THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE
Dear Friends and Colleagues
Increasing Evidence of Detrimental Effects of Glyphosate-based Herbicides on Rats
Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides. Some 8.6 billion kilograms of GBHs have been sprayed worldwide since 1974. Glyphosate use has increased 15-fold since glyphosate-tolerant GM crops were introduced in 1996.
A study (Items 1 & 2) exposed rats, starting from prenatal life until 13 weeks after weaning, to doses of glyphosate and Roundup in drinking water corresponding to the U.S. Environmental Protection Agency’s acceptable daily dietary exposure of 1.75 mg/kg bw/day. Such exposure caused reproductive and developmental effects in both male and female rats, at a dose level currently considered safe in the U.S. Exposure to GBHs was associated with androgen-like effects, including a statistically significant increase of anogenital distance (AGD) in males and females, delay of first estrous, and increased testosterone in females. AGD, the distance between the anus and the genitals, is a sensitive marker of prenatal endocrine disruption affecting genital tract development.
Another recent study has found a variety of diseases and other health problems in the second- and third-generation offspring of rats exposed to glyphosate (Items 3 & 4). Pregnant rats were exposed to glyphosate between their eighth and 14th days of gestation. The dose—half the amount expected to show no adverse effect—produced no apparent ill effects on either the parents or the first generation of offspring. However, there were “dramatic increases” in several pathologies affecting the second and third generations. Descendants of exposed rats developed prostate, kidney and ovarian diseases, obesity and birth abnormalities.
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Item 1
THE RAMAZZINI INSTITUTE 13-WEEK PILOT STUDY GLYPHOSATE-BASED HERBICIDES ADMINISTERED AT HUMAN-EQUIVALENT DOSE TO SPRAGUE DAWLEY RATS: EFFECTS ON DEVELOPMENT AND ENDOCRINE SYSTEM
Fabiana Manservisi, Corina Lesseur†, Simona Panzacchi, et al.
Environmental Health 2019 18:15
https://doi.org/10.1186/s12940-019-0453-y
12 March 2019
https://ehjournal.biomedcentral.com/articles/10.1186/s12940-019-0453-y
Background
Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be “safe” (the US Acceptable Daily Intake – ADI – of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats.
Methods
Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8M+8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73±2; 10M+10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125±2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups.
Results
In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure.
Conclusions
The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.
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Item 2
GLOBAL GLYPHOSATE STUDY PILOT PHASE SHOWS REPRODUCTIVE AND DEVELOPMENTAL EFFECTS AT ‘SAFE’ DOSE
The Ramazzini Institute
11 March 2019
https://glyphosatestudy.org/press-release/global-glyphosate-study-pilot-phase-shows-reproductive-and-developmental-effects-at-safe-dose/?utm_source=newsletter&utm_medium=email&utm_campaign=global_glyphosate_study_pilot_phase_shows_reproductive_and_developmental_effects_at_safe_dose&utm_term=2019-05-02
A new study (1) has found that exposure to glyphosate-based herbicides (GBHs), including Roundup, caused reproductive and developmental effects in both male and female rats, at a dose level currently considered safe in the U.S. (1.75 mg/kg bw/day).
Exposure to GBHs was associated with androgen-like effects, including a statistically significant increase of anogenital distance (AGD) in males and females, delay of first estrous and increased testosterone in females.
AGD, the distance between the anus and the genitals, is a sensitive marker of prenatal endocrine disruption (2) affecting the genital tract development. Exposure to different chemicals including pesticides has been linked previously to altered AGDs and other endocrine effects (3)(4).
This is the fourth in a series of related papers (5) from the pilot phase of the Global Glyphosate Study. The first results of the pilot phase of the study were presented to the European Parliament on May 16th 2018. The previous peerreviewed publications show that exposure to GBHs leads to other effects, including altering the gut microbiota of rats in early development, particularly before the onset of puberty.
The pilot phase of the Study was performed by the Ramazzini Institute and a network of scientific partners including the University of Bologna, the Genoa Hospital San Martino, the Italian National Institute of Health, the University of Copenhagen, the Federal University of Paraná, the Icahn School of Medicine at Mount Sinai and the George Washington University.
The € 300,000 study was funded by 30,000 members of the public in Italy, who are associates of the Ramazzini Institute cooperative.
A crowd-funding campaign has been launched to help support a long-term comprehensive Global Glyphosate Study, which following these results is now urgently required.
Background:
Glyphosate is the most used herbicide in human history. 18.9 Billion pounds (8.6 Billion Kilograms) of glyphosate-based herbicides (GBHs) have been sprayed worldwide since 1974. Glyphosate use has also increased 15-fold since genetically modified crops were introduced in 1996 (6).
In 2015 the International Agency for Research on Cancer (IARC) classified glyphosate as a “probable human carcinogen” (7). The European Food Safety Authority (EFSA), following the German Federal Institute for Risk Assessment (BfR) evaluation, has since stated that glyphosate is “unlikely to pose a carcinogenic hazard to humans” (8) and the European Chemicals Agency (ECHA) stated that “the available scientific evidence did not meet the criteria to classify glyphosate as a carcinogen, as a mutagen or as toxic for reproduction” (9). The U.S. Environmental Protection Agency (EPA) still has a new evaluation of glyphosate pending (10).
The scientific uncertainty surrounding glyphosate and GBHs has also led to political uncertainty, with a shortened 5-year re-approval for glyphosate having been granted by European Union Member States in November 2017.
The Ramazzini Institute and their partners have walked into this unclear situation so as to supply valuable and independent data to enable regulators, governments and the general public of every country to answer the question: Are glyphosate and GBHs safe at real-world levels of exposure?
The pilot study, which is vital for the long-term comprehensive study, aimed to obtain general information as to whether GBHs are toxic at various stages of early life (newborn, infancy and adolescence), and to identify early markers of exposure and effect. Glyphosate and one of its formulates (Roundup Bioflow, MON 52276) were both tested in Sprague Dawley rats, starting from prenatal life until 13 weeks after weaning, exposed to a dose of glyphosate in drinking water corresponding to the U.S. Environmental Protection Agency’s acceptable daily dietary exposure (11), referred to in the U.S. as the chronic reference dose (cRfD) – 1.75 mg/kg/day.
Global Glyphosate Study: Crowdfunding
The Ramazzini Institute, with the support of other independent Institutes and Universities in Europe and the United States, has now launched a crowdfunding campaign for the most comprehensive long-term study ever on GBHs. A longterm study is now necessary to extend and confirm the initial evidence that has emerged in the pilot phase of the Study.
The total budget for this study is € 5 Million and it is already receiving support from the public, politicians and NGOs around the world.
The Ramazzini Institute
The Ramazzini Institute, in over 40 years of activity, has studied more than 200 compounds from the general and occupational environment and many of its results have provided a solid scientific base for regulating and limiting the exposure of a number of substances. Examples include: Vinyl Chloride, Benzene, Formaldehyde, Trichloroethylene and Mancozeb.
Quotes from Scientists:
Prof. Philip J. Landrigan, Schiller Institute for Integrated Science and Society, Boston College
“This very important study from the Ramazzini Institute indicates that glyphosate, the world’s most widely used herbicide, has negative effects on reproductive development in mammalian species even at exposure levels that are currently considered safe and legally acceptable. Although these findings are not definitive, they are very worrisome, and need to be followed closely by national and international regulatory agencies.
Dr. Fiorella Belpoggi, Cesare Maltoni Cancer Research Center, Ramazzini Institute
“A long-term study on GBHs encompassing intrauterine life through to advanced adulthood is needed to confirm and further explore the initial evidence of endocrine-related effects and developmental alterations emerged in this pilot study.”
Prof. Jia Chen, Icahn School of Medicine at Mount Sinai in New York City
“GBHs are of significant public health concern because of their widespread and sharply increased usage and we still do not know enough about their noncancerous effects, in particular in developing children.”
Dr. Alberto Mantovani, Italian National Institute of Health
“A relevant feature of the findings for risk assessors are the definitely stronger endocrine-reproductive effects induced by the product GBH compared to an equivalent dose level of the pure substance glyphosate. The suggestion that other components of GBH may significantly enhance glyphosate toxicity definitely deserves further investigation.”
Prof. Melissa J Perry, George Washington University
“Although glyphosate has been around for decades, its global use has increased rapidly and we know surprisingly little about the human health effects of such widespread use. This study in rats uses doses that compare to what humans are exposed to in their everyday environments including from the food they eat.
“These most recent findings demonstrate important impacts on hormone production that shouldn’t be ignored. The study findings as a whole are providing valuable original information to more clearly assess the health risks to humans.”
Prof. Anderson Joel Martino Andrade, Federal University of Paraná
“This pilot study shows that the development of the reproductive system seems to be particularly sensitive to glyphosate and that formulated pesticides may have a different profile of toxic effects than isolated active ingredients.”
Press Contact:
Vincenzo Branà: comunicazione@ramazzini.it
References:
(1) Manservisi F, Lesseur C, Panzacchi S, Mandrioli D, Falcioni L, Bua L, Manservigi M, Spinaci M, Galeati G, Mantovani A, Lorenzetti S, Miglio R, Andrade AM, Kristensen DM, Perry MJ, Swan SH, Chen J, Belpoggi F. The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human equivalent dose to Sprague-Dawley rats: effects on development and endocrine system. Environmental Health 2019;18:15. https://ehjournal.biomedcentral.com/articles/10.1186/s12940-019-0453-y
(2) Swan SH, Sathyanarayana S, Barrett ES, Janssen S, Liu F, Nguyen RH, Redmon JB; TIDES Study Team. First trimester phthalate exposure and anogenital distance in newborns. Hum Reprod. 2015 Apr;30(4):963-72.
(3) Levine H, Jørgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Mindlis I, Pinotti R, Swan SH. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update. 2017 Nov 1;23(6):646-659.
(4) Dalsager L, Christensen LE, Kongsholm MG, Kyhl HB, Nielsen F, Schoeters G, Jensen TK, Andersen HR.Associations of maternal exposure to organophosphate and pyrethroid insecticides and the herbicide 2,4-D with birth outcomes and anogenital distance at 3 months in the Odense Child Cohort. Reprod Toxicol. 2018 Mar;76:53-62.
(5) https://glyphosatestudy.org/global-glyphosate-study-pilot-phase/
(6) Benbrook CM. Trends in glyphosate herbicide use in the United States and globally. Environ Sci Eur. 2016;28:3.
(7) IARC (International Agency for Research on Cancer). Some Organophosphate Insecticides and Herbicides. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 112 (2017).
(8) EFSA (European Food Safety Authority). Conclusion on the peer review of the pesticide risk assessment of the active substance glyphosate. EFSA Journal 2015;13(11):4302, 107 pp. doi: 10.2903/j.efsa.2015.4302.
(9) European Chemical Agency (ECHA). Glyphosate not classified as a carcinogen by ECHA. ECHA/PR/17/06, 15 March 2017.
(10) US Environmental Protection Agency (EPA). Draft Human Health and Ecological Risk Assessments for Glyphosate. Accessed May 9th, 2018:
https://www.epa.gov/ingredients-used-pesticide-products/draft-humanhealth-and-ecological-risk-assessments-glyphosate
(11) US Environmental Protection Agency (EPA). Glyphosate: Chronic Dietary Exposure Assessment for the Section 3 Registration Action. 2006. Accessed May 9th, 2018: https://www3.epa.gov/pesticides/chem_search/cleared_reviews/csr_PC103601_8-May-06_a.pdf
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Item 3
ASSESSMENT OF GLYPHOSATE INDUCED EPIGENETIC TRANSGENERATIONAL INHERITANCE OF PATHOLOGIES AND SPERM EPIMUTATIONS: GENERATIONAL TOXICOLOGY
https://www.nature.com/articles/s41598-019-42860-0
Scientific Reports volume 9, Article number: 6372 (2019)
Abstract
Ancestral environmental exposures to a variety of factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. One of the most widely used agricultural pesticides worldwide is the herbicide glyphosate (N-(phosphonomethyl)glycine), commonly known as Roundup. There are an increasing number of conflicting reports regarding the direct exposure toxicity (risk) of glyphosate, but no rigorous investigations on the generational actions. The current study using a transient exposure of gestating F0 generation female rats found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed. The transgenerational pathologies observed include prostate disease, obesity, kidney disease, ovarian disease, and parturition (birth) abnormalities. Epigenetic analysis of the F1, F2 and F3 generation sperm identified differential DNA methylation regions (DMRs). A number of DMR associated genes were identified and previously shown to be involved in pathologies. Therefore, we propose glyphosate can induce the transgenerational inheritance of disease and germline (e.g. sperm) epimutations. Observations suggest the generational toxicology of glyphosate needs to be considered in the disease etiology of future generations.
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Item 4
WSU RESEARCHERS SEE HEALTH EFFECTS ACROSS GENERATIONS FROM POPULAR WEED KILLER
https://news.wsu.edu/2019/04/23/wsu-researchers-see-health-effects-across-generations-popular-weed-killer/
April 23, 2019
By Eric Sorensen, WSU News
PULLMAN, Wash. – Washington State University researchers have found a variety of diseases and other health problems in the second- and third-generation offspring of rats exposed to glyphosate, the world’s most popular weed killer. In the first study of its kind, the researchers saw descendants of exposed rats developing prostate, kidney and ovarian diseases, obesity and birth abnormalities.
Michael Skinner, a WSU professor of biological sciences, and his colleagues exposed pregnant rats to the herbicide between their eighth and 14th days of gestation. The dose—half the amount expected to show no adverse effect—produced no apparent ill effects on either the parents or the first generation of offspring.
But writing in the journal Scientific Reports, the researchers say they saw “dramatic increases” in several pathologies affecting the second and third generations. The second generation had “significant increases” in testis, ovary and mammary gland diseases, as well as obesity. In third-generation males, the researchers saw a 30 percent increase in prostate disease—three times that of a control population. The third generation of females had a 40 percent increase in kidney disease, or four times that of the controls.
More than one-third of the second-generation mothers had unsuccessful pregnancies, with most of those affected dying. Two out of five males and females in the third generation were obese.
Skinner and his colleagues call this phenomenon “generational toxicology” and they’ve seen it over the years in fungicides, pesticides, jet fuel, the plastics compound bisphenol A, the insect repellant DEET and the herbicide atrazine. At work are epigenetic changes that turn genes on and off, often because of environmental influences.
Skinner said he decided to study glyphosate “due to it being one of the most commonly used compounds worldwide.”
The chemical has been the subject of numerous studies about its health effects. The Skinner study is the third in the past few months out of Washington alone. A University of Washington study published in February found the chemical increased the risk of non-Hodgkin lymphoma by as much as 41 percent. A Washington State University study published in December found state residents living close to areas subject to treatments with the herbicide are one-third more likely to die an early death from Parkinson’s disease.
The chemical’s generational toxicology represents a new downside that Skinner and his colleagues said should be incorporated into estimates of its risk.
“The ability of glyphosate and other environmental toxicants to impact our future generations needs to be considered,” they write, “and is potentially as important as the direct exposure toxicology done today for risk assessment.”
The research was supported by a grant from the John Templeton Foundation. The paper’s co-authors are Undergraduate Researcher Deepika Kubsad, Research Assistant Professor Eric Nilsson, Research Assistant Stephanie King, Senior Research Associate Ingrid Sadler-Riggleman and Research Associate Daniel Beck.
Contact:
Michael Skinner, professor, Washington State University School of Biological Sciences, 509‑335‑1524, skinner@wsu.edu