Regulatory history of glyphosate carcinogenicity reviews in USA

lucerne The history of Roundup, glyphosate & carcinogenicity reveals a steady decrease, or loosening up, of the carcinogenicity rating.  

Carcinogenicity assessments include only pesticide company directly-funded studies. I believe that Monsanto has submitted every study.  

These assessments conveniently exclude 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 Unpublished Report no.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

Extract from the EPA RED 1993 P.14 : This is the study that decided the classification of Group C Carcinogen – 

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 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 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 00150564) End extract.

A pathology report was produced two years later:

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

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)

US EPA released memorandum dated March 1986, 009824. Subject: Glyphosate Standard Revision.  Contains revised review of toxicity data, updated TOX one liners and revised toxicity assessment. (Carcinogenicity data pp 1 & 2).

26 June 1991 :

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 further elaborated by 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).

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.

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 RED 1993 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

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. Unpublishedstudy 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

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 :

“The carcinogenic potential of glyphosate was evaluated by the HED Cancer Peer Review Committee (26-MAR-1998) and classified as a Group E chemical – no evidence of carcinogenicity in two acceptable animal studies.

I believe these are the two studies the carcinogenicity evaluation is based on:

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

Stout, L.; Ruecker, F. (1990) Chronic Study of Glyphosate Adminitered in Feed to Albino Rats: Lab Project Number: MSL- 10495: R.D. 1014. Unpublished study prepared by Monsanto Agricultural Co. 2175 p.    MRID 41643801

Link to study outlines released to public.

 WHO: studies behind the WHO 2004 carcinogenicity evaluation.

 

References:

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.

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

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