findings in other genotoxicity tests or when determining 
whether a chemical is acting thr ough a mutagenic mode of action .  Additionally, indirect 
mechanisms of DNA damage such as oxidative DNA damage can be de tected by these test 
systems.  Oxidative damage results from oxidative stress, which  occurs when there is a 
disturbance in the balance between the production of reactive o xygen species (ROS) and 
antioxidant defense systems.  Normal cellular metabolism is a s ource of endogenous reactive 
oxygen species that accounts fo r background levels of oxidative damage in normal cells.  Some 
types of oxidative damage are rep airable while others lead to s erious consequences in the cell.  
(Cooke et al, 2003). The various assays evaluating primary DNA  damage in glyphosate 
technical are presented in Tabl e 5.7.  Details of the findings are discussed below. 
Glyphosate technical is  not electrophilic and is not considered  to be DNA-reactive.  In a study to 
evaluate the potential for glyphos ate to directly interact with  DNA, Peluso et al.  (1998) reported 
that glyphosate technical did not f orm DNA adducts in mice when  tested up to 270 mg/kg via i.p. 
Bolognesi et al.  (1997) reported an increase in t he oxidative damage biomarker 8-
hydroxydeoxyguanosine (8-OHdG) in t he liver 24 h after i.p. inj ection of 300 mg/kg in mice.  
No increase in 8-OHdG was seen i n the kidney with glyphosate te chnical.  The dose in this study 
was high (300 mg/kg) for an i.p. injection and within the i.p. LD 50 range (134- 545 mg/kg) that 
has been reported elsewhere (WHO, 1994). 
The comet assay, also known as si ngle cell gel electrophoresis (SCGE), is a sensitive and rapid 
method to detect DNA strand breaks in individual cells. In this  assay, individual cells are 
embedded in agarose.  The cells a re then lysed (which digests the cellular and nuclear 
membranes) and the DNA is allo wed to unwind under alkaline or neutral conditions.  During 
electrophoresis, chromatin (whic h is in a supercoiled state) th at has undergone steric relaxation 
due to DNA damage migrates away f rom the nucleoid (nucleus) tow ard the anode, yielding 
images that resemble a comet.  T he intensity of the comet tail relative to the comet head reflects 
the amount of DNA breakage (Tice et al. , 2000; Collins et al. , 2008). The comet assay can 
detect single and double strand br eaks resulting from direct in teractions with DNA, alkali labile 
sites, or transient DNA breaks resulting during DNA excision re pair. These types of strand 
breaks may be, (a) repaired wit h no persistent effect, (b) be l ethal to the cell or (c) be fixed as a 
mutation (OECD TG 489).  DNA strand breaks in the comet assay can be measured by endpoints 
such as percent tail DNA (also r eferred to as % tail intensity) , tail length, and tail moment.  
However, % tail DNA is the recom mended metric for evaluating an d interpreting results using 
this assay (OECD TG 489). 
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 The five studies that evaluate d glyphosate tec hnical using the comet assay are summarized in 
Table 5.12. Two of the studies w ere conducted using tumor cell  lines.  Koller et al.  (2012) 
reported positive comet effects (increased tail intensity) in a human buccal carcinoma cell line 
(TR146) following a 20-minute tr eatment with ≥ 20 mg/L (~0.118 mM) glyphosate. Although no 
evidence of cytotoxicity was re ported in this study, the authors did report an increase in 
apoptosis and necrosis at the same concentrations (≥ 20 mg/L) w hen the same cell line was tested 
for in vitro  micronuclei induction (discussed previously).  In a study usin g Hep-2 cells 
(presumably a HeLa ce ll derivative), Manas et al.  (2009) reported a statistically significant 
increase in mean tail length, and t ail intensity at all concent rations (3.0-7.5 mM) tested. In a 
comet study conducted on human lym phocytes, Alvarez-Moya et al.  (2014) reported significant 
increases in tail length onl y (but not % tail DNA) following tr eatment with glyphosate 
concentrations of 0.7-700 μM. Mladinic et al.  (2009a) evaluated DNA damage in non-dividing 
human lymphocytes (±S9) follo wing treatment from 0.5 to 580 µg/mL using the standard 
alkaline comet method and a modi fied comet method that detects DNA damage due to oxidative 
damage (human 8-hydroxyguanidine DNA-glycosylase, hOGG1 comet m ethod).  In this study, 
the authors reported statistically significant increases in tai l intensity at 3.5 µg/mL and higher in 
the absence of S9, with signifi cance only at 580 µg/mL (~3.4 mM ) in the presence of S9 using 
the alkaline method.  This concen tration also re sulted in increased apoptosis and necrosis as well 
as an increase in plasma total a ntioxidant capacity (TAC) and c hanges in plasma lipid 
peroxidation (thiobarbituric r eactive substances, TBARs); howev er, only a dose-related increase 
in tail length (not %  tail DNA) was observed at 580 µg/mL (+S9)  using the hOGG1 method.  
When the Manas et al.  (2013) evaluated blood and liver  cells following a 14-day drin king water 
study in mice treated with 40 and 400 mg/kg/day glyphosate, sig nificant increases in tail 
intensity, tail length and tail m oment were reported were obser ved at both doses in both tissues 
(except for DNA tail intensity in liver at 40 mg/kg); however, there were no substantial effects 
on oxidative stress measurements suggesting that DNA damage reported may not be due to 
oxidative damage.   
The Unscheduled DNA Synthesis (UDS) test with mammalian liver c ells in vitro  identifies 
substances that induce DNA repair after excision and removal of  a segment of damaged DNA.  
The test is typically conducted i n liver cells, which have relatively few cells in the S-phase of the 
cell cycle.  The assay measures t he incorporation of radiolabel ed nucleotide [3H]-thymidine into 
DNA during the repair process i n non-S phase cells. (OPPTS 870.5555). Substances that produce 
either a statistically significan t dose-related increase or sta tistically significant and reproducible 
increase in 3H-TdR incorporation in at least one test point are considered t o be positive in this 
test. A UDS study that evaluate d glyphosate technical in rat pr imary hepatocytes was negative 
(Williams, 1978).  Glyphosate technical was also negative in a DNA repair test conducted in 
bacteria (Rec-A test) (Shirasu, 1978). In an alkaline elution assay, whi ch detects single strand DNA b reaks, Bolognesi et al.  (1997) 
reported an increase in single st rand breaks (i.e. increased DN A elution rate) in the liver and 
kidney 4 hours after a single i.p. injection of 300 mg/kg.  The  elution rate returned to control 
levels at 24 hours. Glyphosate technical was also negative in a  DNA repair test conducted in 
Bacillus subtilis  H17 (rec
+) and M45 (rec-) bacterial Rec-A test (Shirasu, 1978). 
Page 123 of 216
	 
 
  
 
 
 Finally, the sister chromatid exc hange (SCE) test is an assay t hat can measure the consequence 
of primary DNA damage.  The mechanism(s) of action for chemical  induction of SCE is unclear.  
The SCE assay detects the exchange of DNA between two sister ch romatid arms within a single 
chromosome.  The assay can be performed in vitro  or in vivo . Following exposure, cells/animals 
are treated with bromodeoxyuridin e (BrdU) to allow for the diff erentiation of the two sister 
chromatids (harlequin staining)  and prior to harv est are treate d with a spindle inhibitor to 
accumulate cells in metaphase.  The chromosome preparations are  then stained and analyzed for 
SCEs (OPPTS 870.5900, 870.5915). The SCE studies that evaluate d glyphosate technical are 
also presented in Table 12.  Positive SCE findings were reporte d in all four studies; two 
evaluating bovine lymphocytes  (Lioi, 1988b, Sivikova and Dianovksy, 2006) and two studies 
evaluating human lymphocyt es (Lioi, 1988a; Bolognesi et al. , 1997). In all four studies the 
induction did not demonstrate a clear dose response. 
Additionally, although it is recognized that mechanisms other t han genotoxicity may be involved 
in cell transformation, glyphosate trimesium salt was evaluated  in the Balb/3T cell 
transformation assay (an in vitro  tumor formation assay) and was negative up to 5.0 mg/ml 
(Majeska, 1982b). 
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 Table 5.7 Assays for Detecting Primary DNA Damage- Glyphosate T echnical. 
Test/Endpoint Test System Route of Doses/ Test Material Results Reference Comments 
Administration Concentrations Purity 
DNA Adducts Swiss CD1 mice Intraperitoneal 0, 130 and 270 Not reported Negative Peluso et al. 
32P-postlabeling (males and females) 
Liver and kidney 
evaluated injection; 24 h 
exposure mg/kg (1998) 
DNA oxidative Swiss CD-1 mice Intraperitoneal 0, 300 mg/kg 99.9% Kidney: Bolognesi et 
damage: (males) injection (single (3/dose) negative al. (1997) 
8-OHdG liver and kidney dose); sampling 
formation evaluated 4 and 24 h after injection Liver: positive  
(24 h) 
Single-cell gel 
TR146 cells NA (in vitro ) -S9: 10-2000 95% Positive  Koller et al. Also measured multiple 
electrophoresis (human-derived mg/L; (2012) cellular integrity 
(SCGE) assays- buccal epithelial cell 20-minute Increased parameters to assess 
Comet assay line). exposure. DNA 
migration 
at >20 
mg/L cytotoxicity.  No clear evidence of cytotoxicity 
seen except for increase 
in enzyme activity (indicative of membrane 
damage) in LDHe 
(extracellular lactate dehydrogenase) assay at 
>80 mg/L. 
No mention of monitoring pH 
Single-cell gel Hep-2 cells NA ( in vitro ) 0, 3, 4.5, 6, 7.5, 96% Positive Manas et al. The authors did not report 
electrophoresis 9, 12 and 15 mM (2009) a source for the Hep-2 
(SCGE) assays- Stat. cells. The agency 
Comet assay significant 
increase in 
mean tail 
length, and 
tail 
intensity at 
all concs. presumes that this is a HeLa derived cervical 
carcinoma cell line.  
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   Table 5.7 Assays for Detecting Primary DNA Damage- Glyphosate T echnical. 
Test/Endpoint Test System Route of Doses/ Test Material 
Administration Concentrations Purity Results Reference Comments 
Single-cell gel Human NA (in vitro ) 0, 0.7, 7, 70, 700 96% Positive at Alvarez-Moya Issues were identified 
electrophoresis lymphocytes µM all doses et al., (2014) with this study resulting 
(SCGE) assays- (increase in in a low quality ranking.  
Comet assay tail length only) These include:  1) blood was washed with PBS 
and then held at 4º C for 
an indeterminate amount 
of time before exposure 
to glyphosate.  (2) Cells 
were treated for 20 hours 
at room temperature.  
(3) The same amount of damage was reported 
across 2 orders of 
magnitude concentration. 
Single-cell gel electrophoresis 
(SCGE) assays- 
Comet assay 
Human 
lymphocytes; ±S9 
Alkaline and hOOG1 
Comet assays 
performed NA (in vitro ) 0, 0.5, 2.91, 3.5, 
92.8 and 580 
µg/mL 98% Positive 
±S9 Mladinic et al. 
(2009a) 
The alkaline comet assay 
-S9: ↑ in mean tail length 
at 580 µg/mL and ↑ in tail 
intensity at ≥ 3.5 µg/mL). 
 +S9: ↑ DNA tail length at ≥3.5 µg/mL. Tail 
intensity ↑ only at 580 
µg/mL 
hOOG1 comet assay: 
-S9 no effect on tail 
length, ↑tail intensity only 
at 3.50 µg/mL +S9: ↑ tail length at 580 
µg/mL, no effect on tail 
intensity compared to controls at any conc. 
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 Table 5.7 Assays for Detecting Primary DNA Damage- Glyphosate T echnical. 
Test/Endpoint Test System Route of Doses/ Test Material 
Administration Concentrations Purity Results Reference Comments 
Single-cell gel electrophoresis 
(SCGE) assays- 
Comet assay with oxidative 
stress measures Balb/C mice; 
evaluated blood and 
liver  Drinking water 
(14 days) 0, 40, and 400 mg/kg  96% Positive  
Blood and 
liver at both doses Manas et al. 
(2013) Only minor effects seen on oxidative stress 
measurements (TBARs, 
SOD, CAT) 
Sister Chromatid Exchange (SCE) Bovine lymphocytes (3 donors) NA (in vitro ) -S9: 0, 17, 85 
and 170 µM; 72 
h exposure ≥98% Positive 
Significant (p>0.05) 
increase in SC/cell at 
all 
concentrati ons Lioi (1998b) 1.8-, 2.1-, 1.6-fold 
increases, respectively  
Sister Chromatid 
Exchange (SCE) Human lymphocytes NA (in vitro ) -S9: 0, 5, 8.5, 17 and 51 µM; 72 h 
exposure ≥98% Positive 
Significant 
(p>0.05) increase in 
SCE/cell at 
≥ 8.5 µM Lioi (1998a) 1.9-, 2.8-, and 2.6-fold 
increase at 8.5, 17 and 51 
µM, respectively  
Sister Chromatid 
Exchange (SCE) Human lymphocytes NA (in vitro ) -S9: 0, 0.33, 1,3 
and 6 mg/mL; 
72 h exposure 99.9% Positive  Bolognesi et 
al. (1997) Very limited information 
was provided on the 
methods used in this 
paper. Authors report a dose –dependent increase 
in SCE frequency; 
however, no statistical analysis for dose response 
was reported. Data 
presented graphically 
with no error bars. 
Sister Chromatid 
Exchange (SCE) Human lymphocytes NA (in vitro ) 28, 56, 140, 280, 560 and 1120 µM; 24 h 
exposure ±S9 62% Positive  Sivikova and 
Dianovsky (2006) The increases in SCEs observed did not show a clear concentration 
related increase across a 
40-fold increase in the 
concentrations tested 
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 Table 5.7 Assays for Detecting Primary DNA Damage- Glyphosate T echnical. 
Test/Endpoint Test System Route of Doses/ Test Material 
Administration Concentrations Purity Results Reference Comments 
Alkaline elution 
assay- DNA 
single strand 
breaks Swiss CD-1 mice (males) 
liver and kidney 
evaluated Intraperitoneal injection (single 
dose); sampling 
8 and 24 h after injection 0, 300 mg/kg (3/dose) 99.9% Positive 
(Increased 
elution 
rate) at 4 hours in 
liver and 
kidney 
At 24 h, 
elution rate 
returned to 
control levels Bolognesi et 
al. (1997) Return to control values may indicate DNA repair 
or reflect rapid 
elimination of compound 
DNA Repair 
Test 
(Rec-A test) B. subtilis  H17 (rec+) 
and M45 (rec-) NA (in vitro ) 20-2000 μg/disk 98.4% Negative Shirasu (1978) 
[MRID 
00078619] 
Unscheduled DNA synthesis 
(DNA repair) F-344 rat primary 
hepatocytes NA (in vitro ) 0, 0.0125, 
0.0625, 0.125, 
0.6.5, 1.25, 12.5, 
125 µg/mL 98% Negative Li and Long 
(1988) 
Cell 
Transformation 
Assay BALB/3T cells NA (in vitro ) 
0.313-5.0 
mg/mL 90% 
Glyphosate 
trimesium salt Negative  Majeska 
(1982b) 
[MRID 
00126616] 
h- hour; CAT= catalase, G6PD= glucose 6-phosphate dehydrogenase , NA= not applicable, hOOG1 = TBARs= thiob arbituric acid reacti ve substances, SOD= 
superoxide dismutase 
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 5.7 Summary and Discussion 
The genotoxic potentia l of glyphosate has been extensively inve stigated using a variety of test 
systems and genetic endpoints.  T his assessment focuses only on test systems that the agency 
considered relevant for assessi ng genotoxic risk s in humans.  T he totality of the genetic 
toxicology information was evalu ated using a weight of evidence  approach to determine the 
genotoxic potential of glyphosate .  This involves the integrati on of in vitro  and in vivo  results as 
well as an overall evaluation of  the quality, consistency, repr oducibility, magnitude of response, 
dose-response relationship and r elevance of the findings. In th e weight of evidence analysis, 
studies evaluating endpoints that measured gene mutations and c hromosomal aberrations (i.e. 
permanent DNA damage) were given more weight than endpoints ref lecting DNA events that 
may be transient or reversible such as primary DNA damage ( e.g., comet assays).  In vivo studies 
in mammals were given the grea test weight and more weight was given to doses and routes of 
administration that were consider ed relevant for evaluating gen otoxic risk based on human 
exposure to glyphosate. Also, since the molecular mechanisms u nderlying the observation of 
SCEs are unclear and thus, the consequences of increased freque ncies of SCEs are unclear, the 
data from this test were given low weight in the overall analysis.  A summary of the various lines 
of evidence of considered in the weight of evidence evaluation for the genotoxic potential of the 
active ingredient glyphosa te is presented below. 
Evidence of primary DNA damage  
Glyphosate technical is not considered to be electrophilic and did not induce DNA adducts in the 
liver or kidney at an i.p. dos e of 270 mg/kg.  However, evidenc e of DNA strand breaks was 
reported in a number mammalian cel l studies using the comet ass ay.  Additionally, transient 
increases in alkali labile site s in the liver and kidney of mic e and an induction of 8-OHdG in 
DNA were seen in the livers of m ice following i.p. injections w ith 300 mg/kg glyphosate.  These 
effects were seen at high doses  for the i.p. route in mice (LD 50 for mouse =130 mg/kg; NTP, 
1992). However, due to technical l imitations identified in a n umber of these studies (e.g. use of 
cancer cell lines that have not b een well-characterized, atypic al exposure protocols and no 
indication of blind to treatment), caution should be exercised in interpreting the results.  
In vitro  mutations 
Glyphosate technical was negative  in all 39 studies for mutagen icity in bacteria.  In the four 
studies that tested for gene m utations in mammalian cells in vitro, no increase in mutations were 
observed. 
In vitro  chromosomal alterations 
Mixed results were observed in studies evaluating in vitro chromosomal alterations with 
glyphosate treatment.  Three SCE studies reported positive findings (Lioi, 1998a, b; Bolognesi et 
al., 1997) bovine and human lymphocyte s.  As stated previously, l ow weight is given to SCE 
results in the overall analysis  given the uncerta inty regarding  the consequence of increases in the 
frequencies of SCEs. The SCE responses were weak and not concen tration dependent.  Eight of 
the 10 studies measuring in vitro  chromosomal aberrations were negative. The two positive 
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 findings were reported by Lioi et al. , one study was conducted wit h bovine lymphocytes and the 
other with human lymphocytes.  T he authors reported positive fi ndings in these studies at 
concentrations much lower than f our other studies that reported  negative results using the same 
cell types.   Additionally, in both studies, Lioi et al.  used an atypical exposure protocol of 72 
hours which is very long for ana lyzing one round of mitosis.  F urthermore, in both studies, 
nearly the same level effect f or aberration frequency and perce nt of cells with aberrations were 
observed for the same concentr ations of glyphosate and the two other chemicals tested in those 
experiments.  
Four of the six studies evaluating micronuclei induction in vitro were positive and two showed 
equivocal results. Three of the  positive responses required S9 activation, two conducted with 
human lymphocytes and one conduc ted with CHO cells.  The remain ing positive micronucleus 
study was conducted using a TR146 cel ls which is a tumor cell l ine derived from human buccal 
mucosa. The authors state that this cell line had not been pre viously used for genotoxicity 
testing. It is difficult to inter pret any genotoxicity finding s conducted in a tumor cell line that 
has not been well-characterize d regarding its DNA damage response and repair capacity, and its 
degree of chromosomal instability. Glyphosate was negative in all three L5178Y mouse lymphoma cell  studies which may detect 
chromosomal damage in addition to mutations.  Mammalian  in vivo chromosomal alterations 
All three in vivo  mammalian studies eva luating chromosomal aberrations with glyp hosate 
technical were negative. Two st udies were conducted in rats (i. p. and oral) and one was 
conducted in mice (oral).  In a ddition, glyphosate was also neg ative in a rodent dominant lethal 
test. Glyphosate was negativ e in 15 of the 19 bone marrow micr onucleus studies evaluated. In 
two of the positive studies, glyphosate technical was administe red by i.p. injec tion.  In these 
studies, the author s reported positive findings at doses of 200-300 mg/kg.  Based on the available 
ADME data for glyphosate, assuming 30% oral absorption, an oral  dose of ~700-1000 mg/kg 
would be needed to achieve a dos e of 200-300 mg/kg in the blood .  Seven other i.p. studies in 
mice reported no increase in micr onuclei induction at doses up to 3000 mg/kg.  The remaining 
positive finding was reported in an oral gavage study in mice w here an approximately 2-fold 
increase in micronuclei were reported in females only at a dose  of 5000 mg/kg, which is 
considerably higher than the cur rent guideline recommended limi t dose of 2000 mg/kg.  The 
effect was not seen in the 7 other oral gavage studies in mice when glyphosate was tested at 
similar doses.  In addition, glyphosat e was negative for micron uclei induction following a 13-
week dietary study with a dose  up to approximately 3000 mg/kg/d ay.  A negative finding was 
also reported in the only study that evaluated in vivo  micronuclei inductio n in the rat using doses 
up to 2000 mg/kg. 
In a meta-analytic rev iew of micronuclei f requency across mamma lian and non-mammalian 
species (primarily fish, amphibian s, reptiles and plants), Ghis i et al.  (2016), not surprisingly, 
reported that different responses  were observed when comparing mammalian results to 
phylogenetically distant non-mamma lian species for micronuclei induction.  Their analyses 
included most, but not all, of the m ammalian studies that the a gency evaluated and determined to 
Page 130 of 216
	  
 
  
 
 
 
  be negative for micronuclei induc tion. The authors reported a s tatistically significant increase in 
micronuclei by the i.p. route acro ss the studies in the data set they considered; however, when 
glyphosate was administered by the oral route (which is the most physiologically relevant route 
for human exposure to glyphosate), no significant difference was observed.  
Conclusion for Glyphosate The overall weight of evidence i ndicates that there is no convi ncing evidence that glyphosate 
induces mutations in vivo  via the oral route. When administered by i.p. injection, the 
micronucleus studies were pre dominantly negative.  In the two cases where an increase in 
micronuclei were reported via th is route, the effects occurred above the reported i.p. LD50 for 
mice and were not observed in othe r i.p. injection studies at s imilar or higher doses.  While there 
is limited evidence genotoxic for effects in some in vitro  experiments, i n vivo  effects were given 
more weight than in vitro  effects particularly when the same genetic endpoint was measured, 
which is consistent with current  OECD guidance.  The only posit ive findings reported in vivo 
were seen at relatively high doses t hat are not relevant for hu man health risk assessment.  
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 6.0 Data Integration & Weight-of-Ev idence Analysis Across Multiple Lines of Evidence 
6.1 Background 
In 2010, OPP developed a draft “Fra mework for Incorporating Hum an Epidemiologic & Incident 
Data in Health Risk Assessment”  which provides the foundation f or evaluating multiple lines of 
scientific evidence (U.S . EPA, 2010).  In 2016, a final version  of the framework was published.  
OPP’s framework is consistent w ith updates to the World Health Organization/International 
Programme on Chemical Safety MOA/ human relevance framework, whi ch highlights the 
importance of problem formulati on and the need to integrate inf ormation at different levels of 
biological organizati on (Meek et al, 2014).   
One of the key components of the agency’s framework is the use of modified Bradford Hill 
Criteria (Hill, 1965) l ike those described in the 2005 Guidelines for Carcinogen Risk 
Assessment.  These criteria are  used to evaluate the experimental support considers such 
concepts as strength, consistency, dose response, temporal conc ordance and biological 
plausibility in a weight-of-evidence analysis. 
6.2 Dose-Response and Temporal Concordance 
Given the lack of consistent posi tive findings particularly at doses < 1000 mg/kg/day across the 
lines of evidence, lack of mech anistic understanding, and lack of biological activity in 
mammalian systems to the parent  compound glyphosate, there are few data to assess key events 
in the biological pathway and a ny associated temporal or dose c oncordance.  Temporal 
concordance can be assessed using the experimental animal studies and epidemiological studies 
that evaluated exposure prior to outcomes.  Similarly, dose con cordance can be assessed using 
findings of apical outcomes in expe rimental animal studies, as well as epidemiological studies 
that utilize exposure metrics that are stratified by the number of exposure days.   
A prospective cohort study is de signed to collect exposure information prior to the development 
of cancer. As such, exposure is known to occur before the outcome.  In De Roos et al.  (2005), a 
prospective cohort study, no asso ciation was observed between g lyphosate exposure and all 
cancer outcomes evaluated in t he AHS cohort.  Although the median follow-up time following 
recruitment into the cohort was approximately 7 years in De Roo s et al.  (2005), an updated 
analysis of the AHS cohort ha s been recently published (Andreot ti et al. , 2017), which included 
an extended follow-up period of  17.5 years and also did not rep ort an association between 
glyphosate exposure and all cancer outcomes evaluated. 
Two case-control studies evalu ating the risk of NHL (Eriksson et al. , 2008 and McDuffie et al. , 
2001) observed increased effect estimates in the highest exposure categories analyzed.  Eriksson 
et al. (2008) found a greater effect estimate for subjects with >10 da ys (based on the median days 
of exposure among controls) and >10  years of exposure (for late ncy analysis) when compared to 
subjects with ≤10 days and 1-10 year s of exposure, respectively; however, this analysis did not 
appear to adjust for co-exposur es to other pesticides.  By divi ding the total number of exposed 
cases and controls using these exposure metr ics, wider confiden ce intervals were observed due to 
smaller sample sizes, which redu ces the reliability of the resu lts to demonstrate a true 
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 association. This may indicate that a longer follow-up time is needed to detect th e risk for NHL; 
however, given the latency analysis of NHL was limited to Eriks son et al.  (2008) and lack of 
NHL latency understanding in genera l, further studies are needed to determine the true latency of 
NHL. McDuffie et al.  (2001), stratifying based on the average number of days per year of 
exposure, observed similar effect  estimates in the lower exposu re category (>0 and ≤2 days/year) 
while a greater effect estimate was observed in the highest exposure category (>2 days/year).  
The results from these two cas e-control studies conflict with t he results observed in the cohort 
study (De Roos et al. , 2005; Andreotti et al. , 2017), where no dose-response was seen across 
three exposure categories (stratified by tertiles ); however, th e case-control studi es did not adjust 
for co-exposure to other pesticides.  It is also difficult to m ake conclusions regarding dose-
response with only two exposure ca tegories used for the analyse s by Eriksson et al.  (2008) and 
McDuffie et al.  (2001). It should also be noted tha t these analyses combine a ll NHL subtypes, 
which may have etiological differences (Morton et al. , 2014). Although some studies did 
provide effect estimates for s ubtypes, as stated in Section 3.5 .2, these were not considered in the 
current evaluation due to the limited sample sizes.  At this time, there are no data available to 
evaluate dose-response for NHL subtypes. 
With respect to animal carcinogen icity studies, key events in a  MOA/AOP are evaluated to 
confirm that they precede tumor appearance.  This temporal conc ordance evaluation cannot be 
conducted for glyphosate since a M OA/AOP has not been establish ed.  It was noted that no 
preneoplastic or related non-neopl astic lesions were reported i n any of the animal carcinogenicity 
studies to support any observed tumors.  Furthermore, genotoxicity assays did not support a 
direct mutagenic MOA.  While there is limited evidence of genot oxicity in some in vitro 
endpoints, multiple in vivo  studies do not support a genotox ic risk at relevant human expo sure 
levels. 
6.3 Strength, Consisten cy, and Specificity 
A large database is available fo r evaluating the carcinogenicit y potential of glyphosate.  Across 
animal carcinogenicity and genotoxi city studies, results were c onsistent.  For epidemiological 
studies, only one or two studies w ere available for almost all cancers investigated.  The largest 
number of studies was available investigating NHL; however, the re were conflicting results 
across studies. 
In epidemiological studies, there  was no evidence of an associa tion between glyphosate exposure 
and solid tumors, leukemia, and H L.  This conclusion is consist ent with those recently conducted 
by IARC, EFSA, and JMPR. Furthermo re, the available studies do  not link glyphosate exposure 
to multiple myeloma. At this time, a conclusion reg arding the association between glyphosate exposure and risk of 
NHL cannot be supported based on the  available data due to conf licting results.  Chance and/or 
bias cannot be excluded as a n explanation for  observed associat ions.  The magnitude of adjusted 
risk estimates for ever/never use were relatively small ranging from 1.0 (no association) to 1.85 
in adjusted analyses, with the w idest confidence intervals observed for the highest effect 
estimates indicating less reliability in these estimates.  All of the ever/never estimates were not 
statistically significant with several effect estimates approxi mately equal to the null.  There were 
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 various limitations identifie d in Section 3.6 for these studies  that could impact calculated effect 
estimates and explain the wea k responses observed.  Meta-risk r atios using these studies were 
also of small magnitude ranging from 1.3-1.5.  As discussed in Section 3.6, meta-analyses should 
be interpreted with caution and are  susceptible to the same lim itations identified for individual 
studies. 
Although none of the effect estimat es were below 1 using the ever/never exposure metric, risk 
estimates were all below 1 (0.6-0.9) when using cumulative life time and intensity-weighted 
cumulative exposure metrics in t he prospective cohort study (De Roos et al. , 2005; Andreotti et 
al., 2017). As discussed in Section 6.2, t wo case-control studies that investigated an exposure-
response relationship conflicted w ith the extensive analyses co nducted for the AHS cohort.  This 
may be due to differences in conf ounding control, differences a ssociated with study design, 
limitations from small sample si zes, and/or, as some may suggest, a potentially s hort follow-up 
time in the cohort.  It should a lso be noted that publication b ias may play a role in this evaluation 
given there is a tendency to only publish positive results and potential concerns regarding 
glyphosate have only been raised in recent years. A total of 14 (8 rat and 6 mouse) a nimal carcinogenicity studie s with glyphosate, glyphosate 
acid, or glyphosate salt s were analyzed for t he current evaluat ion.  None of the tumors evaluated 
were considered to be treatment -related based on weight-of-evid ence evaluations.  Although 
statistically significant trends  were observed following adjust ment for multiple comparisons in a 
limited number of studies, statist ically significant pairwise c omparisons were only observed in 2 
studies indicating tumor inciden ces were generally similar to c oncurrent controls.  Additionally, 
none of the tumor results were reproduced in other studies, including those testing the same 
animal strain with similar or hi gher dosing.  Furthermore, the tumors lacked a monotonic dose-
response and/or corroborating pr eneoplastic or related non-neop lastic lesions. 
Over 80 genotoxicity studies with t he active ingr edient glyphos ate were analyzed for the current 
evaluation. The overall weight-o f-evidence indicates that ther e is no convincing evidence that 
glyphosate is genotoxic in vivo  via the oral route. When adm inistered via i.p. injection the 
studies were predominantly negativ e.  In the two cases where an  increase in micronuclei were 
reported via this rou te, the effects were not observed in other  i.p. injection studies at similar or 
higher doses. Technical glyphosate was negative in all gene mu tation studies.  There was limited 
evidence of positive findings in studies evaluating primary DNA  damage; however, as discussed 
in Section 5.6, the endpoints measur ed in these assays are less  specific in regards to detecting 
permanent DNA changes (mutations) and can be attributed to othe r factors, such as cytotoxicity 
or cell culture conditions.  Although some positive findings we re reported for chromosomal 
alterations in vitro , these findings were limited t o a few studies and are not supp orted by the in 
vivo studies that are the most relev ant for human risk assessment. 
Overall, there is remarkable c onsistency in the database for gl yphosate across multiple lines of 
evidence. For NHL, observed associations in epidemiological st udies were non-statistically 
significant and were of relativel y small magnitude.  Chance and /or bias cannot be excluded as an 
explanation for the observed asso ciations.  For all other cance r types, there were no associations 
found; however, only one or two studi es were available for evaluation of most cancer types.  
Across species, strain, and la boratory, none of the tumors evaluated were considered to be 
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 treatment-related bas ed on weight-of-evidence evaluations.  Sta tistically significant tumor results 
seen in individual studies were  not reproduced in other studies , including those conducted using 
the same strain at similar or hi gher doses.  The genotoxicity s tudies demonstrate that glyphosate 
is not directly mutagenic or genotoxic in vivo . 
6.4 Biological Plausibility and Coherence 
The Guidelines for Carcinogen R isk Assessment (U.S. EPA, 2005) include the following 
guidance regarding th e criteria of biologica l plausibility and coherence: 
“evaluation of the biological pl ausibility of the as sociations observed in epidemiologic 
studies reflects considerati on of both exposure- related factors and toxicological evidence 
relevant to identification of potential modes of  action (MOAs). Similarly, consideration of 
the coherence of health effect s associations reported in the epidemiologic literature 
reflects broad consideration of information pertaining to the natur e of the biological 
markers evaluated in toxicologic and epidemiologic studies . [p.39].”   
The genotoxicity studies demonstr ate that glyphosate is not dir ectly mutagenic or genotoxic in 
vivo. Immunodeficiency is another plausible MOA associated with tumorigenesis (i.e., altered 
immune surveillance). Glyphosat e was negative in an immunotox icity study in mice at doses up 
to 1448 mg/kg/day (MRID 48934207).  Additionally, the toxicolog y database for glyphosate 
does not reveal any evidence of i mmunotoxicity.  Overall, the a vailable data regarding non-
cancer endpoints also do not provi de any support for a carcinog enic process for glyphosate, and 
have shown glyphosate has relative ly low toxicity.  Laboratory  animals generally display non-
specific effects (e.g. , clinical signs, reduced body w eight) following glyphosate expo sure at 
relatively high-doses, and no preneo plastic or related non-neop lastic lesions were observed to 
corroborate any of the observed tum ors in the carcinogenicity s tudies.   
As discussed in Section 4.2, metabol ism studies demonstrate low  oral absorption and rapid 
excretion of glyphosate. The data  are not sufficient to determ ine whether linear kinetics is 
occurring at high doses where t umors were observed.  In the car cinogenicity test guideline 
(OCSPP 870.4200) and the 2005 Guideli nes for Carcinogen Risk As sessment, inappropriate 
toxicokinetics (e.g., overwhelming a bsorption or detoxification  mechanisms) should be avoided.  
A study evaluating the toxicoki netic profile of glyphosate usin g multiple doses is needed to 
further investigate the pharmacokinetic properties between low-  and high-dose levels. 
Although many of the studies inclu ded in this document focus on the potential for glyphosate to 
cause a cancer outcome, the agency is also aware of a limited n umber of studies in the open 
literature that have shown glyphosat e and its metabolite, AMPA,  can inhibit proliferation and 
promote apoptosis in cancer ce lls indicating the compounds have  potential to be developed into 
therapeutic drugs for cancer treatment (Li et al, 2013; Parajuli et al.,  2015; Parajuli et al.,  2016). 
It is unknown if this is due to l ack of additional studies that  have investigated these compounds 
for cancer treatment or if this may be due to publication bias.  The bias towards only publishing 
positive and/or novel results can hamper the ability to evaluat e whether there are plausible 
biological mechanisms for observed outcomes and/or sufficient i nformation to support a cause-
and-effect interpretation of a n association.  Overall, this fur ther supports the need for 
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   mechanistic data to elucidate the true mammalian MOA/AOP for gl yphosate.  There is a distinct 
lack of mechanistic understan ding for the toxicity of glyphosate in mammals and the plant MOA 
is not relevant for mammalian systems.   
The agency does not consider a ny of the tumors observed in the animal carcinogenicity studies to 
be treatment-related; however, s ome believe that the increased tumor incidences in various 
studies at the highest doses te sted are treatment-related.  In almost all of these studies, the highest 
dose tested was approximately equa l to or greater than the limi t dose (1000 mg/kg/day).  It is 
very unlikely for people to be e xposed to such large doses of glyphosate via the oral route.  
Glyphosate is registered for pre- and post-emergence application to a variety of fruit, vegetable, 
and field crops, as well as desicc ant applications to several c ommodities.  The highest dietary 
exposure value for any populati on subgroup in an unrefined chronic dietary analysis would be 
0.23 mg/kg/day for children (1- 2 years old).  Since glyphosate also has residential uses, 
including application to turf, t here is also the potential for children at this age to be exposed via 
incidental oral exposures ( e.g., hand to mouth, object to mouth  and soil ingestion) from playing 
on treated lawns. The highest exposure for the incidental oral  and dermal exposures would be 
0.16 mg/kg/day (from hand-to-mout h behaviors for children) and 0.08 mg/kg/day, respectively.  
Combining exposures from the di etary and residential exposures for children would, therefore, 
result in an aggregate exposure of 0.47 mg/kg/day.  These calcu lations use a number of 
assumptions that have bee n extensively peer-reviewed27 and yet the potential oral exposure of 
glyphosate for the most highly exposed residential population subgroup is more than 2,000 times lower than the highest doses tes ted in the animal carcinogenici ty studies (see Appendix E for 
more details regarding these calculations). The maximum potent ial exposure calculated for 
occupational handlers would be 7 m g/kg/day, which is still sign ificantly lower than the highest 
doses tested in the animal carci nogenicity studies.  As a resul t, even though increased tumor 
incidences were observed in some  of the animal carcinogenicity studies, the possibility of being 
exposed to these excessive dietar y doses over time is considered implausible based on the 
currently registered use pattern and not relevant to human heal th risk assessment. 
6.5 Uncertainty 
When evaluating a database, it is also important to assess the uncertainties associated with the 
available data. When uncertainty  is high there is less confidence in the exposure and effect 
estimates and, therefore, informs the reliability of results.  Understanding the sources of 
uncertainty within a database ca n help characterize observed re sults and aid in developing new 
research with reduced uncertainty. 
In some instances, the agency di d not have access to all of the  data underlying the studies 
analyzed for the current evalua tion.  This includes all of the epidemiological studies, 17 
genotoxicity studies, and 1 ani mal carcinogenicity study.  For these studies, the agency had to 
rely upon information the study aut hors reported.  Without the raw data, statistical analyses could 
not be replicated or recalculated.  On the other hand, studies that include full reports with 
detailed methodology, analytically  measured doses, and individu al animal data may provide a 
27 Using the 2012 Standard Operating Procedures for Residential E xposure Assessment.  Available: 
http://www2.epa.gov/pesticide-sc ience-and-assessing-pesticide-r isks/standard-operating-procedures-residential-
pesticide 
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 higher level of confidence. It also allows the agency to perfo rm its own evaluation of the data 
using current practic es and policies.   
Several uncertainties have a lready been iden tified throughout this document.  There are 
numerous metabolism studies ava ilable for glyphosate; however, the data are not sufficient to 
determine whether linear kineti cs is occurring at high doses wh ere tumors were observed in 
animal carcinogenicity studies.  In the carcinogenicity test gu ideline (OCSPP 870.4200) and the 
2005 Guidelines for Carcinogen Ris k Assessment, inappropriate t oxicokinetics (e.g., 
overwhelming absorption or detoxification mechanisms) should be  avoided.  A study evaluating 
the toxicokinetic profile of glyphosate using multiple doses is  needed to further investigate the 
pharmacokinetic properties betw een low- and high-dose levels.  
With respect to the epidemiologi cal data, the database is limit ed for each investigated cancer 
with only one or two studies ava ilable.  Although numerous studies were used in the evaluation 
of NHL, the results were constrained by the limitations of the individual studies, such as small 
sample size, missing data, and control selection issues.  The quality of the exposur e assessment is 
a major concern since the va lidity of the overall study results depend in large part on the ability 
of the study to correctly quan tify and classify a subject’s exposure.  There was no direct 
information on pesticide exposure or absorbed dose because the exposures were self-reported.  
All of the studies conducted exposure assessments through questionnaires and inter views that are 
susceptible to recall bias, which can result in exposure miscla ssification.  The cohort study (De 
Roos et al. , 2005), which was given a hi gh ranking, did not find an association between 
glyphosate exposure and NHL; howev er, it has been noted that th e median follow-up time for 
this study was ~7 years. Recently, an updated analysis was pub lished (Andreotti et al. , 2017) 
with an extended follow-up peri od of 17.5 years that addresses concerns regarding follow-up 
time.  This study reported no asso ciation between glyphosate ex posure and all 
lymphohematopoietic cancers, NHL, or any of its subtypes across exposure metrics.  No association was observed in unlagged or lagged analyses, after adjustment for pesticides linked 
to NHL in previous AHS analyses, and after exclusion of multiple myeloma from the NHL grouping. Furthermore, with the  increased use of glyphosate fo llowing the introduction of 
glyphosate-tolerant crops in 1996, the re is a need for more rec ent studies since a large number of 
studies were conducted prior t o 1996.  As described in Section 1.1, the use pattern changed 
following the introduction of tra nsgenic crops, which may impac t overall effect estimates.      
Another consideration is that fa rmers and other ap plicators apply formulations, not the active 
ingredient alone. It is possible that different formulations w ere used across and/or within the 
different epidemiological studi es.  Formulations are end-use pr oducts that are sold as a mixture 
of registered pesticidal activ e ingredients, such as glyphosate, and additional substances that 
increase the effectiveness of a  pesticidal product, which are o ften referred to as “inert 
ingredients.” For example, inert  ingredients may act as a solvent to allow a pesticide active 
ingredient to penetrate a plant’s outer surface, may facilitate  and accentuate the dispersion of the 
product, or may extend the pesticide product’s shelf-life
28. Inert ingredients and the proportion 
of these inert ingredients var y across formulations.  It has be en hypothesized that glyphosate 
formulations may be more toxic than glyphosate alone.  Glyphosa te has been studied in a 
multitude of studies and there are studies that have been condu cted on numerous formulations 
28 https://www.epa.gov/pesticide-re gistration/inert-ingredients-o verview-and-guidance 
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 that contain glyphosate; however , there are relatively few research projects that have attempted 
to systematically compare glyphosate and the formulations in th e same experimental design.  
Furthermore, there are even le ss instances of studies comparing toxicity across formulations.  
This is one aspect of the uncerta inty in the database that the agency has been working to address 
by developing a strategic resea rch plan in collaboration with N TP (see Section 7.0). 
It is recognized that these uncertainties e xist for the current database; however, the available data 
are adequate for evaluating the  carcinogenic potential of glyph osate and determine the cancer 
classification using the 2005 Guidelines for Carcinogen Risk As sessment.  As discussed in 
Section 6.3, there are a large num ber of studies available and the database is remarkably 
consistent across these studies. 
6.6 Evaluation of Cancer Classification per the 2005 EPA Guidel ines for Carcinogen 
Risk Assessment 
6.6.1 Introduction 
In the 2005 Guidelines for Carcinogen Risk Assessment, five cla ssification descriptors are 
provided: 
 Carcinogenic to Humans 
 Likely to be Carcinogenic to Humans 
 Suggestive Evidence of Carcinogenic Potential 
 Inadequate Information to Assess Carcinogenic Potential 
 Not Likely to be Carcinogenic to Humans 
Descriptors are assigned using a ll available data from the multiple lines of evidence.  The 
following text has been excerpted /summarized from the guideline s regarding these descriptors: 
Choosing a descriptor is a matte r of judgment and cannot be red uced to a formula.  Each 
descriptor may be applicable t o a wide variety of potential data sets and weights of 
evidence. The weight-of-evidence, including the selected descr iptor, is presented as a 
narrative laying out the complexit y of information that is esse ntial to understanding the 
hazard and its dependence on t he quality, quantity, and type(s)  of data available.  The 
descriptors and narratives are intended to permit sufficient flexibility to accommodate 
new scientific understanding and new testing methods.  The descriptors represent points along a continuum of evidence; con sequently, there are gradatio ns and borderline cases 
that are clarified by the full weight-of-evidence narrative.  R ather than focusing simply 
on the descriptor, the entire ra nge of information included in the weight-of-evidence 
narrative should be considered. 
The weight-of-evidence presen ted in Sections 6.2-6.5 and based on the available 
epidemiological, animal carcinogenicity, and genotoxicity data for glyphosate was considered for 
each classification descriptor. For each descriptor, the guide lines provide examples and/or 
conditions for when the descrip tor may be appropriate and the weight-of-evidence for glyphosate 
is assessed to determine which desc riptor is supp orted by the available data.  As stated in the 
2005 EPA Guidelines for Carcinogen Risk Assessment, “the entire range of information included 
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 in the weight-of-evidence s hould be considered”.  Based on all of the available data, the weight-
of-evidence clearly do not support the descriptors “carcinogeni c to humans” and “likely to be 
carcinogenic to humans” at this time.  According to the 2005 Ca ncer Guidelines, “carcinogenic 
to humans” is appropriate “when there is convincing epidemiologic evidence  of a causal association 
between human exposure and cancer.”  Similarly, “likely to be carcinogenic to humans” descriptor 
is appropriate “when the weight of the evidence is adequate to demonstrate carcinogenic potential to 
humans but does not reach the weight of evidence for the descriptor.” 
In epidemiological studies, there  was no evidence of an associa tion between glyphosate exposure 
and solid tumors, leukemia, or H L.  Furthermore, the available studies do not link glyphosate 
exposure to multiple myeloma.  A conclusion regarding the assoc iation between glyphosate 
exposure and risk of NHL cannot  be determined based on the avai lable data due to conflicting 
results and various limitations i dentified in studies investiga ting NHL.  In 6 of the 14 animal 
carcinogenicity studies, no tumors were identified for evaluati on.  In the remaining 8 studies, the 
agency has concluded that none of t he tumors evaluated in individual rat and mouse 
carcinogenicity studies are treatment-related due to lack of pa irwise statistical s ignificance, lack 
of a monotonic dose response, abs ence of preneoplastic or relat ed non-neoplastic lesions, no 
evidence of tumor progression, and /or historical control inform ation (when available).  Tumors 
seen in individual rat and mouse studies were also not reproduc ed in other studies, including 
those conducted in the same ani mal species and strain at simila r or higher doses.  The tumor 
incidence increases in these studies were seen at or exceeding 1,000 mg/kg/day, except the 
testicular tumors in a singl e rat study, and these high doses w ould also not be cons idered relevant 
for human health risk assessmen t.  The mammalian MOA/AOP is unk nown for glyphosate and 
precursor events are unknown; how ever, the genotoxicity data we re highly reproducible and 
consistent with a clear demonstr ation that glyphosate does not have a mutagenic MOA.       
The descriptor “inadequate information to assess carcinogenic p otential” is used when available 
data are judged inadequate fo r applying one of the other descri ptors.  Given the extensive size of 
the glyphosate database, which includes a multitude of well-des igned and well-conducted 
studies, this classification de scriptor is not supported.  The epidemiological data at this time are 
limited and study results appear to b e inconsistent for some ca ncer types.  However, it is 
important to note that epidemiol ogical studies are not availabl e for most pesticides.  Similarly, 
for most pesticides, generally, onl y two animal bioassays are a vailable.  EPA routinely evaluates 
human cancer potential using the s mall, more typical datasets. As such, for glyphosate, given the 
significant amount of information across multiple lines of evid ence, the agency believes the 
database is sufficient to desi gnate a cancer classification des criptor for glyphosate and that 
“inadequate information to assess  carcinogenic potential” is no t appropriate. 
The remaining two cancer classification descriptors ( “Suggestive Evidence of Carcinogenic 
Potential” and “Not Likely to Be Carcinogenic to Humans”) from the 2005 EPA Guidelines for 
Carcinogen Risk Assessment are  described in detail below.  Subsequently, these descriptors are 
discussed in the context of wheth er the available evidence do o r do not support them. 
“Suggestive Evidence of Carcinogenic Potential” 
This descriptor is appropriate when a concern for potential car cinogenic effects in humans is 
raised, but the data are judged not  sufficient for a stronger conclusion.  It covers a spectrum of 
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  evidence associated with varying levels of concern for carcinog enicity.  Depending on the extent 
of the database, additional stud ies may or may not provide further insights. 
Some examples of when this desc riptor may be appropriate includ e the following: 
	 If a small, and possibly not statis tically significant, increase in tumor incidence observed 
in a single animal or human study that does not reach the weigh t-of-evidence for the 
descriptor of “likely to be carci nogenic to humans.”  The study  generally would not be 
contradicted by other studies of  equal quality in the same popu lation group or 
experimental system; 
	 If there is evidence of a positive response in a study whose po wer, design, or conduct 
limits the ability to draw a c onfident conclusion (but does not  make the study fatally 
flawed), but where the carcinogeni c potential is strengthened by other lines of evidence; 
	 If there is a small increase i n a tumor with a high background rate in that sex and strain, 
when there is some but insuffici ent evidence that the observed tumors may be due to 
intrinsic factors that cause  background tumors and not due to the agent being assessed 
(when there is a high background rate of a specific tumor in an imals of a particular sex 
and strain, then there may be biol ogical factors operating independently of the agent 
being assessed that could be res ponsible for the development of  the tumors).  In this 
case, the reasons for determining that the tumors are not due t o the agent are explained; 
or 
	 If there is a statistically significant increase at one dose on ly, but no significant response 
at the other doses  and no overall trend.   
“Not Likely to Be Carcinogenic to Humans” 
This descriptor is appropriate when the available data are cons idered robust for deciding that 
there is no basis for human hazard concern.  In some instances,  there can be positive results in 
experimental animals when there is strong, consistent evidence that each MOA in experimental 
animals does not operate in humans.   In other cases, there can be convincing evidence in both 
humans and animals that the ag ent is not car cinogenic.   
This descriptor would be appropria te if any of the following wa s observed: 
	 Animal evidence demonstrates l ack of carcinogenic effects in bo th sexes in well-designed 
and well-conducted studies in at least two appropriate animal species in the absence of 
other animal or human data sugge sting a potential for cancer effects, or 
 Convincing and extensive experime ntal evidence showing that the  only carcinogenic 
effects observed in animals are  not relevant to humans, or 
 Convincing evidence that carcinoge nic effects are not likely by  a particular exposure 
route, or 
 Convincing evidence that carcinoge nic effects are not likely be low a defined dose range. 
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 6.6.2 Discussion of Evidence to Support Cancer Classification D escriptors 
As stated above, the available d ata and weight-of-evidence clea rly do not support the descriptors 
“carcinogenic to humans”, “likely to be carcinogenic to humans” , or “inadequate information to 
assess carcinogenic potential”. T he following discusses the re maining cancer classification 
descriptors and how the evidence does or does not support the d escriptors. 
It could be argued that the “s uggestive evidence of carcinogeni c potential” descriptor would be 
appropriate. The evidence to support this includes: 
 Non-statistically significant effect estimates greater than the  null were reported for NHL 
across studies and meta-analyses  based on ever/never use ranged  from 1.3-1.5. 
 There was limited evidence of a  possible exposure-response rela tionship between 
glyphosate exposure and NHL i n case-control studies. 
 In several animal carcinogenicit y studies, a stati stically sign ificant trend was observed.  
In two studies, tumor incidence s at the highest doses tested we re statistically significant 
as compared to concurrent controls. 
 Positive responses were observed in a limited number of genotox icity assays evaluating 
chromosomal and primary DNA damage. 
However, according to the 2005 EPA Guidelines for Carcinogen Risk Assessment, in order for 
the above evidence to support th e “suggestive evidence of carci nogenic potential” descriptor, 
“the study generally would not be contradicted by other studies  of equal quality in the same 
population group or experimental s ystem”.  Furthermore, the guidelines state that “rather than 
focusing simply on the descriptor, the entire range of informat ion included in the weight-of-
evidence narrative should be considered”. For the epidemiologi cal studies evaluating NHL, 
several studies reported effect e stimates approximately equal t o the null.  The widest confidence 
intervals were observed for the  highest effect estimates indica ting these effect estimate are less 
reliable. All of the effect eve r/never estimates were non-stat istically significant.  There were 
conflicting results in exposure-re sponse assessments investigat ing glyphosate exposure and the 
risk of NHL. Although two-case control studies (McDuffie et al. , 2001; Eriksson et al. , 2008) 
reported elevated effect estimat es when analyzing for exposure- response relationships across two 
exposure categories, extensive a nalyses in a study of equal or higher quality (De Roos et al. , 
2005) for cumulative lifetime e xposure and intensity-weighted c umulative exposure contradicted 
these results reporting effect est imates less than null (rangin g from 0.6-0.9) when analyzing 
across tertiles and these analy ses were further supported by th e recent evaluation of the AHS 
cohort by Andreotti et al.  (2017). Furthermore, the two-cas e control studies did not acc ount for 
co-exposure to other pesticides , which would be expected to cau se inflated effect estimates.  
Various limitations that could impact the calculated effect estimate were identified for these studies and discussed in Secti on 3.6.  The effect estimates gre ater than the null were not 
strengthened by other lines of evidence, as described in Sections 6.2-6.5.   
In 6 (4 rat and 2 mouse) of the 14 animal carcinogenicity studi es conducted with glyphosate, no 
tumors were identified for e valuation.  In the remaining 8 studies, although statistically 
significant trends following adjustment for multiple comparison s were observed in 6 of these 
studies for different individual tumor types, almost all of the se lacked pairwise significance 
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 following adjustment for multiple comparisons.  Pairwise signif icance was only observed at the 
highest dose tested for testicul ar tumors (Lankas, 1981) and he mangiomas (Sugimoto, 1997).  
For testicular tumors, a close r examination of the incidence da ta across doses did not 
demonstrate a monotonic dose response and the tumor findings we re not reproduced in studies of 
equal quality, including studies i n the same animal species and  strain at similar or higher doses.  
For hemangiomas, the statistical significance was seen at a dos e more than 4X the limit dose, 
which would not be considered rele vant for human health risk as sessment.  Furthermore, the 
tumor findings were not reproduc ed in studies of equal quality,  including studies in the same 
animal species and strain at similar or higher doses.  In all of the animal carcinogenicity studies, 
there was no evidence of corr oborating pre-neoplastic or relate d non-neoplastic lesions to 
support a treatment-related effect , including the testicular tu mors.  In a limited number of cases, 
the agency also considered histor ical control data to inform th e relevance of tumor findings and 
these data generally indicated t hat incidence rates in the conc urrent controls were unusually low 
and/or observed tumor incidences were within historical control ranges.     
Although positive responses were observed in a limited number o f genotoxicity assays 
evaluating chromosomal and primary DNA damage, the overall weig ht-of-evidence indicates 
that there is no convincing evide nce that glyphos ate induces mu tations in vivo  via the oral route. 
When administered via i.p. injectio n the studies were predomina ntly negative.  In the two cases 
where an increase in micronucle i were reported via this route o f administration, the results were 
contradicted by numerous other st udies at similar or higher doses using the same assays and 
route of administration. Techni cal glyphosate was negative in all gene mutation studies.  There 
was limited evidence of positive findings in studies evaluating  primary DNA damage; however, 
the endpoints measured in these assays are less specific in reg ards to detecting permanent DNA 
changes (mutations) and can be a ttributed to other factors, suc h as cytotoxicity or cell culture 
conditions. Although some positive findings were reported for chromosomal alterations in vitro , 
these findings were limited to a  few studies and are not suppor ted by the in vivo  studies that are 
the most relevant for human risk assessment.  
In summary, considering the en tire range of information for the weight-of-evidence, the evidence 
outlined above to potentially support the “suggestive evidence of carcinogenic potential” 
descriptor are contradicted by ot her studies of equal or higher quality and, therefore, the data do 
not support this cancer cla ssification descriptor. 
For the “not likely to be carci nogenic to humans” descriptor, o ne of the considerations is 
whether there is “convincing evide nce that carcinogenic effects  are not likely below a 
defined dose range”. In the cas e of glyphosate, the agency did  not consider any of the 
tumors observed in the animal car cinogenicity studies to be tre atment-related; however, 
some believe that the increased t umor incidences in various stu dies at the highest doses 
tested are treatment-related.  I n all of these studies, the hig hest dose tested was 
approximately equal to or grea ter than the limit dose (1000 mg/ kg/day), except for the 
testicular tumors observed in a  single study that were not cons idered treatment-related and 
were not reproduced in studies of  equal quality, including stud ies in the same animal 
species and strain at similar or higher  doses.  In genotoxicity  studies, assays with oral 
administration were negative excep t for one instance where an e xtremely high dose (5,000 
mg/kg/day) was administered.     
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 The 2005 EPA Guidelines for Carcinogen Risk Assessment also sta te that “weighing of the 
evidence includes addressing not only the likelihood of human carcinogenic effects of the agent 
but also the conditions under wh ich such effects may be expressed”.  Increased tumor incidence 
was typically observed at doses  of 1,000 mg/kg/day or greater; however, none of these were 
considered treatment-related by t he agency based on the weight-of-evidence evaluations.  
Additionally, the only in vivo  positive assays seen in the genotoxicity studies were administ ered 
via i.p. injection at doses of  200 mg/kg/day and 300 mg/kg/day or orally at 5,000 mg/kg/day.  
These high doses are not consider ed relevant to human health ri sk assessment based on the 
currently registered use pattern f or glyphosate.  Maximum poten tial glyphosate exposure in 
residential and occupational settings have been estimated at 0. 47 mg/kg/day and 7 mg/kg/day, 
respectively, which are well-be low the doses necessary to elici t the effects seen in these animal 
carcinogenicity and genotoxicit y studies.  Additionally, non-li near kinetics may also be 
occurring at the high doses. The carcinogenicity test guidelin es (OCSPP 870.4200 and OCSPP 
870.4300) and the 2005 Guidelines for  Carcinogen Risk Assessment state that inappropriate 
toxicokinetics (e.g., overwhelming a bsorption or detoxification  mechanisms) should be avoided.  
A well-conducted pharmacokinetic s tudy evaluating the toxicokin etic profile of glyphosate is 
needed to further investigate th e toxicokinetic properties betw een high and low dose levels to 
ensure that inappropriate toxicokinetics is avoided.   
Overall, there is not strong support for the “suggestive evidence of carcinogenic potential” 
cancer classification descriptor  based on the weight-of-evidenc e, which includes the fact that 
even small, non-statistically si gnificant changes observed in animal carcinogenicity and 
epidemiological studies were contradicted by studies of equal o r higher quality.  The strongest 
support is for “not likely to be carcinogenic to humans”. 
6.7 Proposed Conclusions Regarding the Carcinogenic Potential o f Glyphosate 
Glyphosate is a non-selective, pho sphonomethyl amino acid herbi cide registered to control 
weeds in various agricultural and non-agricultural settings.  L abeled uses of glyphosate include 
over 100 terrestrial food crops as well as other non-agricultur al sites, such as greenhouses, 
aquatic areas, and residential ar eas.  Following the introducti on of glyphosate-resistant crops in 
1996, glyphosate use increased dramatically; however, glyphosate use has stabilized in recent 
years due to the increasing numb er of glyphosate-resistant weed species. 
Since its registration in 1974, nu merous human and environmenta l health analyses have been 
completed for glyphosate, which consider all an ticipated exposu re pathways.  Glyphosate is 
currently undergoing Registrati on Review.  As part of this process, the hazard and exposure of 
glyphosate are reevaluated to dete rmine its potential risk to h uman and environmental health 
using current practices and policie s.  The human carcinogenic p otential of glyphosate has been 
evaluated by the agency several times.  As part of the current evaluation for Registration Review, 
the agency has performed a compreh ensive analysis of available data from submitted guideline 
studies and the open literature. T his includes epidemiological, animal carcinogenicity, and 
genotoxicity studies. 
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  An extensive database exists fo r evaluating the carcinogenic potential of glyphosate, including 
63 epidemiological studies, 14 animal carcinogenicity studies, and nearly 90 genotoxicity studies 
for the active ingredient glyphos ate.  These studies were evalu ated for quality and results were 
analyzed across studies within e ach line of evidence.  The modified Bradford Hill criteria were 
then used to evaluate multiple lines of evidence using such concepts as strength, consistency, 
dose response, temporal concordance and biological plausibility .  The available data at this time 
do no support a carcinogenic proces s for glyphosate.  Overall, animal carcinogenicity and 
genotoxicity studies were remarkably consistent and did not dem onstrate a clear association 
between glyphosate exposure and ou tcomes of interest related to  carcinogenic potential.  In 
epidemiological studies, there was no evidence of an associatio n between glyphosate exposure 
and numerous cancer outcomes;  however, due to conflicting resul ts and various limitations 
identified in studies investig ating NHL, a conclusion regarding  the association between 
glyphosate exposure and risk of NHL cannot be determined based on the available data.  
Increases in tumor incidence were not considered treatment-related in any of the animal carcinogenicity studies. In 6 of t hese studies, no tumors were  identified for evaluation.  In the 
remaining studies, the tumors we re not considered treatment-related due to lack of pairwise 
statistical significance, lack of  a monotonic dose response, absence of preneoplastic or related 
non-neoplastic lesions, no eviden ce of tumor progression, and/o r historical control information 
(when available). Additionally, t umor findings seen in individ ual rat and mouse studies were 
also not reproduced in other stud ies, including those conducted  in the same animal species and 
strain at similar or  higher doses.  Furthermore, data from epid emiological and animal 
carcinogenicity studies do not re liably demonstrate expected do se-response relationships.  In 
genotoxicity studies, there was no convincing evidence that gly phosate is genotoxic in vivo  via 
the oral route. 
For cancer descriptors, the ava ilable data and weight-of-eviden ce clearly do not support the 
descriptors “carcinogenic t o humans”, “likely to be carcinogeni c to humans”, or “inadequate 
information to assess carcinogenic potential”.  For the “suggestive evidence of carcinogenic 
potential” descriptor, consider ations could be looked at in isolation; however, following a 
thorough integrative weight-of-ev idence evaluation of the avail able data, the database would not 
support this cancer descriptor.  The strongest support is for “ not likely to be carcinogenic to 
humans”.  
This analysis integrating multiple lines of evidence highlights  the need for mechanistic studies to 
elucidate the MOA/AOP of glyphosate, as well as additional epid emiology studies and updates 
from the AHS cohort study to fur ther investigate the carcinogen ic potential of glyphosate in 
humans.  This evaluation focus ed on studies on the active ingre dient glyphosate; however, 
additional research could als o be performed to determine whethe r formulation components, such 
as surfactants, influence the to xicity of glyphosate formulations.  The agency has been working 
on plans to initiate research given these iden tified data gaps and these plans are described in 
Section 7.0. 
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 7.0 Collaborative Research Plan for Glyphosate and Glyphosate Formulations 
As previously mentioned, some have believed that glyphosate for mulations may be more toxic 
than glyphosate alone. Glyphosate has been studied in a multit ude of studies and there are 
studies that have been conducted on numerous formulations that contain glyphosate; however, 
there are relatively few research projects that have attempted to directly compare glyphosate and 
the formulations in the same experimental design.  Furthermore,  there are even less instances of 
studies comparing toxicity across formulations. 
The agency has been collaborating with the NTP Division of the National Institute of 
Environmental Health Sciences to develop a research plan intend ed to evaluate the role of 
glyphosate in product formulations and the differences in formu lation toxicity.  Four objectives 
were identified that laid out how research by NTP might contribute to these research questions: 
1) compare the toxicity of glyphosate vs. formulations, as well as compare formulations vs. 
formulations, 2) provide publicly  available toxicology data on cancer-related endpoints, 3) 
provide publicly available toxicology data on non-cancer endpoi nts, and 4) investigate the 
mechanisms of how glyphosate and formulations cause toxic effec ts.   
As part of the first objective , NTP will investigate the differential biological activity of 
glyphosate, glyphosate formulations, and the individual compone nts of formulations.  The NTP 
Laboratory Branch generated pre liminary data by exposing human hepatoma cells (HepG2) to 
five different glyphosate products bought off the shelf.  The e ndpoint in the assay was cell 
viability, measured by ATP levels.  The data, presented in Figu re 7.1, demonstrate at-a-glance 
that formulations are not equally toxic and that the toxicity is not being driven by the amount of glyphosate in the formulations, at  least for the endpoint of cell viability. This observation 
highlights how informative the data generated from this researc h can be to the overall research 
questions. 
Figure 7.1. Results of HepG2 exposures following 24 hour incub ation using different glyphosate 
formulations.  Note: some of the formulations included other ac tive ingredients besides glyphosate. 
Page 145 of 216
	  
 
  
 
 
 
 
 
 
 
  For the second objective, NTP will contribute to the publicly available knowledge-base 
describing the biological effect s of glyphosate and formulation s by conducting guideline studies 
addressing genotoxicity and studies that evaluate the oxidative  stress potential.  In order to 
organize publicly available da ta on glyphosate and formulations, IARC used 10 key 
characteristics of carcinogens  as a way to help inform their co nclusion (Smith et al. , 2016). 
Their review concluded that data  were only available for two of  these characteristics 
(genotoxicity and oxidative str ess) and little to no informatio n on the remaining characteristics 
was available. However, when members of a NTP workgroup looked at the available data 
included in the IARC review, the group did not agree with IARC that the data provided strong or 
clear evidence for either ge notoxicity or induc tion of oxidativ e stress given prot ocol deficiencies 
that could produce questionable results. 
Currently, the publicly availabl e information regarding non-cancer endpoints for glyphosate and 
glyphosate formulations is limited.  To begin to address the th ird objective, NTP will conduct a 
screening level analysis of the literature using text mining so ftware, for studies regarding non-
cancer endpoints resulting from  glyphosate exposure.  The resul ting scoping report will describe 
the evidence base for health outcomes investigated in connectio n to glyphosate, as well as help 
identify data gaps. As discussed in Section 6.0, there is a need for mechanistic st udies to elucidate the MOA/AOP of 
glyphosate. Although there are data suggesting glyphosate may be genotoxic or cause oxidative 
stress, there is little mechanistic information to support thes e observations.  For the last 
objective, NTP will use in vitro  screening assays to gain mechan istic information on the effect s 
of glyphosate and different formu lations for a variety of endpo ints and allow for direct 
comparisons among them.  The screening approach will also allow  for the identification of test 
substances that would be good candidates for further in vivo  testing. Since in vivo  findings in 
genetic toxicology testing are ge nerally considered as having a  greater relevance to humans than 
in vitro  findings, it is valuable to conf irm the results seen at the ce llular level at the whole animal 
level. 
Page 146 of 216
	  
 
  
 
 
 
 
  
 
 
 
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   Appendix A. Journal articles obtain ed from open literature search
	
Abstract Only Cebollero, L. R., et al. (2011). "Glyphosate based herbicides t oxicity, a new approach." Toxicology 
Letters 205, Supplement: S233. 
Abstract Only Monroy, C. M., et al. (2004). "In vitro evaluation of glyphosat e-induced DNA damage in fibrosarcoma 
cells HT1080 and Chinese hamster ovary (CHO) cells." Environ Mo l Mutagen 44(3): 216-216. 
Abstract Only Ramos-Morales, P., et al. (2008). "Combined use of multiple bio markers to evaluate the genotoxic 
activity of the herbicide Glyphos ate." Environ Mol Mutagen 49(7 ): 577-577. 
Abstract Only/Full article 
already identified Sorahan, T. (2015). "Multiple Myeloma and Glyphosate Use: A Re-Analysis of US Agricultural Health Study (AHS) Data." Int J Environ Res Public Health 12(2): 1548- 1559. 
Article not in English Kwiatkowska, M., et al. (2013). "GLYPHOSATE AND ITS FORMULATION S - TOXICITY, 
OCCUPATIONAL AND ENVIRONMENTAL EXPOSURE." Med Pr 64(5): 717-729 . 
Article not in English Lawson, R. and E. Estrade-Chapellaz (1999). "Intoxication volon taire par le glufosinate (Basta®)." 
Annales Françaises d'Anesthésie et de Réanimation 18(9): 1025-1 026. 
Article not in English Mañas, F., et al. (2009). "Aberr aciones cromosómicas en trabaja dores rurales de la Provincia de Córdoba 
expuestos a plaguicidas." BAG. Journal of basic and applied gen etics 20(1): 0-0. 
Article not in English Martinez, A., et al. (2007). "[Cy totoxicity of the herbicide gl yphosate in human peripheral blood 
mononuclear cells]." Biomedica 27(4): 594-604. 
Article not in English Monroy, C. M., et al. (2005). "[Cytotoxicity and genotoxicity o f human cells exposed in vitro to 
glyphosate]." Biomedica 25(3): 335-345. 
Article not in English Pieniazek, D., et al. ( 2003). "[Glyphosate- -a non-toxic pestici de?]." Med Pr 54(6): 579-583. 
Article not in English Saratovskikh, E. A., et al. (2007). "Genotoxicity of the pestis ide in Ames test and the possibility to 
formate the complexeses with DNA ." Ekologicheskaya genetika V(3 ): 46-54. 
Article not in English В статье представлены результаты генотоксико логических, аллерг ологических и 
иммунологических исследований, проведенных в рамках медико-биол огической оценки 
безопасности генно-инженерно-моди-фицированной кукурузы линии M ON 88017, устойчивой к 
глифосату и жуку Diabrotica spp. Анализ данных, полученных при изучении уровня повреждений 
ДНК и уровня хромосомных аберраций, тяжести активного анафилакт ического шока и 
интенсивности гуморального имму нного ответа, состояния гумораль ного и клеточного звеньев 
иммунитета, не выявил какого-либо генотоксического, аллергенног о, иммуномодулирующего и 
сенсибилизирующего действия ГМ-кукурузы линии MON 88017 по срав нению с ее 
традиционным аналогом. 
Cancer treatment Parajuli, K. R., et al. (2015). "Aminomethylphosphonic acid and  methoxyacetic acid induce apoptosis in 
prostate cancer cells." Int J Mol Sci 16(5): 11750-11765. 
Cancer treatment Li, Q., et al. (2013). "Glyphos ate and AMPA inhibit cancer cell growth through inhibiting intracellular 
glycine synthesis." Drug Des Devel Ther 7: 635-643. 
Cancer treatment Parajuli, K. R., et al. (2016). "Aminomethylphosphonic acid inhibits growth and metastasis of human 
prostate cancer in an orthotopic xenograft mouse model." Oncota rget 7(9): 10616-10626. 
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GLYPHOSATE." Journal of Toxicology and Environmental Health-Par t B-Critical Reviews 15(4): 233-
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Correspondence article Carrasco, A. E. (2011). "Reply to the Letter to the Editor Regarding Our Article (Paganelli et al., 2010)." Chem Res Toxicol 24(5): 610-613. 
Correspondence article de Souza, L. and L. Macedo Oda (2 013). "Letter to the editor." Food and Chemical Toxicology 53: 440. 
Correspondence article de Vendomois, J. S., et al. (2010). "Debate on GMOs Health Risk s after Statistical Findings in Regulatory 
Tests." Int J Biol Sci 6(6): 590-598. 
Correspondence article Farmer, D. R., et al. (2005). "Glyphosate results revisited." E nviron Health Perspect 113(6): A365-A366. 
Correspondence article Grunewald, W. and J. Bury (2013). "Comment on "Long term toxici ty of a Roundup herbicide and a 
Roundup-tolerant genetically modified maize" by Seralini et al. " Food and Chemical Toxicology 53: 447 -
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soybeans on the market: Glyphosa te accumulates in Roundup Ready GM soybeans”, by T. Bøhn, M. 
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   Cuhra, T. Traavik, M. Sanden, J. Fagan and R. Primicerio (Food Chemistry 2014, 153: 207–215)." Food 
Chemistry 172: 921-923. 
Correspondence article Ollivier, L. (2013). "A Comment on “Séralin i, G.-E., et al., Lo ng term toxicity of a Roundup herbicide 
and a Roundup-tolerant genetically modified maize. Food Chem. Toxicol. (2012),” 
http://dx.doi.org/10.1016/j.fct.2012.08.005." Food and Chemical  Toxicology 53: 458. 
Correspondence article P o r t i e r ,  C . J . , e t  a l .  ( 2 0 1 6 ) . " Differences in the carcinogenic evaluation of glyphosate between the 
International Agency for Researc h on Cancer (IARC) and the Euro pean Food Safety Authority (EFSA)." 
J Epidemiol Community Health. 
Correspondence article Roberfroid, M. (2014). "Letter to  the editor." Food and Chemica l Toxicology 66: 385. 
Correspondence article Sanders, D., et al. (2013). "Comment on "Long term toxicity of a Roundup herbicide and a Roundup-
tolerant genetically modified maize" by Seralini et al." Food a nd Chemical Toxicology 53: 450-453. 
Correspondence article Schorsch, F. (2013). "Serious in adequacies regarding the pathol ogy data presented in the paper by 
Séralini et al. (2012)." Food and Chemical Toxicology 53: 465-4 66. 
Correspondence article Wallace Hayes, A. (2014). "Editor in Chief of Food and Chemical Toxicology answers questions on 
retraction." Food and Chemical Toxicology 65: 394-395. 
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processes Benachour, N. and G.-E. Seralini (2009). "Glyphosate Formulatio ns Induce Apoptosis and Necrosis in 
Human Umbilical, Embryonic, and P lacental Cells." Chem Res Toxi col 22(1): 97-105. 
Effects on cellular processes Chaufan, G., et al. (2014). "Gly phosate commercial formulation causes cytotoxicity, oxidative effects, 
and apoptosis on human cells: di fferences with its active ingre dient." Int J Toxicol 33(1): 29-38. 
Effects on cellular 
processes Coalova, I., et al. (2014). "Inf luence of the spray adjuvant on the toxicity effects of a glyphosate 
formulation." Toxicology in Vitro 28(7): 1306-1311. 
Effects on cellular 
processes George, J., et al. (2010). "Studies on glyphosate-induced carci nogenicity in mouse skin: a proteomic 
approach." J Proteomics 73(5): 951-964. 
Effects on cellular 
processes George, J. and Y. Shukla (2013). "Emptying of Intracellular Cal cium Pool and Oxidative Stress 
Imbalance Are Associated with the Glyphosate-Induced Proliferat ion in Human Skin Keratinocytes 
HaCaT Cells." ISRN Dermatol 2013: 825180. 
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processes Heu, C., et al. (2012). "A step further toward glyphosate-induc ed epidermal cell death: Involvement of 
mitochondrial and oxidative mechanisms." Environmental Toxicology and Pharmacology 34(2): 144-153. 
Effects on cellular 
processes Thongprakaisang, S., et al. (2013). "Glyphosate induces human b reast cancer cells growth via estrogen 
receptors." Food Chem Toxicol 59: 129-136. 
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fit for purpose review (1934). "The 1933 meeting of the American society of orthodontists at Oklahoma City." International Journal of Orthodontia and Dentistry for Children 20(1): 102-10 5. 
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fit for purpose review (1938). "Supplementary report of region III: Reports of state c hairmen." The Journal of Pediatrics 
12(<HT>6</HT>): 846-850. 
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fit for purpose review (1939). "Meeting of the Executiv e Board of the American Academy of Pediatrics." The Journal of 
Pediatrics 15(2): 294-315. 
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Journal of Pediatrics 14(2): 251-254. 
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fit for purpose review (1967). "AORN Proceedings." AORN Journal 5(1): 82-91. 
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B., Piercy, D. W. T., Whittem, J. H.&amp; Titchen, D. A. (1969) . Excretion of the pyrrolizidine alkaloid 
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fit for purpose review (1972). "News and comment." American Journal of Orthodontics 62 (3): 319-334. 
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fit for purpose review (1976). "NHI proposals: a wide spectrum." AORN Journal 23(5): 8 14-818. 
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fit for purpose review (1977). "The SR periodicals misce llany." Serials Review 3(2): 1 1-19. 
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fit for purpose review (1981). "Reviews of Books." The Lancet 317(8232): 1239-1240. 
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fit for purpose review (1984). "24–27 October 1984 International meeting on artificial intelligence: Marseilles, France." 
Computer Compacts 2(3–4): 121-122. 
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fit for purpose review (1985). "Newsview." Journal of Allergy and Clinical Immunology 76(2, Part 1): A36-A41. 
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fit for purpose review (1990). "Regional direct marketing clubs/associations support D M education at local 
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fit for purpose review (1990). "Subject index." Toxicology 61(3): 313-316. 
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fit for purpose review (1990). "Volume contents." Toxicology 61(3): 319-320. 
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fit for purpose review (1991). "4971677 Fluorescence detection type electrophoresis ap paratus: Hideki Kambara, Yoshiko 
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fit for purpose review (1991). "4971903 Pyrophosphate-based method and apparatus for s equencing nucleic acids: Edward 
Hyman." Biotechnology Advances 9(1): 89. 
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fit for purpose review (1991). "4971908 Glyphosate-tolerant 5-enolpyruvyl 3-phosphoshi kimate synthase: Ganesh M Kishore, 
Dilip Shah assigned to Monsanto Company." Biotechnology Advance s 9(1): 89. 
Not Relevant to current fit for purpose review (1991). "Author Index." Journal of Chromatography A 540: 479-48 2. 
Not Relevant to current fit for purpose review (1991). "Challenge to US computer fraud &amp; abuse act." Compu ter Fraud & Security Bulletin 
1991(3): 5-6. 
Not Relevant to current fit for purpose review (1991). "Chemical index for volumes 16–17." Fundamental and App lied Toxicology 17(4): 848-850. 
Not Relevant to current 
fit for purpose review (1991). "Court case round-ups." C omputer Fraud & Security Bulle tin 1991(3): 5. 
Not Relevant to current 
fit for purpose review (1991). "FAT attacker!" Computer  Fraud & Security Bulletin 1991(3): 5. 
Not Relevant to current fit for purpose review (1991). "FIGO news." International Journal of Gynecology & Obst etrics 35(3): 265-267. 
Not Relevant to current 
fit for purpose review (1991). "Local direct marketing clubs/associations support unde rgraduate/graduate level DM education." 
Journal of Direct Marketing 5(3): 61-65. 
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fit for purpose review (1991). "Manipulation of molluscan haemocytes in vitro: ∗S.E. Fryer. Department of Zoology, Oregon 
State University, Corvallis OR 97331, USA." Developmental & Com parative Immunology 15, 
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japonicus (Crustacea: Decapoda): J . Rodriguez, V. Boulo, E. Bac hère and E. Mialhe. IFREMER, Unité 
Pathol. Immunol. Génét. Mol., BP 133, 17390 La Tremblade, Franc e." Developmental & Comparative 
Immunology 15, Supplement 1: S73. 
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Not Relevant to current fit for purpose review (1992). "Forthcoming papers." Soil Biology and Biochemistry 24( 1): 79. 
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fit for purpose review (1992). "Subject index volume 85  (1992)." Plant Science 85(2): 235-237. 
Not Relevant to current fit for purpose review (1993). "Media watch." Physiotherapy 79(7): 496-498. 
Not Relevant to current 
fit for purpose review (1993). "Meetings and Notices." J ournal of Equine Veterinary Sc ience 13(9): 481-536. 
Not Relevant to current 
fit for purpose review (1993). "Meetings and notices." J ournal of Equine Veterinary Sc ience 13(8): 432-476. 
Not Relevant to current 
fit for purpose review (1993). "ROUND-UP Publications." Reproductive Health Matters 1( 1): 109-110. 
Not Relevant to current 
fit for purpose review (1994). "Media Watch." Physiotherapy 80(11): 793-795. 
Not Relevant to current 
fit for purpose review (1994). "ROUND-UP Research." Reproductive Health Matters 2(4): 121-122. 
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fit for purpose review (1994). "ROUND-UP Service Deliver y." Reproductive Health Matter s 2(3): 125-128. 
Not Relevant to current 
fit for purpose review (1995). "ROUND-UP Law and Policy. " Reproductive Health Matters 3(<HT>6</HT>): 164-166. 
Not Relevant to current 
fit for purpose review (1995). "ROUND-UP Publications." Reproductive Health Matters 3( 5): 146-151. 
Not Relevant to current 
fit for purpose review (1995). "ROUND-UP Service Deliver y." Reproductive Health Matter s 3(<HT>6</HT>): 167-169. 
Not Relevant to current 
fit for purpose review (1996). "5410871 Emission control device and method: Masters Be n F; Self James M Gastonia, NC, 
United States Assigned to Unlimited Technologies Inc." Environm ent International 22(2): XVI-XVII. 
Not Relevant to current 
fit for purpose review (1996). "5411697 Method for processing contaminated plastic was te: McGraw Peter S; Drake John; Hane 
Thomas H Severna Park, MD, United States Assigned to The United States of America as represented by 
the Secretary of the Navy." Environment International 22(2): XV II. 
Not Relevant to current 
fit for purpose review (1996). "5411944 Glyphosate-sulfuric acid adduct herbicides and use: Young Donald C Fullerton, CA, 
United States Assigned to Union O il Company of California." Env ironment International 22(2): XVII. 
Not Relevant to current 
fit for purpose review (1996). "5412544 Method of illuminating and providing emergency egress guidance for hazardous areas: 
Derrick Donald E; Harris Hollis A; Marion Robert H; Tower Willi am A; Towle L Christophe Hanover, 
NH, United States Assigned to Loctite Luminescent Systems Inc; The MTL Instruments Group." 
Environment Interna tional 22(2): XVII. 
Not Relevant to current fit for purpose review (1996). "Animal breeding and in fertility: M.J. Meredith (Editor ), Blackwell Science, Oxford, 1995, 508 
pp., £60.00, ISBN 0-632-04038-6." Animal Reproduction Science 4 4(2): 135-136. 
Not Relevant to current 
fit for purpose review (1996). "Preliminary program of the ninety-sixth annual session , May 11–15,1996." American Journal of 
Orthodontics and Dentofacial Orthopedics 109(2): 196-214. 
Not Relevant to current fit for purpose review (1996). "Roundup of Federal Regulations on Food and Nutrition Issues." Journal of the American Dietetic Association 96(7): 654. 
Not Relevant to current 
fit for purpose review (1996). "ROUND-UP Research." Reproductive Health Matters 4(8): 149-153. 
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fit for purpose review (1997). "ROUND-UP Conferences." R eproductive Health Matters 5(1 0): 180. 
Not Relevant to current fit for purpose review (1997). "ROUND-UP Research." Reproductive Health Matters 5(10):  162-167. 
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fit for purpose review (1998). "E. coli antiserum." Journal of Equine Veterinary Scien ce 18(8): 507. 
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fit for purpose review (1998). "EIA in wild horses." Journal of Equine Veterinary Scie nce 18(8): 507. 
Not Relevant to current fit for purpose review (1998). "Exercise-induced endotoxemia." Journal of Equine Veter inary Science 18(8): 506-507. 
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fit for purpose review (1998). "Flamel Technologies sur l es starting-blocks." Biofutur 1998(176): 41. 
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fit for purpose review (1998). "Legislative roundup: protection of human subjects key issue for Congress." J Natl Cancer Inst 
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    Not Relevant to current 
fit for purpose review (1998). "ROUND-UP Conferences." R eproductive Health Matters <HT>6</HT>(12): 186. 
Not Relevant to current fit for purpose review (1999). "Research poster summaries from the ENA 1999 Annual Mee ting." Journal of Emergency 
Nursing 25(<HT>6</HT>): 446-456. 
Not Relevant to current 
fit for purpose review (1999). "ROUND-UP Publications." Reproductive Health Matters 7( 14): 196-201. 
Not Relevant to current 
fit for purpose review (2000). "Genome roundup." Nat Biotechnol 18(1): 9. 
Not Relevant to current 
fit for purpose review (2000). "ROUND-UP Law and Policy. " Reproductive Health Matters 8(15): 171-174. 
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fit for purpose review (2000). "ROUND-UP Research." Reproductive Health Matters 8(16):  190-192. 
Not Relevant to current 
fit for purpose review (2000). "Trauma news today." International Journal of Trauma Nu rsing <HT>6</HT>(3): 105-108. 
Not Relevant to current 
fit for purpose review (2001). "ROUND-UP Research." Reproductive Health Matters 9(18):  196-198. 
Not Relevant to current 
fit for purpose review (2002). "ROUND-UP Research." Reproductive Health Matters 10(19) : 209-210. 
Not Relevant to current 
fit for purpose review (2003). "New Web site lights childhood obes ity with fun." Journ al of the American Dietetic Association 
103(<HT>6</HT>): 671-672. 
Not Relevant to current 
fit for purpose review (2003). "ROUND-UP Law and Policy. " Reproductive Health Matters 11(22): 199-203. 
Not Relevant to current 
fit for purpose review (2003). "ROUND-UP Research." Reproductive Health Matters 11(21) : 201-204. 
Not Relevant to current 
fit for purpose review (2004). "Contemporary issues in women's health." International Journal of Gynecology & Obstetrics 
87(2): 111-113. 
Not Relevant to current 
fit for purpose review (2004). "Contents page, CD logo." The Journal of Men's Health &  Gender 1(4): 283-284. 
Not Relevant to current 
fit for purpose review (2004). "Editorial Board." European Journal of Oncology Nursing  8(4): i. 
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fit for purpose review (2004). "Editorial Board." European Journal of Oncology Nursing  8(3): i. 
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fit for purpose review (2004). "Editorial Board." European Journal of Oncology Nursing  8, Supplement 1: i. 
Not Relevant to current fit for purpose review (2004). "Editorial Board." European Journal of Oncology Nursing  8, Supplement 2: i. 
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fit for purpose review (2004). "Research round-up." Complementary Therapies in Nursing and Midwifery 10(4): 262-263. 
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fit for purpose review (2004). "ROUND-UP Condoms." Reproductive Health Matters 12(23):  176-177. 
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fit for purpose review (2004). "ROUND-UP Service Deliver y." Reproductive Health Matter s 12(23): 191-200. 
Not Relevant to current 
fit for purpose review (2004). "Volume Contents Index." T he Journal of Men's Health & Gender 1(4): 413-415. 
Not Relevant to current fit for purpose review (2004). "WebWatch." The Journal of Men's Health & Gender 1(2–3) : 240. 
Not Relevant to current fit for purpose review (2004). "You’ve Been Had! How th e Media and Environmentalists T urned America into a Nation of 
Hypochondriacs: Melvin A. Benarde. Rutgers University Press, 20 02. xiv + 308 pp. $28.00. ISBN 0-
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fit for purpose review (2005). "Contents page, CD logo." The Journal of Men's Health & Gender 2(4): 387. 
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fit for purpose review (2005). "Contents page, CD logo." The Journal of Men's Health &  Gender 2(2): 159-160. 
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       Not Relevant to current 
fit for purpose review (2005). "Editorial Board." European Journal of Oncology Nursing  9(4): i. 
Not Relevant to current fit for purpose review (2005). "Editorial Board." European Journal of Oncology Nursing  9(3): i. 
Not Relevant to current 
fit for purpose review (2005). "Editorial Board." European Journal of Oncology Nursing  9(2): i. 
Not Relevant to current 
fit for purpose review (2005). "Editorial Board." European Journal of Oncology Nursing  9(1): i. 
Not Relevant to current 
fit for purpose review (2005). "JournalWatch." The Journal of Men's Health & Gender 2( 3): 353-356. 
Not Relevant to current 
fit for purpose review (2005). "News Round-up." The Journal of Men's Health & Gender 2 (3): 360-363. 
Not Relevant to current 
fit for purpose review (2005). "News Round-up." The Journal of Men's Health & Gender 2 (1): 116-118. 
Not Relevant to current 
fit for purpose review (2005). "News Round-up for jmhg vol 2 no 4 (Dec 2005)." The Jou rnal of Men's Health & Gender 2(4): 
444. 
Not Relevant to current 
fit for purpose review (2005). "Research round-up: a brief summary of research publica tions in CAM." Complementary 
Therapies in Clinical Pr actice 11(2): 139-141. 
Not Relevant to current 
fit for purpose review (2006). "ACFAOM newsletter." The Foot 16(4): 226-227. 
Not Relevant to current 
fit for purpose review (2006). "Aims &amp; Scope/Editorial board." The Journal of Men' s Health & Gender 3(1): iii. 
Not Relevant to current 
fit for purpose review (2006). "Contents page, CD logo." The Journal of Men's Health &  Gender 3(2): 119-120. 
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fit for purpose review (2006). "Contents page, CD logo." The Journal of Men's Health &  Gender 3(4): 315-316. 
Not Relevant to current 
fit for purpose review (2006). "Editorial Board." European Journal of Oncology Nursing  10(5): i. 
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fit for purpose review (2006). "Editorial Board." European Journal of Oncology Nursing  10(4): i. 
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fit for purpose review (2006). "Editorial Board." European Journal of Oncology Nursing  10(3): i. 
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fit for purpose review (2006). "Editorial Board." European Journal of Oncology Nursing  10(2): i. 
Not Relevant to current fit for purpose review (2006). "Editorial Board." European Journal of Oncology Nursing  10(1): i. 
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fit for purpose review (2006). "Editorial Board/Publication/Advertising info." Progres s in Biophysics and Molecular Biology 
92(1): CO2. 
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fit for purpose review (2006). "News Round-up." The Journal of Men's Health & Gender 3 (1): 93-96. 
Not Relevant to current fit for purpose review (2006). "News Round-up for jmhg vol 3 no 3 (September 2006)." T he Journal of Men's Health & Gender 
3(3): 304-306. 
Not Relevant to current 
fit for purpose review (2006). "Research." Reproductive Health Matters 14(28): 210-218 . 
Not Relevant to current 
fit for purpose review (2006). "Research problems." Discrete Applied Mathematics 154(3 ): 604-607. 
Not Relevant to current fit for purpose review (2006). "Table of Contents." The American Journal of Emergency Medicine 24(4): A3-A4. 
Not Relevant to current 
fit for purpose review (2006). "Volume Contents Index: Vo lume 3." The Journal of Men's  Health & Gender 3(4): 427-431. 
Not Relevant to current 
fit for purpose review (2006). "WebWatch for jmhg vol 3 no 1 (issue 9)." The Journal of Men's Health & Gender 3(1): 88. 
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fit for purpose review (2007). "Art exhibit powered by geothermal energy." Renewable E nergy Focus 8(<HT>6</HT>): 14. 
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fit for purpose review (2007). "Contents." The Journal of Men's Health & Gender 4(2): 113-114. 
Not Relevant to current fit for purpose review (2007). "Contents page." The Jour nal of Men's Health & Gender 4 (1): 1-2. 
Not Relevant to current 
fit for purpose review (2007). "Editorial Board." European Journal of Oncology Nursing  11, Supplement 2: ii. 
Not Relevant to current 
fit for purpose review (2007). "Editorial Board." European Journal of Oncology Nursing  11(5): i. 
Not Relevant to current 
fit for purpose review (2007). "Editorial Board." European Journal of Oncology Nursing  11(4): i. 
Not Relevant to current 
fit for purpose review (2007). "Editorial Board." European Journal of Oncology Nursing  11(3): i. 
Not Relevant to current 
fit for purpose review (2007). "Editorial Board." European Journal of Oncology Nursing  11(2): i. 
Not Relevant to current 
fit for purpose review (2007). "Editorial Board." European Journal of Oncology Nursing  11(1): i. 
Not Relevant to current 
fit for purpose review (2007). "In brief." Renewable Energy Focus 8(<HT>6</HT>): 18-19 . 
Not Relevant to current 
fit for purpose review (2007). "North America." Rene wable Energy Focus 8(5): 6. 
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fit for purpose review G e h i n , A . ,  e t a l . ( 2 0 0 5 ) .  " V i t a m i n s  C  a n d  E  r e v e r s e  e f f e c t  o f h erbicide-induced toxicity on human 
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vitamins C and E." Environmental Toxicology and Pharmacology 22(1): 27-34. 
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analysis of random amplified polym orphic DNA profiles." J Hazar d Mater 298: 320-327. 
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fit for purpose review G u i l h e r m e , S . , e t  a l .  ( 2 0 0 9 ) .  " Tissue specific DNA damage in th e European eel (Anguilla anguilla) 
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fit for purpose review Nwani, C. D., et al. (2014). "Induction of micronuclei and nucl ear lesions in Channa punctatus following 
exposure to carbosulfan, glyphosate and atrazine." Drug Chem To xicol 37(4): 370-377. 
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fit for purpose review Owczarek, M., et al. (1999). "Evaluation of toxic and genotoxic activity of some pesticides in a soil-plant 
system." Human and Environmental Exposure to Xenobiotics: 755-7 62. 
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fit for purpose review Perez-Iglesias, J. M., et al. ( 2016). "Effects of glyphosate on hepatic tissue evaluating 
melanomacrophages and erythrocytes responses in neotropical anu ran Leptodactylus latinasus." Environ 
Sci Pollut Res Int. 
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fit for purpose review Poletta, G. L., et al. (2009). "Genotoxicity of the herbicide f ormulation Roundup (glyphosate) in broad-
snouted caiman (Caiman latirostris) evidenced by the Comet assa y and the Micronucleus test." Mutat Res 
672(2): 95-102. 
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fit for purpose review Siddiqui, S., et al. (2012). "Gl yphosate, alachor and maleic hy drazide have genotoxic effect on Trigonella 
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fit for purpose review Song, H.-Y., et al. (2012). "Cellular Toxicity of Surfactants U sed as Herbicide Additives." J Korean Med 
Sci 27(1): 3-9. 
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fit for purpose review Unver, T., et al. (2010). "Genome-wide profiling and analysis o f Festuca arundinacea miRNAs and 
transcriptomes in response to foliar glyphosate application." M ol Genet Genomics 283(4): 397-413. 
Relevant- Cancer Epi Acquavella, J. F., et al. (2006). "Exposure misclassification i n studies of agricultural pesticides - Insights 
from biomonitoring." Epidemiology 17(1): 69-74. 
Relevant- Cancer Epi Acquavella, J. F., et al. (2005). "Implications for epidemiolog ic research on variation by pesticide in 
studies of farmers and their families." Scandinavian Journal of Work Environment & Health 31: 105-
109. 
Relevant- Cancer Epi Baker, B. A., et al. (2005). "Farm Family Exposure Study: metho ds and recruitment practices for a 
biomonitoring study of pesticide exposure." Journal of Exposure Analysis and Environmental 
Epidemiology 15(6): 491-499. 
Relevant- Cancer Epi Chang, E. T. and E. Delzell (2016). "Systematic review and meta -analysis of glyphosate exposure and 
risk of lymphohematopoietic cancers." J Environ Sci Health B 51 (6): 402-434. 
Relevant- Cancer Epi De Roos, A. J., et al. (2005). "Cancer incidence among glyphosa te-exposed pesticide applicators in the 
Agricultural Health Study." Envi ron Health Perspect 113(1): 49- 54. 
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  Relevant- Cancer Epi Firth, H. M., et al. (2007). "Chemical exposure among NZ farmer s." International Journal of 
Environmental Health R esearch 17(1): 33-43. 
Relevant- Cancer Epi Lash, T. L. (2007). "Bias analysis applied to Agricultural Health Study publications to estimate non-
random sources of uncertainty." J Occup Med Toxicol 2: 15. 
Relevant- Cancer Epi Mink, P. J., et al. (2012). "Epidemiologic studies of glyphosat e and cancer: a review." Regul Toxicol 
Pharmacol 63(3): 440-452. 
Relevant- Cancer Epi Sorahan, T. (2012). "Multiple myeloma and glyphosate use: A re-analysis of US Agricultural Health 
Study data." Toxicology Letters 211, Supplement: S169. 
Relevant- 
Carcinogenicity Greim, H., et al. (2015). "Evaluation of carcinogenic potential of the herbicide glyphosate, drawing on 
tumor incidence data from fourteen chronic/carcinogenicity rode nt studies." Crit Rev Toxicol 45(3): 185 -
208. 
Relevant- 
Carcinogenicity Williams, G. M., et al. (2000). "Safety Evaluation and Risk Ass essment of the Herbicide Roundup and 
Its Active Ingredient, Glyphosate, for Humans." Regulatory Toxi cology and Pharmacology 31(2): 117 -
165. 
Relevant- Genotoxicity Alvarez-Moya et al. (2014) “Comparison of the in vivo and in vi tro genotoxicity of glyphosate 
isopropylamine salt in three different organisms”. Genetics and Molecular Biology , 37, 1, 105-110 
Relevant- Genotoxicity Chan, P. and J. Mahler (1992). "NTP technical report on the tox icity studies of Glyphosate (CAS No. 
1071-83-6) Administered In Dosed Feed To F344/N Rats And B6C3F1 Mice." Toxic Rep Ser 16: 1-d3. 
Relevant- Genotoxicity Bakry, F. A., et al. (2015). "Glyphosate herbicide induces geno toxic effect and physiological disturbances 
in Bulinus truncatus snails." Pestic Biochem Physiol 123: 24-30 . 
Relevant- Genotoxicity Bolognesi, C., et al. (1997). "Genotoxic activity of glyphosate  and its technical formulation roundup." J 
Agric Food Chem 45(5): 1957-1962. 
Relevant- Genotoxicity Bolognesi, C., et al. (2009). "Biomonitoring of genotoxic risk in agricultural workers from five colombian 
regions: association to occupational exposure to glyphosate." J Toxicol Environ Health A 72(15-16): 986-
997. 
Relevant- Genotoxicity Da Silva, F. R., et al. (2014). "Genotoxic assessment in tobacco farmers at different crop times." Science 
of the Total Environment 490: 334-341. 
Relevant- Genotoxicity Dimitrov, B. D., et al. (2006). "Comparative genotoxicity of th e herbicides Roundup, Stomp and Reglone 
in plant and mammalian test syste ms." Mutagenesis 21(6): 375-38 2. 
Relevant- Genotoxicity El-Shenawy, N. S. (2009). "Oxida tive stress responses of rats e xposed to Roundup and its active 
ingredient glyphosate." Environ Toxicol Pharmacol 28(3): 379-38 5. 
Relevant- Genotoxicity Fortes, C., et al. (2016). "Occupational Exposure to Pesticides With Occupational Sun Exposure Increases 
the Risk for Cutaneous Melanoma. " J Occup Environ Med 58(4): 37 0-375. 
Relevant- Genotoxicity Ghisi Nde, C., et al. (2016). "Do es exposure to glyphosate lead to an increase in the micronuclei 
frequency? A systematic and meta-analytic review." Chemosphere 145: 42-54. 
Relevant- Genotoxicity Heydens, W. F., et al. (2008). "Genotoxic potential of glyphosa te formulations: mode-of-action 
investigations." J Agric Food Chem 56(4): 1517-1523. 
Relevant- Genotoxicity K a l e , P . G . , e t  a l .  ( 1 9 9 5 ) .  " M U T A G E N I C I T Y  T E S T I N G  O F 9 H E R B I C I D ES AND PESTICIDES 
CURRENTLY USED IN AGRICULTURE." Environ Mol Mutagen 25(2): 148- 153. 
Relevant- Genotoxicity Kier, L. D. (2015). "Review of genotoxicity biomonitoring studi es of glyphosate-based formulations." 
Crit Rev Toxicol 45(3): 209-218. 
Relevant- Genotoxicity Koller, V. J., et al. (2012). "Cytotoxic and DNA-damaging prope rties of glyphosate and Roundup in 
human-derived buccal epithelial cells." Arch Toxicol 86(5): 805 -813. 
Relevant- Genotoxicity Li, A. P. and T. J. Long (1988) . "An evaluation of the genotoxi c potential of glyphosate." Fundam Appl 
Toxicol 10(3): 537-546. 
Relevant- Genotoxicity Lioi, M. B., et al. (1998). "Genotoxicity and oxidative stress induced by pesticide exposure in bovine 
lymphocyte cultures in vitro." Mutat Res 403(1-2): 13-20. 
Relevant- Genotoxicity Manas, F., et al. (2009). "Genotoxicity of AMPA, the environmen tal metabolite of glyphosate, assessed 
by the Comet assay and cytogenetic tests." Ecotoxicol Environ S af 72(3): 834-837. 
Relevant- Genotoxicity Manas, F., et al. (2009). "Genotoxicity of glyphosate assessed by the comet assay and cytogenetic tests." 
Environmental Toxicology and Pharmacology 28(1): 37-41. 
Relevant- Genotoxicity Mandel, J. S., et al. (2005). "Biomonitoring for farm families in the farm family exposure study." 
Scandinavian Journal of Work Environment & Health 31: 98-104. 
Relevant- Genotoxicity Mladinic, M., et al. (2009). "Evaluation of genome damage and i ts relation to oxidative stress induced by 
glyphosate in human lymphocytes in vitro." Environ Mol Mutagen 50(9): 800-807. 
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  Relevant- Genotoxicity Mladinic, M. and D. Zeljezic (2008). "Assessment of oxidative D NA damage by glyphosate applying 
hOGG1 modified comet and micronucleus assay." Toxicology Letter s 180: S170-S171. 
Relevant- Genotoxicity Paz-y-Mino, C., et al. (2011). "Baseline determination in socia l, health, and genetic areas in communities 
affected by glyphosate aerial spraying on the northeastern Ecua dorian border." Rev Environ Health 26(1): 
45-51. 
Relevant- Genotoxicity Paz-y-Mino, C., et al. (2007). "Evaluation of DNA damage in an Ecuadorian population exposed to 
glyphosate." Genetics and Molecular Biology 30(2): 456-460. 
Relevant- Genotoxicity Peluso, M., et al. (1998). "32P-postlabeling detection of DNA a dducts in mice treated with the herbicide 
Roundup." Environ Mol Mutagen 31(1): 55-59. 
Relevant- Genotoxicity Piesova, E. (2005). "The effect of glyphosate on the frequency of micronuclei in bovine lymphocytes in 
vitro." Acta Veterinaria-B eograd 55(2-3): 101-109. 
Relevant- Genotoxicity Prasad, S., et al. (2009). "Clas togenic effects of glyphosate i n bone marrow cells of swiss albino mice." 
J Toxicol 2009: 308985. 
Relevant- Genotoxicity Rank, J., et al. (1993). "Genotoxicity testing of the herbicide Roundup and its active ingredient glyphosate 
isopropylamine using the mouse bone marrow micronucleus test, S almonella mutagenicity test, and 
Allium anaphase-telophase test." Mutat Res 300(1): 29-36. 
Relevant- Genotoxicity Roustan, A., et al. (2014). "Genotoxicity of mixtures of glypho sate and atrazine and their environmental 
transformation products before and after photoactivation." Chem osphere 108: 93-100. 
Relevant- Genotoxicity Silva Kahl, V. F., et al. (2016) . "Telomere measurement in indi viduals occupationally exposed to 
pesticide mixtures in tobacco fields." Environ Mol Mutagen 57(1 ): 74-84. 
Relevant- Genotoxicity Sivikova, K. and J. Dianovsky (2006). "Cytogenetic effect of te chnical glyphosate on cultivated bovine 
peripheral lymphocytes." Int J Hyg Environ Health 209(1): 15-20 . 
Relevant- Genotoxicity Vigfusson, N. V. and E. R. Vyse (1980). "The effect of the pest icides, Dexon, Captan and Roundup, on 
sister-chromatid exchanges in human lymphocytes in vitro." Muta t Res 79(1): 53-57. 
Retracted Article Séralini, G.-E., et al. (2014). "Retraction notice to “Long ter m toxicity of a Roundup herbicide and a 
Roundup-tolerant genetically modi fied maize” [Food Chem. Toxico l. 50 (2012) 4221–4231]." Food and 
Chemical Toxicology 63: 244. 
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 Appendix B 
Figure B.1. Visual representation of studies included in De Ro os et al.  (2003). 
Figure B.2. Visual representation of studies included in Harde ll et al.  (2002). 
Figure B.3. Visual representation of the association between M cDuffie et al. (2001) and the follow-up analysis 
by Hohenadal et al. (2011). 
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Figure B.4. Visual representation of the association between C arreon et al. (2005), which inv estigated gliomas 
in women only, and Yiin et al.  (2012), which investigated both sexes. 
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 Appendix C 
Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
Alavanja et al. 
(2003) USA: Iowa and 
North Carolina Enrollment (1993-
1997) through 2001 Males enrolled in AHS; 
licensed private and 
commercial applicators Males enrolled in AHS; 
licensed private and 
commercial applicators 566 cases 
54,766 controls not reported No 
Andreotti et al. 
(2009) USA: Iowa and 
North Carolina Enrollment (1993-
1997) through 2004 Participants enrolled in 
AHS; licensed private and 
commercial applicators 
and spouses Participants enrolled in 
AHS; licensed private and 
commercial applicators and 
spouses 93 cases (64 
applicators, 29 
spouses) 
82,503 controls 
(52,721 applicators, 
29,782 spouses) 55 cases 
48,461 controls No 
Band et al. (2011) Canada: British 
Columbia 1983-1990 Male residents in British 
Columbia identified as 
cancer patients in British 
Columbia Cancer Registry 
(excluding farmers that 
worked all outside British 
Columbia) Male residents in British 
Columbia identified as 
cancer patients in British 
Columbia Cancer Registry 
(excluding farmers that 
worked all outside British 
Columbia) with other 
cancer sites excluding lung 
cancer and cancers of 
unknown primary site 1,153 cases 
3,999 controls 25 cases 
60 controls Yes (included 
in adjustment) 
Brown et al. (1990) USA: Iowa and 
Minnesota Iowa: 1981-1983; 
Minnesota: 1980 -
1982 
Initial interview 
1981-1984 and 
supplemental 
interviews (Iowa 
only) in 1987 White males (30 years or 
older) residing in Iowa or 
Minnesota diagnosed with 
leukemia White males without 
lymphatic or hematopoietic 
cancer selected by random 
digit dialing (< age 65), 
Medicare records (age > 
65) and state death 
certificate files (deceased 
controls) - frequency 
matched for 5-year age 
group, vital status, and state 
of residence Initial: 578 cases; 
1245 controls  
Supplemental: 92 
cases; 211 controls 15 cases 
49 controls Yes (not 
evaluated) 
Brown et al. (1993) USA: Iowa Iowa: 1981-1983; 
Interview 1981-
1984 White males (30 years or 
older) residing in Iowa 
diagnosed with multiple 
myeloma White males without 
lymphatic or hematopoietic 
cancer selected by random 
digit dialing (< age 65), 
Medicare records (age > 173 cases 
650 controls 11 cases 
40 controls Yes (not 
evaluated) 
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 Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
65) and state death 
certificate files (deceased 
controls) - frequency 
matched for 5-year age 
group, vital status, and state 
of residence 
Cocco et al.  (2013) Czech Republic, 
France, Germany, 
Italy, Ireland, and 
Spain 1998-2004 Adult patients first 
diagnosed with lymphoma 
residing in the referral 
area of the participating 
centers Controls from Germany 
and Italy were randomly 
selected by sampling from 
the general population, 
matched to cases on sex, 5-
year age-group, and 
residence area. The rest of 
the centers used matched 
hospital controls, with 
eligibility criteria limited to 2,348 cases 
2,462 controls 4 cases 
2 controls No 
diagnoses other than 
cancer, infectious diseases, 
and immunodeficient 
diseases 
De Roos et al. 
(2003) USA: Nebraska, 
Iowa, Minnesota, 
and Kansas Nebraska: 1983 -
1986 
Iowa: 1981-1983 
Minnesota: 1980 -
1982 
Kansas: 1979-1981 White males diagnosed 
with NHL in one of the 4 
states (21 years or older in 
Nebraska and Kansas; 30 
years or older in Iowa and 
Minnesota) Males living in same 
geographic area obtained 
by random digit dialing, 
Medicare records and state 
mortality files - frequency 
matched for race, sex, age, 
and vital status 870 cases 
2,569 controls 36 cases 
61 controls Yes (not 
significant in 
covariate 
analysis) 
De Roos et al. 
(2005) USA: Iowa and 
North Carolina Enrollment (1993-
1997) through 2001 Participants enrolled in 
AHS; licensed private and 
commercial applicators 
and spouses Participants enrolled in 
AHS; licensed private and 
commercial applicators and 
spouses 54,315 subjects 
included in this 
analysis All cancers – 358 cases 
Lung – 26 cases 
Oral cavity – 10 cases 
Colon – 15 cases 
Rectum – 14 cases 
Pancreas – 7 cases 
Kidney – 9 cases 
Bladder – 17 cases 
Prostate – 145 cases No 
Melanoma – 14 cases 
All lymphohematopoietic 
cancers – 36 cases 
NHL – 17 cases 
Leukemia – 9 cases 
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 Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
Multiple myeloma – 6 
cases 
(13,280 subjects not 
exposed to glyphosate 
used for comparison 
population) 
Engel et al. (2005) USA: Iowa and 
North Carolina Enrollment (1993-
1997) through 2000 Wives of applicators 
enrolled in AHS study 
with no history of breast 
cancer Wives of applicators 
enrolled in AHS study with 
no history of breast cancer 309 cases 
30,145 controls 82 cases; 10,016 controls No 
Eriksson et al. 
(2008) Sweden 1999-2002 Patients (18-74 years of 
age) residing in Sweden 
and diagnosed with NHL Swedish residents randomly 
selected living in same 
health service regions as 
cases - frequency matched 
for age (in 10 years) and 
sex 910 cases 
1,016 controls 29 cases 
18 controls No 
Flower et al. (2004) USA: Iowa 1993-1997 Children (born after 1975) 
of participants enrolled in 
AHS study who were 
diagnosed with childhood 
cancer up to 19 years of 
age Children (born after 1975) 
of participants enrolled in 
AHS study not diagnosed 
with childhood cancer up to 
19 years of age 50 cases out of 17,357 
total study population Maternal use: 13 cases of 
6075 total exposed 
Paternal use: 6 cases of 
3231 total exposed No 
Hardell et al. (2002) Sweden NHL: 1987-1990      
HCL: 1987-1992 NHL: Male residents of 
one of four northern or 
three middle counties in 
Sweden age 25 years and 
older diagnosed with 
NHL; identified from 
regional cancer registries    
HCL: Living male 
residents of 
Sweden age 25 years and 
older 
diagnosed with HCl; 
identified from 
the Swedish Cancer 
Registry NHL: Two male controls 
for each case matched by 
age, year of death if 
deceased, and county HCL: 
Four male cont rols for each 
case matched by age and 
county 515 cases 
1,141 controls 8 cases 
8 controls Yes (not 
evaluated) 
Kachuri et al. 
(2013) Canada: Alberta, 
British Columbia, 
Manitoba, Ontario, 1991–1994 Men aged ≥ 19 years (≥ 30 
years in analysis) - pulled 
from hospital records in 
Quebec, Men aged ≥ 19 years (30 
years in analysis) - pulled 
from provincial health 
insurance records in 342 cases 
1,357 controls 32 cases 
121 controls  Yes (included 
in adjustment) 
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   Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
Quebec, and 
Saskatchewan cancer registries in all 
other 
provinces Alberta, Saskatchewan, 
Manitoba, and Quebec; 
computerized telephone 
listings in Ontario; voter 
lists in British Columbia 
Karunanayake et al. 
(2012) Canada: Alberta, 
British Columbia, 
Manitoba, Ontario, 
Quebec, and 
Saskatchewan 1991–1994 Men aged ≥ 19 years -
pulled from hospital 
records in Quebec, 
cancer registries in all 
other 
provinces Men aged ≥ 19 years -
pulled from provincial 
health insurance records in 
Alberta, Saskatchewan, 
Manitoba, and Quebec; 
computerized telephone 
listings in Ontario; voter lists in British Columbia 316 cases 
1,506 controls 38 cases 
133 controls No 
Koureas et al. 
(2014) Greece 2010 Inhabitants 
of the city of Larissa; Eligibility criteria for 
pesticide sprayers were 
1) to personally apply 
pesticides systematically, 
and 2) to have recently 
applied pesticides (no 
longer than 7 days 
between last application 
and 
sampling). The rural residents group 
were occupied in 
administrative services, 
public order services, health 
services, education or trade. 
Inclusion criteria for this 
group: absence of any 
involvement in agricultural 
activities either as a 
primary or secondary 
occupation by participant or 
any member of household.  
Also recruited urban 
residents (mainly blood 
donors) from the city of 
Larissa. 80 pesticide sprayers, 
85 rural residents, and 
121 individuals Not reported No 
Koutros et al. 
(2013) USA: Iowa and 
North Carolina Enrollment (1993-
1997) through 2007 Males enrolled in AHS; 
licensed private and 
commercial applicators Males enrolled in AHS; 
licensed private and 
commercial applicators 1,962 incident cases 
(including 919 
aggressive prostate 
cancers) among 
54,412 applicators 1464 cases 
42,420 controls No 
Landgren et al. 
(2009) USA: Iowa and 
North Carolina Exposure 
information: 
enrollment (1993-
1997) and 5-year 
follow-up interview Males enrolled in AHS; 
licensed private and 
commercial applicators Males enrolled in AHS; 
licensed private and 
commercial applicators 678 participants 27 cases out of 570 total 
exposed No 
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 Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
Blood samples: 
2006-2007 (Iowa) 
and 2008 (North 
Carolina) 
Frequency matched by age 
and sex to the combined 
Lee et al. (2004b) USA: Nebraska 1988-1993 White residents of 1 of 66 
Nebraska counties age 21 
years or older with a 
newly confirmed case of 
adenocarcinoma of the 
stomach or Cases 
identified from the 
Nebraska Cancer Registry 
(1988–1990) or from 
discharge diagnosis and 
pathology records from 14 
Nebraska hospitals (1991– 
1993) distribution of glioma, 
stomach, and esophageal 
cancer cases from a control 
group from a previous 
study (1986–1987) that 
selected controls from the 
general population by 
random digit dialing for 
those under 65 years, 
Health Care Financing 
Administration Medicare 
files for those over 65 
years, mortality records for 
deceased and matched by 
race, sex, vital status (or 
year of death if deceased) Stomach: 170 cases 
Esophagus: 137 cases 
502 Controls 12 cases 
46 controls Yes (analysis 
showed 
differences) 
Lee et al. (2005) USA: Nebraska 1988-1993 White residents of 1 of 66 
Nebraska counties age 21 
years or older with 
confirmed adult glioma. 
Cases identified from 
Nebraska Cancer Registry 
or from participating 
hospitals in Lincoln and 
Omaha, Nebraska Frequency matched by age, 
sex, and vital status to the 
combined distribution of 
glioma, stomach, and 
esophageal cancer cases 
from a control group from a 
previous study (1986–1987) 
that selected controls from 
the general population by 
random digit dialing for 
those under 65 years, 
Medicare files for those 
over 65 years, mortality 
records for deceased and 
matched by rac e, sex, vital 
status (or year of death if 
deceased), and 5-year age 
groups to the overall case 
distribution. Additional 251 glioma cases 
498 controls 17 cases 
32 controls Yes (analysis 
showed 
differences, 
included in 
adjustment) 
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 Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
younger controls were 
brought into the study 
through random digit 
dialing and from death 
certificates 
Lee et al. (2007) USA: Iowa and 
North Carolina 1993-97; follow-up 
to 2002 Agricultural Health Study 
participants: private and 
commercial applicators 
licensed in Iowa or North 
Carolina with no history 
of colorectal cancer at 
enrollment. Followed 
through 2002 for incident 
colorectal cancer Agricultural Health Study 
participants: private and 
commercial applicators 
licensed in Iowa or North 
Carolina with no history of 
colorectal cancer at 
enrollment. Followed 
through 2002 for incident 
colorectal cancer 56,813 licensed 
pesticide applicators 
305 incident colorectal 
cancer cases (212 
colon, 93 rectum) 
56,508 controls Colon - 151 cases; 
49 controls 
Rectum - 74 cases; 
18 controls 
Colorectal - 225 cases; 
67 controls No 
McDuffie et al. 
(2001) Canada: Alberta, 
British Columbia, 
Manitoba, Ontario, 
Quebec, and 
Saskatchewan 1991-1994 Male residents of six 
Canadian provinces age 
19 years and older 
diagnosed with STS, HD, 
NHL, or MM; this study 
only evaluated those with 
NHL. Cases were 
identified from Canadian 
Cancer Registries; in 
Quebec, hospital 
ascertainment was used Random control subject 
selection using Health 
Insurance records, 
computerized telephone 
listings, and voters’ lists; 
males 19 years and older 
from same six Canadian 
provinces as ca ses matched 
by age (within 2 years) 517 cases 
1506 controls Univariate analysis:  
51 cases; 133 controls 
(multivariate analysis 
also conducted -
glyphosate exposed 
numbers not reported) No 
Orsi et al. (2009) France 2000-2004 Men aged 20–75 years 
living in the catchment 
areas of the main hospitals 
in Brest, Caen, Nantes, 
Lille, Toulouse, and 
Bordeaux, with no history 
of immunosuppression or 
taking immunosuppressant 
drugs.  Cases ascertained 
from hospital records. Patients from the same 
hospital catchment area as 
the cases.  Patients were 
hospitalized for orthopedic 
or rheumatological 
conditions (89.3%), 
gastrointestinal or 
genitourinary tract diseases 
(4.8%), cardiovascular 
diseases (1.1%), skin and 
subcutaneous tissue disease 
(1.8%), and infections 
(3.0%), excluding patients 
admitted for cancer or a 
disease 
directly related to 491 cases 
456 controls NHL: 12 cases 
24 controls 
HL: 6 cases 
15 controls 
Lymphoproliferative 
syndromes: 4 cases 
18 controls 
Multiple myeloma: 
5 cases;18 controls 
Lymphoid neoplasms: 27  
cases; 24 controls No 
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 Table C.1. Design Characteristi cs of Epidemiolog ical Studies E valuated for Study Quality. 
Study Location Study Years Case Population Control Population Total Number of 
Subjects Number of Glyphosate 
Exposed Cases Proxy Use 
occupation, 
smoking, or alcohol abuse 
Pahwa et al. (2011) Canada (Alberta, 
British Columbia, 
Manitoba, Ontario, 
Quebec, and 
Saskatchewan) 1991-1994 Men aged ≥ 19 years -
pulled from hospital 
records in Quebec, 
cancer registries in all 
other 
provinces Men aged ≥ 19 years -
pulled from provincial 
health insurance records in 
Alberta, Saskatchewan, 
Manitoba, and Quebec; 
computerized telephone 
listings in Ontario; voter 
lists in British Columbia 342 cases 
1,506 age/resident 
matched controls 32 cases 
133 controls No 
Pahwa et al. (2012) Canada (Alberta, 
British Columbia, 
Manitoba, Ontario, 
Quebec, and 
Saskatchewan) 1991-1994 Men aged ≥ 19 years -
pulled from hospital 
records in Quebec, 
cancer registries in all 
other 
provinces Men aged ≥ 19 years -
pulled from provincial 
health insurance records in 
Alberta, Saskatchewan, 
Manitoba, and Quebec; 
computerized telephone 
listings in Ontario; voter 
lists in British Columbia 342 cases 
1506 age/resident 
matched controls 32 cases 
133 controls No 
Yiin et al. (2012) USA: Upper 
Midwest Health 
Study (Iowa, 
Michigan, 
Minnesota and 
Wisconsin) 1995-1997 Age 18–80 (at 
ascertainment or diagnosis 
in 1995 through January 
1997) residing in counties 
where the largest 
population center had 
fewer than 250,000 
residents. Referral by 
physicians or through state 
cancer registries with 
cases verified by 
histological evaluation. Controls age 18–64 
randomly selected from 
state driver’s 
license/nondriver ID 
records, and those age 65– 
80 were selected from 
Health Care Financing 
Administration's (HCFA) 
Medicare data within 10 -
year age group strata, with 
the proportion/stratum 
determined by the age 
distribution of glioma cases 
in that state from 1992 to 
1994. Controls were 
frequency-matched within a 
state but not by county of 798 glioma cases; 
1,175 controls  12 cases 
19 controls Yes (analysis 
showed no 
differences) 
residence.  Selected even if 
they had a self-reported 
history of cancer other than 
glioma. 
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 Appendix D. List of studies a ssigned a low quality ranking and not evaluated in detail 
As described in Section 3.2, if studies did not collect exposur e information on glyphosate from 
all subjects, did not assess an outcome (e.g. , biomonitoring studies), and/or did not provide a 
quantitative measure of an association between glyphosate and a  cancer outcome, then these 
studies were assigned a low quality ranking and were not furthe r evaluated in detail.  These 
studies included the  following 32 studies: 
Acquavella et al.  2006; Andre et al. , 2007; Baker et al.  2005; Benedetti et al. , 2013; Bolognesi et 
al., 2002; Bolognesi et al. , 2004; Bolognesi et al.  2009; Bortoli et al. , 2009; Costa et al. , 2006; 
Da Silva et al.  2014; Dennis et al.  2010; Firth et al.  2007; Gomez-Arroyo et al. , 2013; Gregio 
D’Arce et al. , 2000; El-Zaemey et al. , 2013; Fortes et al. , 2016; Fritschi et al. , 2005; Hernandez 
et al., 2006; Kaufman et al.  2009; Khayat et al. , 2013; Lebailly et al., 2003; Mandel et al.  2005; 
Martinez-Valenzuela et al. , 2009; Monge et al. , 2007; Pastor et al. , 2003; Paz-y Mino et al., 
2007; Paz-y Mino et al.  2011; Ruder et al. 2004; Shaham et al. , 2001; Silva Kahl et al.  2016; 
Simoniello et al., 2008; Vlastos et al., 2006. 
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 Appendix E 
Chronic Dietary Exposure The agency uses Dietary Exposure Evaluation Model- Food Consump tion Intake Database 
(DEEM-FCID; version 3.16), which i ncorporates consumption data from United States 
Department of Agriculture (USDA)  National Health and Nutrition Examination Survey, What 
We Eat in America (NHANES/WWEI A; 2003-2008) to calculate potent ial chronic dietary 
exposures. In an unrefined chroni c dietary analysis, several conservative assumptions are used 
to generate high end estimates of potential exposure.  These as sumptions include tolerance-level 
residues for all registered c ommodities, 100% crop treated, and  drinking water values from a 
direct application to water scen ario, as well as DEEM default p rocessing factors.  For 
glyphosate, the highest exposure  value for any population subgr oup in an unrefined chronic 
dietary analysis would be 0.23 mg/ kg/day for children 1-2 years  old (Table E.1; see T. Bloem, 
30-NOV-2017, D429229 for DEEM input s and results).   
Table E.1. Chronic dietary exposure estimates 
Population Subgroup Exposure (mg/kg/day) 
General U.S. Population 0.089771 
All Infants (< 1 year old) 0.138338 
Children 1-2 years old 0.228379 
Children 3-5 years old 0.212036 
Children 6-12 years old 0.147749 
Youth 13-19 years old 0.088362 
Adults 20-49 years old 0.074650 
Adults 50-99 years old 0.061258 
Females 13-49 years old 0.069318 
Post-application Incidental  Oral and Dermal Exposure 
Glyphosate has residential uses , including application to turf,  which would result in the highest 
potential post-applica tion exposures; therefor e, there is poten tial for children to be exposed via 
incidental oral and dermal route s from playing on treated lawns.  For this assessment, the agency 
evaluates exposures from hand- to-mouth behavior, object-to-mout h behavior, incidental soil 
ingestion, and dermal contact u sing the 2012 Standard Operating  Procedures for Residential 
Pesticide Exposure Assessment29. Incidental oral exposures f rom hand-to-mouth, object-to-
mouth, and incidental soil inges tion are considered inter-relat ed and, therefore, not combined.  
To calculate high end estimates  of exposures, the following is assumed according to the 2012 
SOP to be health-prot ective:  1) maximum label rates are applie d to the turf, 2) exposures are 
assumed to occur every day to the  residue values on the day of application (i.e., no dissipation), 
and 3) individuals engage in post- application act ivities for th e maximum amount of time 
represented by data for childre n spending time outdoors and not  specifically engaged in activities 
29 Available: http://www2.epa.gov/pesticide-sc ience-and-assessing-pesticide-r isks/standard-operating-procedures-
residential-pesticide 
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  on turf, when in actuality child ren do not spend all of their o utdoor time on turf.  The highest 
exposure from incidental oral scenarios using the maximum appli cation rate for turf applications 
would be 0.16 mg/kg/day from hand -to-mouth behaviors by childre n (1 to <2 years old).  Dermal 
post-application to children 1 to <2 years old would be 0.08 mg /kg/day.   
Table E.2. Post-application Expo sure Estimates for Application  of Glyphosate to Turf1. 
Lifestage Post-application Exposure Scenario Exposure (mg/kg/day) 
Children 1 to <2 year old Turf – sprays Hand-to-Mouth 0.16 
Object-to-Mouth 0.005 
Incidental Soil Ingestion 0.0003 
Dermal (high contact activities) 0.08 
1 Based on Roundup® Weed & Grass Super Concentrate, EPA Reg. No. 71995-25. 
Page 201 of 216
	  
 
  
 
 
 
 Appendix F 
Genotoxicity Studies with Gly phosate Based Formulations  
While the focus of this analysis  to determine the genotoxic pot ential of glyphosate, the agency 
has identified numerous studies  conducted with glyphosate-based  formulations that contain 
various concentrations of the gl yphosate as well as other components of the end use products and 
are presented in Tables F.1-F.5. 
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  Table F.1. In vitro Test for Gene Mutations in Bacteria: Glyphosate Formulations. 
Test/Endpoint Test System Concentrations Test Material/ Results Reference Comments 
Concentration 
Bacterial S. typhimurium 1.6-5000 ICIA 0224 57.6% Negative ± Callander 
Reverse TA1535, µg/plate ± S9 in water S9 (1988) 
Mutation TA1537, 
TA1538, TA98 and 
TA100; E. coli 
WP2 uvrA 
pKM101 ± S9 (plate 
incorporation) 
Bacterial S. typhimurium 100-5000 TMSC (tri- Negative ± Callander 
Reverse TA98, TA100, µg/plate ±S9 methyl-sulfonium S9 (1993) 
Mutation TA1535, 
TA1537 ; E. 
coli WP2P and 
uvrA ± S9 plate incorporation & 
pre-incubation protocols chloride) 95% 
purity 
Bacterial S. typhimurium 26, 43, 72, 120, Glyphosate liquid Negative ± Camolesi 
Reverse TA98, TA100, 200 μg/plate formulation (480 S9 (2009)
1 
Mutation TA102, 
TA1535, and 
TA1537 ± S9 g/L 
isopropylamine 
salt) 
Bacterial S. typhimurium 26, 43, 72, 120, MON 77280 Negative ± Camolesi 
Reverse TA98, TA100, 200 μg/plate equivalent of S9 (2010) 
Mutation TA102, 
TA1535, and 
TA1537 ± S9 glyphosate acid: 
495 g/L 
Bacterial S. typhimurium 0.2-2000 MON 76190 Negative ± Catoyra (2009)1 
Reverse TA98, TA100, μg/plate 53.2% glyphosate S9 
Mutation TA102, 
TA1535, and 
TA1537 ± S9 
Bacterial S. typhimurium 2 μg/plate (toxic) Perzocyd 10 SL Negative ± Chruscielska et 
Reverse TA97a, TA98, formulation S9 al. (2000) 
Mutation TA100 and 
TA102 ± S9 
Bacterial 
Reverse 
Mutation S. typhimurium 
TA98, TA100, 
TA102, 0.03-3.0 μL/plate MON 8080 
(87.6%) Negative ± S9 Flowers (1981) 
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  Table F.1. In vitro Test for Gene Mutations in Bacteria: Glyphosate Formulations. 
Test/Endpoint Test System Concentrations Test Material/ Results Reference Comments 
Concentration 
TA1535, and 
TA1537 ± S9 
Bacterial S. typhimurium 3.16-1000 TROP M Negative ± Flügge (2010a)1 
Reverse TA98, TA100, μg/plate (Glyphosate 480); S9 
Mutation TA102, TA1535, and 
TA1537 ± S9 35.84% purity 
based on acid, 
48.46% pure 
based on IPA salt 
Bacterial S. typhimurium 0.316-100 Glyphosate 757 Negative ± Flügge (2010d)
1 
Reverse TA98, TA100, g/kg granular S9 
Mutation TA102, TA1535, and 
TA1537 ± S9 formulation 
(76.1% 
monoammonium 
glyphosate salt) 
Bacterial S. typhimurium 1-5000 μg/plate Roundup WG Negative ± Gava (1998) 
Reverse TA97a, TA98, 784 g/kg S9 
Mutation TA100, and TA1535 ± S9 ammonium salt equivalent 
Bacterial S. typhimurium 50-5000 μg/plate Rodeo® Negative ± Kier et al., 
Reverse TA98, TA100, (containing IPA S9 (1992) 
Mutation TA1535, TA1537± S9 salt and water only); 40% glyphosate (acid 
equivalent) 
Bacterial S. typhimurium 5-500 μg/plate  MON 2139 Negative ± Kier et al. , Cytotoxic at top 
Reverse TA98, TA100, (-S9)/ 15-1500 (Roundup®) 31% S9 (1992) concentrations 
Mutation TA1535, 
TA1537 ± S9 μg/plate (+S9) Glyphosate (acid equivalent) 
Bacterial S. typhimurium 5-500 μg/plate  MON 14445 Negative ± Kier et al. , Cytotoxic at the top 
Reverse TA98, TA100, (-S9)/ 15-1500 (Direct®); 75% S9 (1992) concentrations, 
Mutation TA1535, 
TA1537 ± S9 μg/plate (+S9) Glyphosate (acid equivalent) occasionally at lower concentrations 
Bacterial S. typhimurium 0.2-2000 MON 79672 Negative ± Lope (2008)
1 
Reverse TA98, TA100, μg/plate (Roundup S9 
Mutation TA1535, TA1537 ± S9 Ultramax); 74.7% monoammonium 
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   Table F.1. In vitro Test for Gene Mutations in Bacteria: Glyphosate Formulations. 
Test/Endpoint Test System Concentrations Test Material/ Results Reference Comments 
Concentration 
glyphosate salt; 
68.2% glyphosate 
Bacterial S. typhimurium 0.617-50 SC-0224, 19.2% Negative ± Majeska (1982) 
Reverse TA1535, μL/plate ± S9 purity S9 
Mutation TA1537, TA1538, 
TA98 and 
TA100 ± S9 
Bacterial S. typhimurium TA strains: 10 - MON 78239 Negative Mecchi (2003a) Increase in revertants 
Reverse TA98, TA100, 5000 μg/plate 36.6% glyphosate seen in TA98 and 
Mutation TA1535, (+S9); 3.33-3330 (44.9% potassium TA1535 -S9 on first 
TA1537 and μg/plate (-S9); E. salt of glyphosate) trial, not conc-dep; 
E. coli  WP2 coli: 33.3-5000 however no increase 
uvrA ± S9 μg/plate (+/- S9) in revertants seen in repeat in those strains; 
overall negative. 
Bacterial S. typhimurium TA strains: 3.33 -MON 78634 Negative Mecchi (2003b) 
Reverse TA98, TA100, 3330 μg/plate 65.2% w/w 
Mutation TA1535, (+S9); 1.0-1000 glyphosate 
TA1537 and μg/plate (-S9); E. (71.8% w/w as 
E. coli  WP2 coli: 33.3-5000 monoammonium 
uvrA ± S9 μg/plate (+/- S9) salt of glyphosate) 
Bacterial S. typhimurium 10 - 5000 MON 79864 Negative Mecchi (2008a) Inhibited growth seen 
Reverse TA 98, μg/plate (+/-S9) 38.7% glyphosate at ≥2000 -S9 
Mutation TA100, 
TA1535, 
TA1537 and 
E. coli  WP2 
uvrA ± S9 acid (wt %) 
Bacterial S. typhimurium 33.3-5000 MON 76313 Negative Mecchi (2008b) 
Reverse TA 98, μg/plate 30.9% glyphosate 
Mutation TA100, 
TA1535, 
TA1537 and 
E. coli  WP2 
uvrA ± S9 acid 
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  Table F.1. In vitro Test for Gene Mutations in Bacteria: Glyphosate Formulations. 
Test/Endpoint Test System Concentrations Test Material/ Results Reference Comments 
Concentration 
Bacterial S. typhimurium 10-5000 μg/plate MON 76171 Negative Mecchi 
Reverse TA 98, (+/-S9) 31.1% glyphosate (2008c)1 
Mutation TA100, 
TA1535, TA1537 and 
E. coli  WP2 
uvrA ± S9 
Bacterial S. typhimurium 10-5000 μg/plate MON 79991 Negative Mecchi (2009a) 
Reverse TA 98, (+/-S9) 71.6% glyphosate 
Mutation TA100, 
TA1535, 
TA1537 and 
E. coli  WP2 
uvrA ± S9 acid 
Bacterial S. typhimurium 10-5000 μg/plate MON 76138 Negative Mecchi 
Reverse TA 98, (+/-S9) 38.5% glyphosate (2009b)
1 
Mutation TA100, TA1535, 
TA1537 and 
E. coli  WP2 
uvrA ± S9 
Bacterial S. typhimurium 1-5000 μg/plate MON 77280 Negative Perina (1998) 
Reverse TA97a, TA98, 646.4 g/L salt 
Mutation TA100, and TA1535 ± S9 equivalent 
Bacterial S. typhimurium 0-1440 μg/plate Roundup, 480 g/L Negative – Rank et al. Stat significant 
Reverse TA98 and (calculated as glyphosate S9, (1993) increase at 360 
Mutation TA100 ± S9 glyphosate IPA 
salt) isopropylamine salt Equivocal +S9 μg/plate for TA98 (-S9) and 720 μg/plate 
for TA100 (+S9).  Not 
significant at higher 
concentrations and 
were not replicated. Effects occurred at 
close to toxic levels. 
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  Table F.1. In vitro Test for Gene Mutations in Bacteria: Glyphosate Formulations. 
Test/Endpoint Test System Concentrations Test Material/ Results Reference Comments 
Concentration 
Bacterial S. typhimurium 500-5000 495 g/L Negative ± Silvino (2011) 
Reverse TA98, TA100, μg/plate;  glyphosate S9 
Mutation TA102, 
TA1535, and TA1537 ± S9 isopropylamine salt; 371.0 g/L (equivalent of 
glyphosate acid) 
Bacterial S. typhimurium 1.5-5000 MON 8709 Negative ± Silvino (2011) 
Reverse TA98, TA100, μg/plate 495 g/L S9 
Mutation TA102, 
TA1535, and TA1537 ± S9 glyphosate isopropylamine salt; 371.0 g/L 
(equivalent of 
glyphosate acid) 
Bacterial S. typhimurium 15-5000 μg/plate MON 76313 Negative ± Silvino (2012) Cytotoxic at 5000 
Reverse TA98, TA100, 468 g/L S9 µg/plate for some 
Mutation TA102, TA1535, and TA1537 ± S9 glyphosate isopropylamine salt (351 g/L 
glyphosate acid 
equivalent) strains 
Bacterial S. typhimurium 1-5000 μg/plate Glifos Negative ± Vargas (1996) Cytotoxic at the two 
Reverse TA97a, TA98, formulation S9 upper concentrations 
Mutation TA100 and TA1535 ± S9 (glyphosate isopropylammoni um salt, Berol 907 
and water) 
Bacterial S. typhimurium 3.16-316 FSG 3090-H1 Negative ± Uhde (2004)
1 
Reverse TA98, TA100, µg/plate 360 g/L S9 
Mutation TA102, 
TA1535, TA1537± S9 
Bacterial 
Reverse 
Mutation S. typhimurium 
TA98, TA100 
± S9 0.01-100 
µg/plate 64% (glyphosate Isopropylammoni 
um salt) Negative ± 
S9 Wang et al. 
(1993) 
Bacterial 
Reverse 
Mutation S. typhimurium 
TA98, TA100, 
TA1535, All strains: 33.3 -
5000 μg/plate MON 78910 
30.3% glyphosate 
acid Negative ± 
S9 Xu (2006)  Cytotoxic ≥1000 μg/plate (-S9) 
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 Table F.1. In vitro Test for Gene Mutations in Bacteria: Glyphosate Formulations. 
Test/Endpoint Test System Concentrations Test Material/ Results Reference 
Concentration Comments 
TA1537 and 
E. coli  WP2 
uvrA ± S9 (+S9); 10-3330 μg/plate (-S9) 
1 Study was cited in Kier and Kirkland (2013).  Supplementary inf ormation about the study was provided online including test gui deline, test material purity, 
control chemicals and summary data tables. 
Table F.2. In Vitro Tests for Chromosome Damage in Mammalian Cells- Glyphosate Formulations 
Test/Endpoint Test System Concentrations Test Material/ Results Reference 
Concentration Comments 
In vitro Chromosomal Aberration using 
fluorescent in 
situ hybridization 
(FISH) Bovine lymphocytes 
(from two 6-8 month old calves) 
-whole chromosome (1) 
painting probe 28-1120 µM 
24 h exposure 62% 
Isopropylamine salt of glyphosate 
(38% inert 
ingredients) Negative. Holeckova (2006) Small but significant increase in polyploidy seen at 56µM 
No positive control 
reported. 
In vitro 
Cytokinesis 
Block Micronucleus 
Assay 
(with FISH analysis) 
TR146 cells ( human‐
derived	buccal	
epithelial
cell	line ) 0, 10, 15 and 20 
mg/L; 
20 minute exposure. Roundup Ultra 
Max (450 g/l 
glyphosate acid) Positive 
Increase in 
MN at all 
test 
concentratio ns Koller et al. 
(2012) No apoptosis observed at 
any conc. 
Necrosis reported at 20 
mg/L.  
Increase in NB and NPB 
seen at all concentrations 
MI= mitotic index. FISH= fluores cent in situ hybridization, MN=  micronuclei; NB= nuclear buds;  NPB= nucleoplasmic bridges.
	
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   Table F.3. In Vivo  Tests for Chromosomal Aberrations in Mammals- Glyphosate Formu lations. 
Test/Endpoint Test System Route of Doses Test Material Results Reference Comments 
Administration Purity 
Bone Marrow Swiss albino mice Intraperitoneal 0, 25 and 50 Roundup Positive Prasad et al. Significant decrease 
Chromosomal (males only) injection; mg/kg (>41% (2009) in mitotic index seen 
Aberration Vehicle: DMSO sampling 24, 48 
and 72 h (5/dose) isopropylamine glyphosate) Increase in MN at all time points 
at both doses at all doses and time 
points 
Bone Marrow C57BL mice  Oral 0.05, 0.01, Roundup Negative Dimitrov et al. 
Chromosomal (males only) administration; 0.5 and (2006) 
Aberration Vehicle: water sampling 6, 24, 1.0% 
48, 72, 96 and 120 h (8/dose) 
Bone Marrow New Zealand white Drinking water 0, 750 ppm Roundup Positive Helal and 
Chromosomal rabbits for 60 days (5/dose) Moussa (2005) 
Aberration (males only) Vehicle: 
BM= bone marrow, SC= spermatocyte. 
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 Table F.4. In Vivo  Tests for Micronuclei Induction  in Mammals- Glyphosate Formula tions. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material Purity 
Bone Marrow Swiss CD1 mice Intraperitoneal 0, 450 mg/kg Roundup, Positive  Bolognesi et Stat significant 
Micronucleus (males only) injection; 2 roundup, equiv. 30.4% al. (1997) increase in MN 
Test injections of half the dosage of 
135 mg/kg 24 h 
apart; sampling at 6 and 24 h to 135 kg glyphosate 
(3/dose) glyphosate at 6 and 24 h 
Bone Marrow 
C3H mice Intraperitoneal 0, 90 mg/kg Not Negative Chruscielska et 
Micronucleus (males only) Injection reported al. (2000) 
Test Vehicle: water (single 
treatment); 
sampling after 
24, 48 and 72 h 
Bone Marrow Swiss mice Intraperitoneal 0, 50, 100 and 480g/L Negative Grisolia (2002) 
Micronucleus (males and females) Injection 200 mg/kg Isopropyla 
Test Vehicle: water (2 treatments, 24 
h apart); 
sampling after 24 h (last treatment) mine salt of 
glyphosate 
Bone Marrow CD-1 mice Intraperitoneal 0, 140, 280, and Roundup Negative Kier (1992) Some deaths observed 
Micronucleus (males and females) injection; 555 mg/kg (31% at high dose (HD), 
Test sampling 24, 48 
and 72 h glyphosate salt) ↓PCE/NCE ratio at HD at 48 h in males.  
Bone Marrow Swiss albino mice Intraperitoneal 0, 212.5, 425 and MON Negative  Monma (1998) Doses tested 
Micronucleus (males and females) Injection 637.5 mg/kg 77280 corresponded to 25%, 
Test (2 treatments, 24 h apart); 
sampling after 24 
h (last treatment) 646.4 g/L glyphosate 
salt 
equivalent 50% and 75% LD50 
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 Table F.4. In Vivo  Tests for Micronuclei Induction  in Mammals- Glyphosate Formula tions. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material 
Purity 
Bone Marrow NMRI-Bom mice Intraperitoneal 0, 133 and 200 Roundup, Negative Rank et al. BM toxicity indicated 
Micronucleus Injection (single mg/kg 480 g (1993) by %PCE decreased 
Test treatment); sampling after 24 
h (4/sex/dose) glyphosate 
isopropyla 
mine salt 
per liter at 200 mg/kg 
Bone Marrow Swiss albino mice Oral gavage (two 0, 2000 mg/kg MON Negative Claro (2011) OECD 474 Guideline 
Micronucleus (males only
2) treatments, 24 h 8709494.7 No significant signs 
Test Vehicle: water apart); sampled at 18 and 24 h 
after last dose g/L salt of 
isopropyla 
mine (371.0 
glyphosate acid) of toxicity observed in main study. 
Bone Marrow C57BL mice  Oral 0.05, 0.01, 0.5 Roundup Negative Dimitrov et al. Toxicity seen in 1.0% 
Micronucleus (males only) administration; and 1.0% (2006) dose group 
Test Vehicle: water sampling 6, 24, 
48, 72, 96 and 
120 h (1%=1080 
mg/kg) 
(8/dose) 
Bone Marrow Crl:CD-1(ICR) BR Oral gavage 0, 500, 1000, and MON Negative Erexson EPA Guideline (84-2) 
Micronucleus mice (single 2000 (mg/kg) 78239 (2003a) No significant signs 
Test (males only
2) 
Vehicle: water treatment); sampling after 24 
and 48 h (high dose only) (5/dose) (36.6% 
glyphosate) of toxicity observed in main study. 
Bone Marrow Crl:CD-1(ICR) BR Oral gavage 0, 500, 1000, and MON Negative Erexson EPA Guideline (84-2) 
Micronucleus mice (single 2000 (mg/kg) 78634 (2003b) No significant signs 
Test (males only
2) 
Vehicle: water treatment); 
sampling after 24 
and 48 h (high dose only) (5/dose) (65.2% 
glyphosate) of toxicity observed in main study. 
Bone Marrow Crl:CD-1(ICR) BR Oral gavage 0, 500, 1000, and MON Negative Erexson (2006) EPA Guideline (84-2) 
Micronucleus mice (single 2000 (mg/kg) 78910 No significant signs 
Test (males only
2) 
Vehicle: water treatment); 
sampling after 24 
and 48 h (high 
dose only) (5/dose) (30.3% 
glyphosate) of toxicity observed in main study. 
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 Table F.4. In Vivo  Tests for Micronuclei Induction  in Mammals- Glyphosate Formula tions. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material 
Purity 
Bone Marrow NMRI mice Oral gavage 0, 500, 1000, and TROP M Negative Flügge OECD Guideline 474 
Micronucleus (males and females) (single 2000 mg/kg (Glyphosate (2010c)1 No significant signs 
Test Vehicle: 0.8% 
hydroxypropylmethyl 
cellulose treatment); 
sampling after 24 
and 48 h (high 
dose only) (5/sex/dose) 480); 358.4 
g/L 
glyphosate 
acid; 483.6 g/L IPA salt of toxicity observed in main study. 
Bone Marrow Swiss mice Oral gavage 0, 2000 mg/kg A17035A Negative Negro Silva OECD Guideline 474 
Micronucleus (males only
2) (2 treatments, 24 (6/dose) 289.7 g/L (2009)1 No significant signs 
Test Vehicle: water h apart); 
sampling after 24 
h (last treatment) glyphosate of toxicity observed 
in main study. 
Bone Marrow Swiss mice Oral gavage 0, 2000 mg/kg Glyphosate Negative Negro Silva OECD Guideline 474 
Micronucleus (males only2) (2 treatments, 24 (6/dose) SL (499.35 (2011)1 No significant signs 
Test Vehicle: water h apart); 
sampling after 24 h (last treatment) g/L glyphosate) of toxicity observed in main study 
Bone Marrow Hsd:CD-1(ICR) mice Oral gavage 0, 500, 1000, and MON Negative # Xu (2008a) EPA Guideline (84-2) 
Micronucleus (males only
2) (single 2000 (mg/kg) 79864 /OECD 474 
Test Vehicle: water treatment); sampling after 24 
and 48 h (high 
dose only) (5/dose) (38.7% glyphosate) No significant signs of toxicity observed 
in main study. 
Bone Marrow CD-1(ICR)BR mice Oral gavage 0, 500, 1000, and MON Negative  Xu (2008b) EPA Guideline (84-2) 
Micronucleus (males only
2) (single 2000 (mg/kg) 76171 /OECD 474 
Test Vehicle: water treatment); 
sampling after 24 
and 48 h (high 
dose only) (5/dose) (31.1% glyphosate) No significant signs of toxicity observed 
in main study. 
Bone Marrow CD-1(ICR)BR mice Oral gavage 0, 500, 1000, and MON Negative Xu (2009a) EPA Guideline (84-2) 
Micronucleus (males only
2) (single 2000 (mg/kg) 79991 /OECD 474 
Test Vehicle: water treatment); 
sampling after 24 
and 48 h (high 
dose only) (5/dose)  (71.6% 
glyphosate) No significant signs of toxicity observed 
in main study. 
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 Table F.4. In Vivo  Tests for Micronuclei Induction  in Mammals- Glyphosate Formula tions. 
Test/Endpoint Test System Route of Doses Test Results Reference Comments 
Administration Material 
Purity 
Bone Marrow CD-1(ICR)BR mice Oral gavage 0, 500, 1000, and MON Negative Xu (2009b)1 EPA Guideline (84-2) 
Micronucleus (males only2) (single 2000 (mg/kg) 76138 /OECD 474 
Test Vehicle: water treatment); sampling after 24 
and 48 h (high 
dose only) (5/dose) (38.5% glyphosate) No significant signs of toxicity observed 
in main study. 
Bone Marrow Hsd:CD-1(ICR)BR Oral gavage 0, 500, 1000, and MON Negative Xu (2009c)
1 EPA Guideline (84-2) 
Micronucleus mice (single 2000 (mg/kg) 76313 /OECD 474 
Test (males only2) 
Vehicle: water treatment); 
sampling after 24 
and 48 h (high 
dose only) (5/dose) (30.9% glyphosate) No significant signs of toxicity observed 
in main study. 
Bone Marrow CD rats Oral gavage 0, 500, 1000, and 757 g/kg Negative Flügge OECD Guideline 474 
Micronucleus (males and females) (single 2000 mg/kg granular (2010e)
1 No significant signs 
Test Vehicle: 0.8% 
hydroxypropylmethyl cellulose treatment); sampling after 24 and 48 h (high 
dose only) (5/sex/dose) formulation 
(69.1% glyphosate 
acid) of toxicity observed 
in main study 
1 Study was cited in Kier and Kirkland (2013).  Supplementary inf ormation about the study was provided online including test gui deline, test material purity, 
control chemicals and summary data tables. 
2 Only males tested; report indicat ed that there was no differen ce between sexes seen in range finding study.
	
BM= bone marrow, CA= chromosomal aberrations, MN= micronucleate d erythrocytes, NCE= normochromatic erythrocytes, PCE=polychrom atic erythrocytes.
	
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    Table F.5. Other Assays for Detec ting DNA Damage- Glyphosate Formulations. 
Test/Endpoint Test System Route of Doses/ Test Material/ Results Reference Comments 
Administration Concentrations Concentration 
Bacterial SOS 
Chromotest Escherichia coli PQ37 
strain NA (in vitro ) 0.25µg/sample Roundup BIO 
formulation; Positive Raipulis et al. 
(2009) 
DNA Adducts Swiss CD1 mice Intraperitoneal 0, 400, 500 and Roundup Positive Peluso et al. 
32P- (males and females) injection 600 mg/kg, (30.4% (liver and (1998) 
postlabeling Liver and kidney evaluated corresponding to 122, 152 and 
182 mg/kg 
glyphosate salt isopropylammo nium salt of 
glyphosate) kidney) 
DNA oxidative Swiss CD-1 mice Intraperitoneal 900 mg/kg 900 mg/kg Kidney: Bolognesi et 
damage: (males) injection (single corresponding corresponding positive at al. (1997) 
8-OHdG liver and kidney dose); sampling to 270 mg/kg to 270 mg/kg 8 and 24 h 
formation evaluated 4 and 24 h after 
injection glyphosate (3/dose) glyphosate 
Liver: 
negative 
Single-cell gel 
electrophoresis (SCGE) assays- 
COMET assay TR146 cells (human ‐
derived	buccal
epithelial
cell	line ). Alkaline 
conditions NA (in vitro ) Roundup Ultra 
Max (450 g/l 
glyphosate acid) Induced DNA migration 
at >20 
mg/L Koller et al. 
(2012) Also measured multiple cellular integrity parameters to 
assess cytotoxicity.  
Formulation was more 
toxic than technical.   
Significant increase in LDHe at all 
concentrations tested.  
Cytotoxic ≥ 60 mg/L 
Sister Bovine lymphocytes NA (in vitro ) 28 - 1112 µM; 62% Positive Sivikova & 
Chromatid ±S9; sampling Isopropylamine Dianovsky 
Exchange at 24 and 48 h salt of (2006) 
(SCE) glyphosate 
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  Table F.5. Other Assays for Detec ting DNA Damage- Glyphosate Formulations. 
Test/Endpoint Test System Route of Doses/ Test Material/ Results Reference Comments 
Administration Concentrations Concentration 
Sister Human lymphocytes NA (in vitro ) 250, 2500 and Roundup; Stat. Vigfusson and No growth seen at 
Chromatid (2 donors) 25000 µg/mL Isopropylamine significant Vyse (1980) highest concentration 
Exchange salt of increase (25 mg/mL) 
(SCE) glyphosate 
(purity not 
stated) (p<0.001) 
at 250 
µg/mL in 
both donors, 
and in one 
donor at 
2500 
µg/mL 
Sister 
Human lymphocytes NA (in vitro ) -S9: 0, 0.1 and Roundup, Positive Bolognesi et Stat significant 
Chromatid 0.33 mg/mL; 72 30.4% al. (1997) increase in SCE/cell 
Exchange h exposure glyphosate  at ≥ 0.1 mg/mL 
(SCE) 
Alkaline Swiss CD-1 mice Intraperitoneal 900 mg/kg 900 mg/kg Positive Bolognesi et Return to control 
elution assay- (males) injection (single corresponding corresponding (Increased al. (1997) values at 24 h may 
DNA single liver and kidney dose); sampling to 270 mg/kg to 270 mg/kg elution indicate DNA repair 
strand breaks evaluated 4 and 24 h after 
injection glyphosate (3/dose) glyphosate rate) at 4 hours in liver and 
kidney 
At 24 h, 
returned to 
control levels or reflect rapid elimination of compound 
h= hour, NA= not applicable, SCE= sister chromatid exchange, LD He= extracellular lactate dehydrogenase
	
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 Appendix G 
The following studies were considered during the systematic review, but were excluded from the 
analysis.
	
Amer S.M. et al (2006).  In vitr o and in vivo evaluation of the  genotoxicity of the herbicide 
glyphosate in mice.  Bulletin of the  National Research Centre (Cairo) 31 (5): 427-446. 
Aboukila, R.S. et al.  (2014). Cytogenetic Study on the  Effect of Bentazon and Glypho sate 
Herbicide on Mice. Alexandria J ournal of Veterinary Sciences, 41: 95-101.  
Majeska (1982d) MRID 00126616 
Majeska (1982e) MRID 00126614 
Majeska (1982f) MRID 00126615 
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