A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment

Figures & data

Figure 1. Structure of glyphosate.

Table 1. Composition of the four Expert Panels.

Expert panel group*	Name of participating scientist	Affiliation of scientist
Human exposures	Keith R. Solomon	Centre for Toxicology, University of Guelph, Guelph, ON Canada
Carcinogenicity bioassays	Gary M. Williams	Professor of Pathology, New York Medical College, Valhalla, NY
	Sir Colin Berry	Emeritus Professor of Pathology, Queen Mary, University of London, London, UK
	Michele M. Burns	Boston Children’s Hospital, Boston, MA, USA
	Joao Lauro Viana de Camargo	Professor of Pathology, Botucatu Medical School, São Paulo State Univ, UNESP, SP, Brazil
	Helmut A. Greim	Emeritus Professor of Toxicology and Environmental Hygiene, Technical University of Munich, Germany
Genotoxicity	David Brusick	Toxicology Consultant, Bumpass, VA, USA
	Marilyn Aardema	Marilyn Aardema Consulting, LLC, Fairfield, OH, USA
	Larry D. Kier	Private Consultant, Buena Vista, CO USA
	David J. Kirkland	Kirkland Consulting, Tadcaster, UK
	Gary M. Williams	Professor of Pathology, New York Medical College, Valhalla, NY
Epidemiology	John Acquavella	Professor, Department of Clinical Epidemiology, Aarhus University, Denmark
	David Garabrant	EpidStat Institute; Emeritus Professor of Occupational Medicine and Epidemiology, University of Michigan
	Gary Marsh	Professor of Biostatistics, Director and Founder, Center for Occupational Biostatistics & Epidemiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, USA
	Tom Sorahan	Professor of Occupational Epidemiology, University of Birmingham, Birmingham, UK
	Douglas L. Weed	DLW Consulting Services, LLC; Adjunct Professor, University of New Mexico School of Medicine, Albuquerque, NM, USA

* Ashley Roberts of Intertek Scientific & Regulatory Consultancy served as facilitator for each of the four panels.

Table 2. Relevant studies for glyphosate review: non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM).

First author (year)	Study location(s)	Study design	More recent analysis	Outcome
Cantor et al. (1992)	Iowa + Minnesota	Case–control	de Roos et al. (2003)	NHL
Nordstrom et al. (1998)	Sweden	Case–control	Hardell et al. (2002)	HCL
Hardell and Eriksson (1999)	Sweden	Case–Control	Hardell et al. (2002)	NHL excluding HCL
McDuffie et al. (2001)	Canada	Case–control	n/a	NHL
Hardell et al. (2002)	Sweden	Case–control (pooled)	n/a	NHL + HCL
de Roos et al. (2003)	Nebraska,Iowa/Minnesota,Kansas	Case–control (pooled)	n/a	NHL
de Roos et al. (2005)	Iowa, North Carolina	Cohort	n/a	NHL, MM
Eriksson et al. (2008)	Sweden	Case–control	n/a	NHL
Orsi et al. (2009)	France	Case–control	n/a	NHL, MM
Hohenadel et al. (2011)	Canada	Case–control	Extension of McDuffie et al. (2001)	NHL
Cocco et al. (2013)	Czech, France, Germany, Ireland, Italy, Spain	Case–control	n/a	B-cell lymphoma
Brown et al. (1993)	Iowa	Case–control	n/a	MM
Landgren et al. (2009)	Iowa	Prevalence,	n/a	MGUS
	North Carolina	Case–control
	Minnesota
Pahwa et al. (2012)	Canada	Case–control	Kachuri et al. (2013)	MM
Kachuri et al. (2013)	Canada	Case–control	n/a	MM
Sorahan (2015)	Iowa, North Carolina	Cohort	Reanalysis of de Roos et al. (2005)	MM

n/a: not available.

Table 3. Key validity considerations in glyphosate epidemiological studies.

First author (year)	Study design	Outcome	Recall bias	Selection bias	Proxy respondents	Adequate control for confounding	Exposure-response and trend test
de Roos et al. (2005)	Cohort	NHL, MM	No	Unlikely	No	Yes	Yes, yes
McDuffie et al. (2001)	Case–control	NHL	Likely	Likely	21% cases 15% controls	No	Yes, no trend test
Hardell et al. (2002)	Case–control	NHL, HCL	Likely	Unlikely	43% NHL cases and controls, 0% for HCL	No	No
de Roos et al. (2003)	Case–control	NHL	Likely	Likely	31% for cases; 40% for controls	Yes	No
Eriksson et al. (2008)	Case–control	NHL	Likely	Unlikely	No	No	Yes, no trend test
Orsi et al. (2009)	Case–control	NHL, MM	Likely	Likely	No	No	No
Cocco et al. (2013)	Case–control	NHL	Likely	Likely	No	No	No
Brown et al. (1993)	Case–control	MM	Likely	Unlikely	42% for cases; 30% for controls	No	No
Kachuri et al. (2013)	Case–control	MM	Likely	Likely	Excluded in analysis	No	Yes, no trend test

NHL: non-Hodgkin’s lymphoma; MM: multiple myeloma.

Whether recall bias, exposure misclassification, or selection bias was classified as likely or unlikely was based on a consensus after an in person discussion of each study by the authors.

Table 4. Regulatory agency reviews of three studies evaluated by IARC.

		Conclusions of review – tumors related to treatment?
	Regulatory authorities	Mouse study(Monsanto 1983)	Rat study(Stout & Ruecker 1990)	Mouse study(Cheminova 1993)
2015	WHO/IARC	Yes	Yes	Yes
2016	WHO/JMPR	*	No	*
2016	US EPA Registration Review**	–	–	–
2016	Japan Food Safety Commission ADI Review**	No	No	–
2015	EU Annex I Renewal (BFR)**	No	No	No
2015	Canada PMRA Registration Review**	No	No	No
2013	Australia	No	No	No
2012	US EPA Human Health RA	No	No	–
2005	WHO/Water Sanitation Health	No	No
2004	WHO/JMPR	–	No	No
2002	EU Annex I	No	No	No
1999	Japan Food Safety Commission	No	No	–
1994	WHO/IPCS	No	No	–
1993	US EPA RED	No	No	–
1991	Canada PMRA	No	No	–
1991	US EPA Cancer Classification	No	No	–
1987	WHO/JMPR	No	–	–

* The meeting could not exclude the possibility that glyphosate is carcinogenic in mice at very high doses.

** Evaluation not completed.

Table 5. Tumor incidence/number of animals examined (mg/kg bw/day)*.

	Males				Females
	0	100	300	1000	0	100	300	1000
Hemangiosarcoma	0/50	0/50	0/50	4/50 (8%)	0/50	2/50 (4%)	0/50	1/50 (2%)

* Taken from Greim et al. (2015).

Table 6. Sprague-Dawley male rats, hepatocellular tumor rates+, and Cochran–Armitage trend and Fisher’s exact tests results (p values).

	Dose (ppm)
Tumors	0	2000	8000	20 000
Carcinomas	3/34	2/45	1/49	2/48†
(%)	(7)	(4)	(2)	(4)
p	.324	.489	.269	.458
Adenomas	2/44	2/45	3/49	7/48‡
(%)	(5)	(4)	(6)	(15)
p	.016*	.683	.551	.101
Adenoma + carcinoma	5/44	4/45	4/49	9/48
(%)	(11)	(9)	(8)	(19)
p	.073	.486	.431	.245
Hyperplasia only	0/44	0/45	1/49¶	0/48
(%)	(0)	(0)	(2)	(0)
p	.462	1.000	.527	1.000

Source: US EPA (1991a,b).

* Number of tumor-bearing animals/number of animals examined, excluding those that died or were sacrificed before week 55.

† First carcinoma observed at week 85 at 20 000 ppm.

‡ First adenoma observed at week 88 at 20 000 ppm.

¶ First hyperplasia observed at week 89 at 8000 ppm.

Significance of trend denoted at Control. Significance of pair-wise comparison with control denoted at dose level. If then p < .05.

Table 7. Tumor incidence/number of animals examined (mg/kg bw/day)*.

	Males				Females
	0	89	362	940	0	113	457	1183
Thyroid C-cell adenoma	2/60	4/58	8/58	7/60	2/60	2/60	6/60	6/60
Thyroid C-cell carcinoma	0/60	2/58	0/58	1/58	0/60	0/60	1/60	0/60

*Stout and Ruecker (1990) (all deaths reported).

Table 8. Summary of the Panel’s evaluation of human, non-human mammalian and selected microbial genotoxicity studies from IARC section 4.2.1 and other published sources.

Source	Test category	Endpoint	Weight	Glyphosate(Pos/Neg)	GBFs(Pos/Neg)	AMPA(Pos/Neg)	Total(Pos/Neg)
Kier and Kirkland (2013) and other published studies not Included in IARC	Bacterial reverse mutation	Gene mutation	High	0/19	0/20	0/1	0/40
	Mammalian in vitro	Gene mutation	Moderate	0/2	ND	ND	0/2
		Chromosomal aberrations	Moderate	1/5	1/0	ND	2/5
		Micronucleus	Moderate	2/0	1/0	ND	3/0
		UDS	Low	0/1	ND	0/1	0/2
		SCE	None	ND	1/0	ND	1/0
	Mammalian in vivo	Chromosomal aberrations	High	0/1	2/0	ND	2/1
		Micronucleus	High	0/13	0/17	0/1	0/31
		SCE	None	ND	1/0	ND	1/0
IARC monograph 112	Bacterial reverse mutation	Gene mutation	High	0/1	0/0	ND	0/1
	Mammalian in vitro	Gene mutation	Moderate	0/1	ND	ND	0/1
		Chromosomal aberrations	Moderate	1/2	ND	1/0	2/2
		Micronucleus	Moderate	2/0	ND	1/0	3/0
		Comet/DNA breaks	Low	5/0	2/0	1/0	8/0
		UDS	Low	0/1	ND	ND	0/1
		SCE	None	3/0	2/0	ND	5/0
	Mammalian in vivo	Chromosomal aberrations	High	0/1	1/1	ND	1/2
		Micronucleus	High	2/1	2/3	1/0	5/4
		Comet/DNA breaks	Moderate	1/0	1/0	ND	2/0
		Dominant lethal	High	0/1	ND	ND	0/1
	Human in vivo	Chromosomal aberrations	High	ND	0/1	ND	0/1
		Micronucleus	High	ND	0/3	ND	0/3
	High weight Combined totals (IARC results only)			2/37 (2/4)	5/45 (3/5)	½ (1/0)	8/84 (6/9)
	Moderate weight Combined totals (IARC results only)			7/10 (4/3)	3/0 (1/0)	2/0 (2/0)	12/10 (7/3)
	Low weight Combined totals (IARC results only)			5/2 (5/1)	2/0 (2/0)	1/1 (1/0)	8/3 (8/1)

ND: no data.

All responses based on study critiques and conclusions of Expert Panel members.

Non-mammalian responses from IARC Monograph in this table did not include 4 positive studies measuring DNA strand breaks in bacteria and 1 negative Rec assay in bacteria from Monograph Table 4.6.

Table 9. Summary of studies presented in Kier and Kirkland (2013) and of other publicly available studies not included in the IARC review.

Test category	Endpoint	Glyphosate (Pos/Neg)	GBFs (Pos/Neg)	AMPA (Pos/Neg)	Total (Pos/Neg)
Non-mammalian (bacterial reverse mutation)	Gene mutation	0/19	0/20	0/1	0/40
Mammalian in vitro	Gene mutation	0/2	ND	ND	0/2
	Chromosomal aberrations	1/5	1/0	ND	2/5
	Micronucleus	2/0*	1/0	ND	3/0
	UDS	0/1	ND	0/1	0/2
	SCE	ND	1/0	ND	1/0
Mammalian in vivo	Chromosomal aberrations	0/1	2/0*	ND	2/1
	Micronucleus	0/13*	0/17	0/1	0/31
	SCE	ND	1/0	ND	1/0
Total		3/41	6/37	0/3	9/81

* Inconclusive studies not included in count. ND: not done.

Table 10. Comparison of test response profiles from glyphosate, GBFs, and AMPA to the profile characteristics of confirmed genotoxic carcinogens.

Characteristic	Carcinogens with a proven genotoxic mode of action	Glyphosate, GBFs, and AMPA study data
Profile of test responses in genetic assays	Positive effects across multiple key predictive endpoints (i.e. gene mutation, chromosome aberrations, aneuploidy) both in vitro and in vivo	No valid evidence for gene mutation in any test; no evidence for chromosome aberrations in humans and equivocal findings elsewhere
Structure–activity relationships	Positive for structural alerts associated with genetic activity	No structural alerts for glyphosate or AMPA suggesting genotoxicity
DNA binding	Agent or breakdown product are typically electrophilic and exhibit direct DNA binding	No unequivocal evidence for electrophilic properties or direct DNA binding by glyphosate or AMPA
Consistency	Test results are highly reproducible both in vitro and in vivo	Conflicting and/or non-reproducible responses in the same test or test category both in vitro and in vivo
Response kinetics	Responses are dose dependent over a wide range of exposure levels	Many positive responses do not show significant dose-related increases
Susceptibility to confounding factors (e.g. cytotoxicity)	Responses are typically found at nontoxic exposure levels	Positive responses typically associated with evidence of overt toxicity

AMPA: aminomethylphosphonic acid; GBF: glyphosate-based formulation.

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