Regulatory history of glyphosate carcinogenicity reviews in USA

Of course Monsanto is unimpressed with the IARC classification of glyphosate as a probable carcinogen.  And for good reason. To date Monsanto has submitted nearly every study used by the US EPA to decide glyphosate's carcinogenicity rating. For decades.  Perhaps it is time the IARC, the US EPA and the European Union (and my own country New Zealand) looked at studies other than studies selected by the same corporation that sells the product.

Back in 1985, glyphosate was declared a Class C carcinogen. Why and how did it change?

Carcinogenicity assessments to date appear to include only pesticide company directly-funded studies submitted by the company. I believe that Monsanto has submitted every study.  

NB: When I started documenting glyphosate regulatory assessment and toxicity studies the EPA 1993 Glyphosate Reregistration Eligibilty Decision (RED) document was freely available on the net including references and data for all studies. In the past year it has been removed. Here is a PDF link.

These assessments conveniently exclude a broad swathe of independent studies by scientists working in the public domain. And they never, of course, study the full solution, or formulation, of Roundup.

Very few studies have been used to establish the classification of Group E - non-carcinogenic.  A very small pool to establish this status for the USA population of 314 million people. Please feel free to demand the original documents from the EPA to confirm this.

There are significant effects dismissed - these studies should be publicly released for transparent consultation & peer review by independent scientists.

4 March 1985 :

Toxicology Branch Ad Hoc Committee, comprised of members of the Toxicology Branch of the Hazard Evaluation Division.  The Committee in a consensus review dated 04-MAR-1985 classified glyphosate as a Group C Carcinogen based on an increased incidence of renal tubular adenomas in male mice. According to the consensus review, the tumour is rare, it occurred in a dose-related manner, and the incidence was outside the reported historical control range. The Committee also concluded that dose levels tested in a 26 month rat feeding study were not adequate for the assessment of glyphosate’s carcinogenic potential in this species.

Knezevich, A.; Hogan, G. A chronic feeding study of glyphosate (Roundup technical) in mice. Unpublished Report no. BDN-77420, project no. 77-2061, 1983, submitted to U.S. Environmental Protection Agency by Monsanto Company, prepared by BioDynamics, Inc. Reregistration Eligibility Decision (RED) Glyphosate; EPA-738-F-93-011; U. S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances, Office of Pesticide Programs, U.S. Government Printing Office: Washington, DC, 1993.  MRID 00130406

McConnel, R. A chronic feeding study of glyphosate (Roundup technical) in mice: pathology report on additional kidney sections. Unpublished project no. 77-2061A, 1985, submitted to U.S. Environmental Protection Agency prepared by BioDynamics, Inc. Reregistration Eligibility Decision (RED) Glyphosate; EPA-738-F-93-011; U. S. Environmental Protection Agency, Office of Prevention, Pesticides, and Toxic Substances, Office of Pesticide Programs, U.S. Government Printing Office: Washington, DC, 1993.Study:  MRID 00150564

Further content Pp 5 & 6.

Extract from the EPA 1993 Glyphosate Reregistration Eligibilty Decision (RED) P.14 : This is the study that decided the classification of Group C Carcinogen - though it is unclear as it appears under 2 study authors (as above):

A carcinogenicity study in mice was conducted with CD-1mice fed diets containing 0, 150, 750 or 4500 mg/kg/day of glyphosate for 18 months. No effects were observed in the low-doseand mid-dose groups. The following findings were observed in thehigh-dose group: (1) decreased body weight gain in males and females; (2) increased incidence of hepatocellular hypertrophy, hepatocellular necrosis and interstitial nephritis in males; (3)increased incidence of proximal tubule epithelial basophilia and hypertrophy in females; and (4) slightly increased incidence of renaltubular adenomas, a rare tumor, in males. Based on these effects,the systemic NOEL and LOEL were 750 mg/kg/day and 4500mg/kg/day, respectively. The Agency concluded that the occurrenceof these adenomas was spontaneous rather than compound-induced because the incidence of renal tubular adenomas in males was not statistically significant when compared with the concurrent controls. An independent group of pathologists and biometricians alsoconducted extensive evaluations of these adenomas and reached the same conclusion. Therefore, glyphosate was not considered to be carcinogenic in this study.  (MRIDs 00130406, and 00150564End extract.

McConnel, R. (1985) A Chronic Feeding Study of Glyphosate (Roundup Technical in Mice): Pathology Report on Additional Kidney Sections: Addendum to Final Report Dated July 21, 1983: Project No. 77-2061A. Unpublished study prepared by Bio/dynamics Inc. 59 p. MRID 00150564 (Bio/dynamics studies are usually Monsanto paid)

24 Feb 1986:

The kidney slides from the long-term mouse feeding study were subsequently re-examined by several pathologists, and one pathologist diagnosed an additional kidney tumour in the control males. These findings were presented to the FIFRA Scientific Advisory Panel (SAP) which proposed glyphosate be classified into Group D (inadequate animal evidence of carcinogenic potential).  The SAP in their meeting of 11/12 FEB-1986 (report dated 24-FEB-1986), concluded that, after adjusting for the greater survival in the high dose mice compared to the concurrent controls, no statistically significant pairwise differences existed, although the trend was significant.  The SAP further noted that, although comparison of these findings to historical incidences yielded a statistically significant result, this finding did not override the lack of pairwise significance of comparisons to concurrent controls.

The SAP determined that the carcinogenic potential of glyphosate could not be determined from existing data and proposed that rat and/or mouse studies be repeated in order to clarify these equivocal findings.  A new 2 year rat study was performed up to the limit dose of 20,000 ppm. (Stout & Ruecker 1990)

Information:  EPA Memorandum date 17 August 2000 : Glyphosate in/on Alfalfa hay and forage; Field corn forage; Stover and straw of the cereal grains crop group; numerous minor crops; and flax in Northern Dakota. HED Risk Assessment. Page 6.

Information repeated: 30 October 1991 - US EPA Second Peer Review of Glyphosate. Memorandum 1071-83-6.  P.3/4

26 June 1991 - Second Peer Review:

The Health Effects Division (HED) Carcinogenicity Peer Review Committee (CPRC) convened on 26-JUN-1991 to discuss and evaluate the weight of the evidence on glyphosate with particular emphasis on its carcinogenic potential. The Committee concluded that glyphosate should be classified as a Group E chemical (evidence of non-carcinogenic to humans), based upon a lack of convincing carcinogenicity evidence in adequate studies in two animal species.

As part of their consideration the CPRC examined data on the following tumours observed in the second rat study: pancreatic islet cell adenomas in males, thyroid C-cell adenomas and/or carcinomas in males and females, and hepatocellular adenomas and carcinomas in males. None of them were considered to be biologically significant. As for the mouse study, the CPRC concluded that the renal tubular neoplasms in high dose male mice were not compound-related due to the lack of pairwise significance and the lack of pre-neoplastic kidney lesions in males.

This is discussed in a Cornell University paper:

This classification is based on the following findings: (1) None of the types of tumors observed in the studies (pancreatic islet cell adenomas in male rat,thyroid c-cell adenomas and/or carcinomas in male and female rats, hepatocellular adenomas and carcinomas in male rats, and renal tubular neoplasms in male mice) were determined to be compound related; (2) glyphosate was tested up to the limit dose on the rat and up to levels higher than the limit dose in mice; and (3) there is no evidence of genotoxicity for glyphosate. Accordingly, EPA concludes that glyphosate has not been "found to induce cancer when ingested by man or animal." 21 U.S.C.348(c)(3).

Memorandum 30 October 1991 - Second Peer Review of Glyphosate (thank you www.momsacrossamerica.com for retrieving this paper).

Memorandum 1071-83-6

D. Evaluation of Carcinogenicity Data. (Second Peer Review)

1. Lankas, G.R.; Hogan, G.K. (1981) A Lifetime Feeding Study of Glyphosate (Roundup Technical) in Rats: Project No. 772062. (Unpublished study received Jan 20, 1982 under 524-308; prepared by Bio/dynamics, Inc., submitted by Monsanto Co., Washington, D.C.; CDL:246617-A; 246618; 246619; 246620; 246621)   MRID 00093879

Groups of 50 male and 50 female Charles River Sprague-Dawley rats were fed technical glyphosate in their diets at dose levels of 3, 10,or 31 mg/kg b.w./day (males) and 3.4, 11, or 34 mg/kg b.w./day(females) for approximately 26 months.

Discussion of Tumor Data: An increase in the incidence of interstitial cell tumours of the testes was observed in male rats. Because of the absence of a dose-response relationship, the lack of preneoplastic changes, the wide variability in the spontaneous incidence of this tumor, the the similarity in incidences between the high-dose group and the historical controls, and lack of any evidence of genotoxicity, it was concluded by the previous Peer Review Committee that the observed incidence did not reflect a carcinogenic response.

Additionally, there was the question of possible thyroid carcinomas in high-dose females. After a review of the slides by a consulting pathologist, and a reassessment of all relevant data, including the fact that no effect of the treatment on timor latency of the combined incidences of adenoma and carcinoma was apparent, the earlier Peer Review Committee concluded that the data did not demonstrate a carcinogenic response in the thyroid.

Further reading Second Peer Review page 5.

  1. Incidence of tumors of the testes dismissed, primarily because no dose response relationship. Effects on the thyroid dismissed. (EDC?)

2. Stout, L.; Ruecker, F. (1990) Chronic Study of Glyphosate Administered in Feed to Albino Rats: Lab Project Number: MSL- 10495: R.D. 1014. Unpublished study prepared by Monsanto Agricultural Co. 2175 p.    MRID 41643801 (The study 41643801 continued for 2 years - this review is half way through the study) 

This chronic toxicity/carcinogenicity study in the rat was submitted to the Agency as a replacement study for the 26 month 1981 chronic toxicity/carcinogenicity study in the rat. In this study randomised groups of 60 male and 60 female young (8 weeks old) Sprague Dawley rats were fed dietary levels of 0, 2000, 8000, or 20,000 ppm or the equivalent of 0, 100, 400, and 1000 mg/kg/day of technical glyphosate for 2 years. At 12 months 10 animals sex/group were sacrificed.

Discussion of Tumor Data: Age adjusted statistical analyses of the tumor data are presented. The most frequently observed tumors in this study were pancreatic islet cell adenomas in males, thyroid C-cell adenomas and/or carcinomas in males.  Further reading Second Peer Review tumor type page 5-13.

  1. It appears these rats were not dosed until 8 weeks old - adult - doesn't that miss a vital development gap?
  2. The results are unclear - I cannot see the results of the 20 animals sacrificed at 12 months?
  3. Committee interpretation: Dismiss incidences that exceed historical control range. Dismiss effects where no dose related trend. Declare not compound related. How? (pp 7 & 8) (EDC?)

3. Hogan, G.K. (1983). A chronic feeding study of glyphosate in mice. Unpublished report prepared by Bio/Dynamics Inc., dated July 21, 1983. Report No. 77-2061. EPA Acc. Nos. 251007-251009, and 251014.

Also referred to as: Knezevich, A.L. and Hogan, G.K. (1983) A Chronic Feeding Study of Glyphosate (Roundup technical) in Mice: Project No. 77-2061. (Unpublished study received Aug. 17, 1983 under 524-308; prepared by Bio/dynamics, Inc., submitted by Monsanto Co. Accession #251007-251014  MRID 130406

Groups of 50 male and 50 female CD-1 mice were administered glyphosate in the diet at concentrations of 1000, 5000 or 30,000 ppm for 18 months. Glyphosate produced an equivocal carcinogenic response in males characterised by an incidence of renal tubular neoplasms of 1/49, 0/49, 1/50 in the control, low, mid, high dose groups respectively.

Extract from the EPA 1993 Glyphosate Reregistration Eligibilty Decision (RED) P.14: A carcinogenicity study in mice was conducted with CD-1 mice fed diets containing 0, 150, 750 or 4500 mg/kg/day of glyphosate for 18 months. No effects were observed in the low-dose and mid-dose groups. The following findings were observed in the high-dose group: (1) decreased body weight gain in males and females; (2) increased incidence of hepatocellular hypertrophy, hepatocellular necrosis and interstitial nephritis in males; (3) increased incidence of proximal tubule epithelial basophilia and hypertrophy in females; and (4) slightly increased incidence of renal tubular adenomas, a rare tumor, in males. Based on these effects, the systemic NOEL and LOEL were 750 mg/kg/day and 4500 mg/kg/day, respectively. The Agency concluded that the occurrence of these adenomas was spontaneous rather than compound-induced because the incidence of renal tubular adenomas in males was not statistically significant when compared with the concurrent controls. An independent group of pathologists and biometricians also conducted extensive evaluations of these adenomas and reached the same conclusion. Therefore, glyphosate was not considered to be carcinogenic in this study. (MRIDs 00130406, and 00150564) End Extract.

Further reading Second Peer Review including extensive discussion tumors pp 13-15.

E. Additional Toxicology Data on Glyphosate (Second Peer Review)

1. Metabolism

Ridley, W.; Mirly, K. (1988) The Metabolism of Glyphosate inSprague Dawley Rats--Part I. Excretion and Tissue Distribution of Glyphosate and Its Metabolites following Intravenous and OralAdministration: Laboratory Project No. 86139 (MSL-7215): R.D.No. 877. Unpublished study prepared by Monsanto Co. 587 p.

Howe, R.; Chott, R.; McClanahan, R. (1988) Metabolism ofGlyphosate in Sprague-Dawley Rats. Part II. Identification,Characterization, and Quantitation of Glyphosate and ItsMetabolites after Intravenous and Oral Administration:Laboratory Project No. MSL-7206: R.D. No. 877. Unpublished study prepared by Monsanto Co. 155 p.

2. Mutagenicity - there are no references - however these are the studies held with the US EPA RED 1993 for mutagenicity.

Kier, L.D.; Flowers, L.J.; Hannah, L.H. (1978) Final Report onSalmonella Mutagenicity Assay of Glyphosate: Test No. LF-78-161.(Unpublished study received Apr 25, 1979 under 524-308; submitted by Monsanto Co., Washington, D.C.; CDL:238233-B)  MRID 00078620

Li, A.; Kier, L.; Folk, R. (1983) CHO/HGPRT Gene Mutation Assaywith Glyphosate: EHL Study No. ML-83-155. Final rept. (Unpublished study received Nov 15, 1983 under 524-308; submitted by Monsanto Co., Washington, DC; CDL:251737-B) MRID 00132681

Li, A.; Kier, L.; Folk, R. (1983) In vivo Bone Marrow Cytogenetics Study of Glyphosate in Sprague-Dawley Rats: Study No. 830083. (Unpublished study received Nov 15, 1983 under 524-308; submitted by Monsanto Co., Washington, DC; CDL:251737-D)   MRID 00132683

Shirasu, Y.; Moriya, M.; Ohta, T. (1978) Microbial MutagenicityTesting on CP67573 (Glyphosate). (Unpublished study received Apr25, 1979 under 524-308; prepared by Institute of EnvironmentalToxicology, Japan, submitted by Monsanto Co., Washington, D.C.; CDL:238233-A) MRID 00078619

3. Developmental and Reproductive toxicity. Pp 16 & 17 (studies extracted from US EPA RED 1993 p. 15 & 16)

Rodwell, D.E.; Tasker, E.J.; Blair, A.M.; et al. (1980)Teratology Study in Rats: IRDC No. 401-054. (Unpublished studyincluding IRDC no. 999-021; received May 23, 1980 under 524-308; prepared by International Research and Development Corp.,submitted by Monsanto Co., Washington, D.C.; CDL:242516-A) MRID 00046362

Rodwell, D.E.; Tasker, E.J.; Blair, M.; et al. (1980) Teratology Study in Rabbits: IRDC No. 401-056. (Unpublished study received May 23, 1980 under 524-308; prepared by International Research and Development Corp., submitted by Monsanto Co., Washington, D.C.; CDL:242516-B) MRID 00046363

Street, R. (1982) Letter sent to R. Taylor dated Jul 6, 1982: Roundup herbicide: Addendum to pathology report for a three-­generation reproduction study in rats with glyphosate. (Unpublished study received Jul 7, 1982 under 524-308; submitted by Monsanto Co., Washington, DC; CDL:247793-A) MRID 00105995

4. Structure - Activity Relationships. (No studies submitted)

5. Acute, subchronic and chronic feeding / oncogenicity data. P.17. (studies extracted from US EPA RED 1993 p. 10 & 13)

Birch, M.D. (1970) Toxicological Investigation of CP 67573-3: Project No. Y-70-90. (Unpublished study received Jan 30, 1973 under 524-308; prepared by Younger Laboratories, Inc., submitted by Monsanto Co., Washington, D.C.; CDL:008460-C) MRID 00067039

Reyna, M. (1985) Twelve Month Study of Glyphosate Administered by Gelatin Capsule to Beagle Dogs: Project No. ML-83-137: Study No. 830116. Unpublished study prepared by Monsanto Company Environmental Health. 317 p. MRID 00153374

END OF STUDIES in Second Peer Review Paper.

G. Classification p. 19 (Second Peer Review)

Considering criteria contained in the EPA Guidelines (FR 51:33992-34003, 1986) for classifying a carcinogen, the Committee concluded that Glyphosate should be classified as a Group E (evidence of Non-carcinogenicity to humans), based on lack of convincing carcinogenicity evidence in adequate studies in two animal species.

It should be emphasised, however, that designation of an agent in Group E is based on the available evidence at the time of evaluation and should not be interpreted as a definitive conclusion that the agent will not be a carcinogen under any circumstances.

End discussion Second Peer Review Paper.

26 March 1998

Information retreived from:  EPA Memorandum date 17 August 2000 : Glyphosate in/on Alfalfa hay and forage; Field corn forage; Stover and straw of the cereal grains crop group; numerous minor crops; and flax in Northern Dakota. HED Risk Assessment. P. 6/7

Section:  Dose Response Assessment

On 26 March 1998 the HED Hazard Identification Assessment Review Committee (HIARC) evaluated the toxicology database, selected doses and endpoints for chronic dietary risk assessment, considered the carcinogenic potential and addressed the sensitivity of infants and children from exposure to glyphosate as required by the Food Quality Protection Act (FQPA) of 1996 (HED Doc. No. 12586, W. Dykstra and J. Rowland, 20-APR-1998).


The FQPA Safety Factor Committee (SFC) met on April 6, 1998 and addressed the potential of enhanced sensitivity to infants and children as required by FQPA (HED Doc. 012584 B. Tarplee and J. Rowland  17-APR-1998). The Committee recommended the 10X FQPA Safety Factor be reduced to 1X in assessing the risk posed by this chemical because: 1) the toxicology data base is complete; 2) there is no indication of susceptibility of rats to in utero and/or postnatal exposure to glyphosate (in the prenatal development study in rats, effects in the offspring were observed only at or above the treatment levels which resulted in the evidence of appreciable maternal toxicity), and 3) the use of generally high quality data, conservative models and/or assumptions in the exposure assessment provides adequate protection of infants and children.


An acute dose and endpoint were not selected for any population subgroups because no effects could be attributed to a single exposure (dose) were observed in oral toxicity studies including the development toxicity studies in rats and rabbits.  Therefore a dose and endpoint were not identified for acute dietary risk assessment.


Memorandum Page 6. I believe the studies this was based on are as follows:


CRfD 2.0mg/kg/day based on rabbit developmental study with NOAEL 175 mg/kg/day:
Rodwell DE; Tasker EJ; Blair M; et al. (1980) : Teratology Study in Rabbits. Unpublished. Pre GLP. Monsanto Company. 1980b. Report no. IR-79_018. MRID No. 00046363. IRDC No. 401-056. International Research and Development Corp


4 month mouse carcinogenicity study (NOAEL 750 mg/kg/day):
2 McConnel, R. (1985) A Chronic Feeding Study of Glyphosate (Roundup Technical in Mice): Pathology Report on Additional Kidney Sections: Addendum to Final Report Dated July 21, 1983: Project No. 77-2061A. Unpublished study prepared by Bio/dynamics Inc. 59 p. MRID 00150564  Bio/dynamics studies are almost always Monsanto submitted


1 yr dog study (NOAEL 500 mg/kg/day)
Reyna, M. (1985) Twelve Month Study of Glyphosate Administered by Gelatin Capsule to Beagle Dogs: Project No. ML-83-137: Study No. 830116. Unpublished study prepared by Monsanto Company Environmental Health. 317 p. MRID 00153374


2 year chronic/onco rat study (NOAEL 400 mg/kg/day):
tout, L.; Ruecker, F. (1990) Chronic Study of Glyphosate Administered in Feed to Albino Rats: Lab Project Number: MSL- 10495: R.D. 1014. Unpublished study prepared by Monsanto Agricultural Co. 2175 p.    MRID 41643801

2 generation rat reproduction study (NOAEL 500 mg/kg/day):
Reyna, M. (1990): Two Generation Reproduction Feeding Study with Glysophate in Sprague-Dawley Rats: Lab Project No: MSL-10387. MRID 41621501 Unpublished study prepared by Monsanto Agricultural Co.  1158


Rat development toxicity study (NOAEL 1000 mg/kg/day):
Rodwell, D.E.; Tasker, E.J.; Blair, A.M.; et al. (1980): Teratology Study in Rats: IRDC No. 401-054. MRID 00046362 (Unpublished study including IRDC no. 999-021; received May 23, 1980 under 524-308; prepared by International Research and Development Corp., submitted by Monsanto Co., Washington, D.C.; CDL:242516-A)


An uncertainty factor (UF) of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variation (10X).  The chronic population adjusted dose (cPAD) is equal to the cRfD divided by the FQPA Safety Factor. Because the 10X safety factor was reduced to 1X, the cPAD is equivalent to the cRfD of 2.0 mg/kg/day.
Because of the lack of evidence of carcinogenicity in mice and rats at doses that were judged to be adequate to assess the carcinogenic potential, glyphosate was classified as a ‘Group E’ chemical.

Further reading and link to study outlines released to public.  EPA Memorandum date 17 August 2000

 WHO: studies behind the WHO 2004 carcinogenicity evaluation.

PLEASE ADVISE ME IF THERE HAS BEEN A CARCINOGENICITY REVIEW SINCE 1998. I DO NOT BELIEVE THIS HAS OCCURRED.

PLEASE ALSO ADVISE ME IF YOU SEE INCORRECT CONTENT. THIS HAS BEEN CARRIED OUT TO THE BEST OF MY ABILITY AND THERE IS NO INTENTION TO DECEIVE. 

References:

EPA 1993 Glyphosate Reregistration Eligibilty Decision (RED) PDF (EPA has removed this from public access during 2014/2015)

Information for the 1985 & 1991 evaluations has been extracted from an EPA Memorandum date 17 August 2000 for a HED risk assessment for glyphosate.  pp. 5/6

Cornell Paper: Proposed Pesticide Tolerance Glyphosate 5/93.

Information regarding the 1998 evaluations extracted from an EPA Memorandum dated March 13 2002  from an occupational exposure risk assessment. Page 6.

30 October 1991 - US EPA Second Peer Review of Glyphosate. Memorandum 1071-83-6. From William Dykstra and George Z Ghali.  http://www.epa.gov/opp00001/chem_search/cleared_reviews/csr_PC-103601_30-Oct-91_265.pdf