Background: Glyphosate, formulated as Roundup, is the world’s most widely used herbicide. Glyphosate is used extensively on genetically modified (GM) food crops designed to tolerate the herbicide, and global use is increasing rapidly. Two recent reviews of glyphosate’s health hazards report conflicting results. An independent review by the International Agency for Research on Cancer (IARC) found that glyphosate is a “probable human carcinogen”.Areview by the European Food Safety Agency (EFSA) found no evidence of carcinogenic hazard. These differing findings have produced regulatory uncertainty. Regulatory actions: Reflecting this regulatory uncertainty, the European Commission on November 27 2017, extended authorization for glyphosate for another 5 years, while the European Parliament opposed this decision and issued a call that pesticide approvals be based on peer-reviewed studies by independent scientists rather than on the current system that relies on proprietary industry studies. Ramazzini Institute response: The Ramazzini Institute has initiated a pilot study of glyphosate’s health hazards that will be followed by an integrated experimental research project. This evaluation will be independent of industry support and entirely sponsored by worldwide crowdfunding. The aim of the Ramazzini Institute project is to explore comprehensively the effects of exposures to glyphosate-based herbicides at current real-world levels on several toxicological endpoints, including carcinogenicity, long-term toxicity, neurotoxicity, endocrine disrupting effects, prenatal developmental toxicity, the microbiome and multi-generational effects. Keywords: Glyphosate, Roundup, Glyphosate based herbicides, GBH, Carcinogenicity, Crowdfunding Background to increase and by 2020 is estimated to reach one million History and use tons per year. Glyphosate is the world’s most widely used herbicide . Glyphosate, formulated as Roundup, is used on corn Glyphosate Based Herbicides (GBHs) were first authorised and soybeans that have been genetically engineered to for agricultural use in the US in 1974 by the Environmen- be resistant to glyphosate. These “Roundup- Ready” tal Protection Agency. In Europe, glyphosate was crops were first introduced in the mid-1990s and now authorised by the European Commission in 2002. In the account for more than 90% of the corn and soybeans US, glyphosate use has increased by more than 250-fold in planted in the United States . Today glyphosate is the past 4 decades — from 0.4 million kg in 1974 to 113 contained in over 750 commercial herbicide products million kg in 2014. Global glyphosate use has also in- designed for intensive crop-growing, market gardening creased from 3200 tons/year in 1974 to 825,000 tons/year and gardens in general. This massive use of glyphosate in 2014, and glyphosate is now used in over 140 countries in the most varied sectors of agriculture has led to wide- . In future years, glyphosate use is projected to continue spread environmental dissemination. Trace levels of gly- phosate can now be found widely in soil, foodstuffs, air * Correspondence: firstname.lastname@example.org; https://www.ramazzini.org and water as well as human urine [3–5]. Cesare Maltoni Cancer Research Center Ramazzini Institute, Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Landrigan and Belpoggi Environmental Health (2018) 17:51 Page 2 of 4 Regulatory actions industry had tainted scientific reviews in Europe by On November 27 2017, the European Commission ex- interfering in them. tended the authorization for glyphosate for another 5 years. The European Parliament, however, opposed this Main text decision and issued a call for pesticide approvals to be The Ramazzini Institute research project based on published peer-reviewed studies by independent Pilot study scientists instead of the current system, which is largely A ‘pilot’ experimental study of the toxicity of GBHs was based on unpublished proprietary studies. Regulatory un- carried out at the Ramazzini Institute in 2016 (Minister- certainty and debate are extensive [6, 7]. Key milestones in ial Authorization N° 710/2015-PR, issued on 17/7/2015) the risk assessment process that has led to the current where both glyphosate alone and its formulation regulatory debate about the safety of glyphosate may be Roundup have been tested. In fact glyphosate alone and summarized as follows: its formulations could have different effects. For ex- ample, the adjuvants present in the formulation might – March 2015: the World Health Organization’s potentiate the toxic effects of glyphosate . To set this International Agency for Research on Cancer study in motion, the Institute built up a network of au- (IARC) conducted an extensive review of the thoritative partners including the University of Bologna published peer-reviewed epidemiologic, toxicologic (Departments of Agriculture, Veterinary Science and and genetic literature on glyphosate, independent of Biostatistics), the Genoa Istituto Tumori, the Istituto influence by the pesticide manufacturing industry, Superiore di Sanità (ISS), the Icahn School of Medicine and concluded that glyphosate is “probably at Mount Sinai, New York, and the George Washington carcinogenic to man” (Category 2A ). University, Washington, DC. – November 2015: the EFSA deemed glyphosate The study was designed to assess the techniques and “unlikely to pose a cancer risk for man”. That methods for detecting glyphosate and its metabolites in conclusion was based on a glyphosate renewal different matrices  and to develop methods for asses- assessment report (RAR) presented in January 2014 sing organ toxicity, genotoxicity, molecular toxicity, repro- by the Federal German Institute for Risk Assessment ductive/developmental toxicity, endocrine disruption and (Bundesinstitut für Risikobewertung, BfR) . The microbiome alteration . In this pilot study, glyphosate EFSA and RAR review groups included scientists and Roundup were both tested at a dose considered to be that did not disclose their names and financial “safe”- corresponding to the ADI of glyphosate currently interests and also relied on unpublished, non-peer- allowed in the US, defined as the chronic Reference reviewed reports generated by industry . Dose (cRfD) determined by the US EPA , namely – March 2017: following a heated argument over the 1.75 mg/kg bw/day. safety of glyphosate, and numerous deferments of Initial results from this pilot study were presented dur- the European ballot, the European Union (EU) ing the Annual Ramazzini Days (26–29 October 2017). appointed the European Chemicals Agency (ECHA) These preliminary findings suggest that glyphosate and to look into the issue of glyphosate toxicity. The Roundup – even at doses deemed safe, i.e., at doses ECHA’s Risk Assessment Committee analysed an equivalent to the current ADI and with relatively short enormous amount of scientific data and concluded exposure time, from pregnancy until 13 weeks after that “the scientific evidence so far available does not weaning in human-equivalent terms from pregnancy to satisfy the criteria for classifying glyphosate as approximately 18 years of age – might be able to alter carcinogenic, mutagenic or toxic for reproduction.” certain important biological parameters related to sexual . According to the ECHA, glyphosate may cause development, genotoxicity and alteration of the intes- grave damage to the eyes and be toxic to aquatic tinal bacterial flora. Other important parameters are organisms with long-term effects. under investigation that pertain to effects on target or- – November 2017: The EU voted to extend glyphosate gans such as mammary gland, kidney and liver, the hor- authorization for an abbreviated period of five years; monal status in the blood, and chromosome alterations the Acceptable Daily Intake (ADI) was increased in sperm. All the results will be submitted for publica- from 0.3 to 0.5 mg/kg bw/day . The deliberation tion in this journal [14, 15]. frustrated parties on all sides. Agrochemical A pilot study is, by definition, of short duration and companies criticized the review process as driven involves fewer animals than a comprehensive experi- more by politics than science after it became clear ment. Therefore, it can provide only limited information that the weed killer’s use would not be re-authorized and is not designed to detect chronic effects and dis- for the 15 years typical for such chemicals. eases of late onset such as cancer. Thus the Ramazzini Environmental advocates said that the agrochemical Institute pilot study is not able to resolve the current Landrigan and Belpoggi Environmental Health (2018) 17:51 Page 3 of 4 regulatory uncertainty around glyphosate. However, the To provide ongoing review of the integrated study, we findings of the pilot study do highlight potentially ser- intend to set up an external international scientific com- ious health effects that might manifest as long-term on- mittee that will evaluate the study plan, the conduct of cologic pathology and could affect very large numbers of the study and review study results as they become avail- people, given the great and growing global use of the able. We also plan to gather together all stakeholders in- GBHs. Clearly these findings deserve further follow-up. terested in using our results to ascertain the degree of hazard involved in GBH exposure. These will include: Future research IARC, EFSA, ISS, the National Institute of Environmen- To follow up on the Ramazzini Institute pilot study, a tal Health Sciences, and others, including NGOs repre- more comprehensive investigation is necessary and it sentatives. Study results will be available by the time of must examine the effects of a range of different environ- the next EU decision on the reauthorization of glypho- mentally relevant doses of glyphosate alone and GBHs. sate in 2022. Therefore, in 2015, the Ramazzini Institute designed a comprehensive, integrated experimental approach to a Conclusions long-term project following an already published protocol Whatever the outcome of the Ramazzini Institute study, through which numerous parameters bearing on human the findings will provide regulatory agencies and policy- health might be simultaneously monitored, thereby spar- makers with solid independent results obtained by a ing animals . In fact, proprietary studies conducted on shared research project on which they can confidently behalf of the manufacturers often represent a limited in- base their risk assessments and their evaluations, includ- vestigation of the various toxicological effects now studied ing the upcoming decision for the reauthorization for by academic and government scientists. The integrated glyphosate use in Europe in 2022. study proposed by the Ramazzini Institute is based on a Abbreviations stepwise process that includes the priority end points of ECHA: European Chemicals Agency; EFSA: European Food Safety Agency; the Economic Co-operation and Development and the EU: European Union; GBH: Glyphosate Based Herbicides; GM: Genetically National Toxicology Program guidelines on carcinogen- modified; IARC: International Agency for Research on Cancer; ISS: Istituto Superiore di Sanità; RAR: Renewal assessment report icity and chronic toxicity in addition to developmental and reproductive toxicity, exploring multiple windows of Authors’ contributions susceptibility of specific interest for risk assessments and Both authors provided substantial contributions to the conception of the work, analysis or interpretation of the data, revised the manuscript critically, public health decision-making such as prenatal, lactational and approved the final version for submission. Both authors read and and neonatal exposures. Such an integrated toxicological approved the final manuscript. study is needed, together with further epidemiological evi- dence, for an independent and comprehensive assessment Ethics approval and consent to participate N/A of the possible risks resulting from the ubiquitous expos- ure to GBHs. Competing interests As in the pilot study, both glyphosate and the com- The authors declare that they have no competing interests. mercial formulation Roundup will be tested in the inte- grated study. A human-equivalent model will be used to Publisher’sNote determine the dose-levels to be administered and the ex- Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. posure period, which will include mating and gestation. Detailed assessments will examine the toxic effects in Author details terms of the intestinal microbiome, gene expression and Environmental Medicine and Pediatrics Arnhold Institute for Global Health Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box parameters relating to fertility, defects in development, 1057, New York, NY 10029, USA. Cesare Maltoni Cancer Research Center effects on the nervous system and any treatment-related Ramazzini Institute, Via Saliceto, 3, 40010 Bentivoglio, Bologna, Italy. differences in the incidence of various tumours. This will Received: 5 February 2018 Accepted: 10 May 2018 be the most comprehensive study on GBHs to date and it will last 3–4 years. To preserve independence from the pesticide- References manufacturing industry and from its competitor (i.e. or- 1. Benbrook C. Trends in the use of glyphosate herbicide in the U.S. and globally. 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Published: May 29, 2018