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Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement Myers, John P; Antoniou, Michael N; Blumberg, Bruce; Carroll, Lynn; Colborn, Theo; Everett, Lorne G; Hansen, Michael; Landrigan, Philip J; Lanphear, Bruce P; Mesnage, Robin; Vandenberg, Laura N; vom Saal, Frederick S; Welshons, Wade V; Benbrook, Charles M Feb 17, 2016

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REVIEW Open AccessConcerns over use of glyphosate-basedherbicides and risks associated withexposures: a consensus statementJohn Peterson Myers1,13*, Michael N. Antoniou2, Bruce Blumberg3, Lynn Carroll4, Theo Colborn4, Lorne G. Everett5,Michael Hansen6, Philip J. Landrigan7, Bruce P. Lanphear8, Robin Mesnage2, Laura N. Vandenberg9,Frederick S. vom Saal10, Wade V. Welshons11 and Charles M. Benbrook12*AbstractThe broad-spectrum herbicide glyphosate (common trade name “Roundup”) was first sold to farmers in 1974. Sincethe late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold.Further increases in the volume applied are likely due to more and higher rates of application in response to thewidespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs weredeveloped to replace or reduce reliance on herbicides causing well-documented problems associated with driftand crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHsposed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to sethigh acceptable exposure limits. To accommodate changes in GBH use patterns associated with geneticallyengineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed(soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published inthe last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World HealthOrganization’s International Agency for Research on Cancer recently concluded that glyphosate is “probablycarcinogenic to humans.” In response to changing GBH use patterns and advances in scientific understanding oftheir potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to thesafety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanismsof action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of currenthuman safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usagecontinues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially inagricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4)Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs arerising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates oftolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. Weoffer a series of recommendations related to the need for new investments in epidemiological studies,biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether theeffects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations ofGBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National(Continued on next page)* Correspondence: jpmyers@ehsic.org; charlesbenbrook@gmail.com1Environmental Health Sciences, Charlottesville, VA, and Adjunct Professor,Carnegie Mellon University, Pittsburg, PA, USA12Benbrook Consulting Services, 90063 Troy Road, Enterprise, OR 97828, USAFull list of author information is available at the end of the article© 2016 Myers et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe 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.Myers et al. Environmental Health  (2016) 15:19 DOI 10.1186/s12940-016-0117-0(Continued from previous page)Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control andPrevention.Keywords: Glyphosate, Acceptable daily intake (ADI), AMPA, Consensus statement, Endocrine disruptor, Referencedose (RfD), Risk assessment, Roundup Ready, ToxicologyBackgroundThis Statement of Concern is directed to scientists, phy-sicians, and regulatory officials around the world. Wehighlight changes in the scope and magnitude of risks tohumans and the environment stemming from applica-tions of glyphosate-based herbicides (GBHs). The objec-tives of this statement are to: 1) demonstrate the needfor better monitoring of GBH residues in water, food,and humans; (2) identify limitations or weaknesses inthe way the EPA, the German Federal Institute for RiskAssessment, and others have previously assessed the po-tential risks to humans from exposure to GBHs; and (3)provide recommendations on data needs and ways tostructure future studies addressing potential health risksarising from GBH exposures.Our focus is on the unanticipated effects arising fromthe worldwide increase in use of GBHs, coupled withrecent discoveries about the toxicity and humanhealth risks stemming from use of GBHs. Our con-cern deepened when the World Health Organization’sInternational Agency for Research on Cancer (IARC)re-classified glyphosate as “probably carcinogenic tohumans” (i.e., Group 2A) [1].We highlight a number of issues that influence ourconcern about GBHs including: 1) increased use ofGBHs over the past decade, including new uses for theseherbicides just prior to harvest that can lead to highdietary exposures; 2) detection of glyphosate and its me-tabolites in foods; 3) recent studies that reveal possibleendocrine system-mediated and developmental impactsof GBH exposures; and 4) additional complications forfarmers, most acutely the emergence and spread ofweeds resistant to glyphosate and the concomitant useof multiple herbicides in mixtures, both of which in-crease the risk of human and environmental harm. Wediscuss evidence pointing to the need to adjust down-ward the acceptable daily intake for glyphosate. Ourmajor concerns are embodied in a series of consensuspoints that explicitly address the strength of the support-ing evidence, and our recommendations focus on re-search essential in narrowing uncertainty in future GBHrisk assessments.When regulatory agencies conducted their initial as-sessments of glyphosate toxicity (in the 1970s) and ap-proved a wide array of agricultural and non-agriculturaluses, only limited and fragmentary data on GBH toxicityand risks were available. Testing done by contract la-boratories were commissioned by the registrant and sub-mitted to regulatory agencies. Results indicated minimalmammalian toxicity. A large review published in 2000,written by consultants associated with the registrant anddrawing on unpublished industry reports, agreed with andreinforced that conclusion [2]. However, their review didnot address some statistical differences reported betweentest and control groups that could be interpreted morecautiously, and surely warrant further assessment [3, 4].In killing weeds and indeed almost all growingplants, the primary mode of glyphosate herbicidal ac-tivity is the inhibition of a key plant enzyme, namely5-enolpyruvylshikimate-3-phosphate synthase (EPSPS).This enzyme is part of the shikimic acid pathway andis essential for the synthesis of aromatic amino acidsthat govern multiple, essential metabolic processes inplants, fungi, and some bacteria. Since this EPSPS-driven pathway does not exist in vertebrate cells, somescientists and most regulators assumed that glyphosatewould pose minimal risks to mammals. However, sev-eral studies, some described below, now show thatGBHs can adversely affect mammalian biology viamultiple mechanisms.Glyphosate use is increasing significantlyThe United States has the world’s most complete, pub-licly accessible dataset on GBH use trends over the past40 years. Usage trends have been analyzed by EPA in aseries of pesticide sales and use reports spanning 1982–2007 [5, 6], U.S. Geological Survey scientists [7, 8], theUSDA’s National Agricultural Statistics Service (NASS)[9], and academic and industry analysts [10–12].Briefly, glyphosate was registered in 1974 in the U.S.Initially, this broad-spectrum, contact herbicide wassprayed by farmers and ranchers primarily to kill weedsbefore the planting of fields, and for weed control inpastures and non-crop areas. In 1987 between 6 and 8million pounds (~2.72–3.62 million kilograms) were ap-plied by U.S. farmers and ranchers [5]. In 1996, the firstyear genetically engineered (GE), glyphosate-tolerantcrops were planted commercially in the U.S., glyphosateaccounted for just 3.8% of the total volume of herbicideactive ingredients applied in agriculture [7].By 2007, the EPA reports agricultural use of glyphosatein the range of 180–185 million pounds (~81.6–83.9Myers et al. Environmental Health  (2016) 15:19 Page 2 of 13million kilograms) [6]. The USGS team projects that gly-phosate accounted for 53.5% of total agricultural herbi-cide use in 2009 [7]. In the 20-year timespan covered byEPA sales and usage reports (1987–2007), glyphosateuse rose faster and more substantially than any otherpesticide. Usage in the range of 81.6–83.9 million kilo-grams, which occurred in 2007, was more than doublethe next most heavily sprayed pesticide (atrazine, 73–78million pounds; ~33.1–35.4 million kilograms). For overa decade, GBHs have been, by far, the most heavily ap-plied pesticides in the U.S.By 2014, annual farm-sector glyphosate usage increasedto approximately 240 million pounds (~108.8 million kilo-grams), based on average annual crop use reported by theNASS [9, 12]. Available use data published by the USDA,USGS, and EPA show that a surprisingly large share(approximately two-thirds) of the total volume of GBH ap-plied since 1974 has been sprayed in just the last decade.Glyphosate residues are found in foodsGBHs are widely used on a range of crops includingmaize, soy grain, canola, wheat, barley, and edible beans,among others [9]. GBH application to these crops canresult in residues of glyphosate and its primary metabol-ite AMPA in crops at harvest [13], as well as in proc-essed foods. For example, the UK-Food Standard Agencyresidue testing conducted in October 2012 found gly-phosate residues at or above 0.2 mg/kg in 27 out of 109samples of bread [14]. Testing by the US Department ofAgriculture in 2011 revealed residues of glyphosate in90.3% of 300 soybean samples, and AMPA in 95.7% ofsamples at concentrations of 1.9 ppm and 2.3 ppm re-spectively [13]. Other laboratories have reported muchhigher levels in soybeans in recent years (e.g., [15, 16]).Late season, harvest aid use of GBHs is an importantnew contributor to the increase in residue frequency andlevels in some grain-based food products. This is par-ticularly true in humid, temperate-climate countriessuch as the UK. Such applications are made within oneto two weeks of harvest to accelerate crop drying, thuspermitting harvest operations to begin sooner (a so-called“green burndown” use [17]). Such late season applicationstypically result in much higher residue levels in the finalharvested product compared to crops subjected to typicalapplication rates at earlier stages in the crop growth cycle.Pre-plant applications of GBHs, as well as post-harvest orfallow period applications, rarely result in detectable resi-dues in grain, oilseeds, or forage crops.Data from humans and laboratory animals indicatehazards associated with exposureClassical toxicity studies assess high doses and examine‘validated’ endpoints – those that have been shown to bereplicated easily in many laboratories [18]. Althoughthese endpoints are known to represent adverse out-comes, they typically do not correlate with human dis-eases, and are not considered comprehensive for alltoxicological endpoints [19, 20]. Regulatory long-term(2 year) toxicity studies in rodents revealed adverse ef-fects of glyphosate on the liver and kidney (reviewed in[3, 4]). These studies, however, typically do not addressa wide range of potential adverse effects triggered bydisruption in endocrine-system mediated developmen-tal or metabolic processes [3, 21–24]. Studies examin-ing low doses of GBHs, in the range of what are nowgenerally considered ‘safe’ for humans, show that thesecompounds can induce hepatorenal damage [25–28].Concerns about the carcinogenic properties of GBHshave increased after the World Health Organization’sInternational Agency for Research on Cancer (IARC)re-classified glyphosate as “probably carcinogenic tohumans” [1]. This decision was based on a small num-ber of epidemiological studies following occupationalexposures, rodent studies showing associations betweenglyphosate and renal tubule carcinoma, haemangiosar-coma, pancreatic islet cell adenoma, and/or skin tu-mors, and strong, diverse mechanistic data.Human epidemiological [23, 29–31] and domesticatedanimal studies [32, 33] suggest associations between expo-sures to GBHs and adverse health outcomes. For example,congenital malformations have been reported in youngpigs fed GBH residues-contaminated soybeans [32]. Thissuggests that GBHs may be at least a contributing factorto similar birth defects observed in human populationsliving in and near farming regions with substantial landarea planted to GBH-tolerant GE crop cultivars [23, 34].Collectively, studies from laboratory animals, humanpopulations, and domesticated animals suggest that currentlevels of exposure to GBHs can induce adverse health out-comes. Many of these effects would likely not be detectedin experiments adhering to traditional toxicology testguidelines promulgated by pesticide-regulatory authorities.Further complications: resistance and mixturesGenetically engineered crops with tolerance to glypho-sate are widely grown, and their use has led to increasedapplication of GBHs [10, 35]. This increased use hascontributed to widespread growth of glyphosate-resistantweeds [36, 37]. To combat the proliferation of glyphosate-resistant weeds, GE plant varieties have been approved forcommercial use that are resistant to multiple herbi-cides, including several older compounds that are pos-sibly more toxic and environmentally disruptive thanGBHs (for example, 2,4-D and dicamba).While farmers have struggled for 30 years with thesteady increase in the number of weeds resistant to oneor more herbicides, the geographic scope and severity ofthe weed control challenges posed, worldwide, by theMyers et al. Environmental Health  (2016) 15:19 Page 3 of 13emergence and spread of glyphosate-resistant weeds isunprecedented [37]. Moreover, the consequences trig-gered by the spread of glyphosate-resistant weeds, incontrast to the emergence in the past of other herbicide-resistant weeds, are unparalleled, and include the needfor major changes in tillage and cropping patterns, andlarge increases in farmer costs and the diversity and vol-ume of herbicides applied [10, 36, 38, 39].In addition to resistance, concerns have been raisedabout the toxicity of herbicide mixtures, because currentdata suggest that chemicals in combination can have ef-fects that are not predicted from tests of single com-pounds [40, 41]. GBHs themselves are chemical mixtures;in addition to the inclusion of glyphosate (the active in-gredient), these herbicides include adjuvants such assurfactants, which can make GBH-product formula-tions more toxic than glyphosate alone [42–44]. In lightof the increased numbers, levels and extent of herbicideuse elicited by weed resistance, it is reasonable to pre-dict that there will be a marked increase in the diversityof biological pathways affected, the number and dur-ation of high-exposure periods, and the magnitude ofpotential risks facing non-target organisms, includinghumans. Such impacts could be limited, or even largelyprevented, if there are substantial changes in weed-management systems and regulatory policy, includingenforceable limits on herbicide-use patterns known tocause relatively high and potentially unsafe residuelevels in food, water, and the air.Setting an acceptable intake level of GBHsDifferent countries have established a range of “accept-able” daily intake levels of glyphosate-herbicide expo-sures for humans, generally referred to in the U.S. as thechronic Reference Dose (cRfD), or in the E.U. as theAcceptable Daily Intake (ADI).The current U.S. Environmental Protection Agency(EPA) cRfD is 1.75 mg of glyphosate per kilogram bodyweight per day (mg/kg/day). In contrast, the current E.U.ADI is more than 5-fold lower at 0.3 mg/kg/day, a leveladopted in 2002. The data upon which these exposurethresholds are based were supplied by manufacturers dur-ing the registration process, are considered proprietary,and are typically not available for independent review.The German Federal Institute for Risk Assessment is thelead regulatory authority currently conducting an E.U.-widereassessment of GBHs. Their renewal assessment reportcalls for an increase of the E.U. ADI from 0.3 mg/kg/day to0.5 mg/kg/day [45]. However, from an analysis of their as-sessment, it is difficult to understand the basis on which theGerman regulators are making this recommendation, sincethey still rely on the same proprietary, industry-supplieddataset that led to setting a lower ADI (0.3 mg/kg/day) in2002. In contrast, an international team of independentscientists concluded that the current E.U. ADI is probablyat least three-fold too high, based on a transparent, fullydocumented review of the same dataset [3]1.In December 2009, the U.S. EPA’s re-registration reviewof glyphosate identified a number of issues of ongoing con-cern, as well as GBH data gaps [46]. In particular, it notedthat data relating to the effects of GBHs on the immuneand neurological systems were limited and announced thatfuture registrants would be required to conduct bothneurotoxicity and immunotoxicity studies. The U.S. EPA’supdated risk assessment and final re-registration decisionon GBHs is scheduled to be completed in 2015–2016.As noted above, most GBH use has occurred in thelast 10 years, while most studies considered by regula-tory agencies for the assessment of GBHs focused juston the active ingredient, and were conducted in the1970s through mid-1980s. Since the late 1980s, only afew studies relevant to identifying and quantifying hu-man health risks have been submitted to the U.S. EPAand incorporated in the agency’s GBH human-healthrisk assessment2.We believe that the ability to establishappropriate GBH exposure and use levels should be en-hanced and grounded in “up-to-date science” to supportrefined and accurate assessments of GBH health risksand to assure that regulators understand both the likelyand possible consequences of the decisions they make.Table 1 lists a few of the known environmental risksarising from use of GBHs.Table 1 Environmental RisksThis overview of possible adverse effects associated with rising GBH use is focused on mammalian health risks. There are also many environmentaland soil-ecosystem problems associated with heavy and repeated uses of GBHs affecting other organisms (for example, fish, butterflies, earth-worms, beneficial soil microorganisms) [47].These problems arise from the large volumes of GBHs applied across vast areas in many farming areas (for example, 80% or more of the harvestedcropland in many counties in the U.S., and provinces or political jurisdictions in other countries, are sprayed with GBHs).Glyphosate binds strongly to some soils, but not others. After repeated applications, it can accumulate and become a long-term source of soil andgroundwater contamination [48]. The main pathways of GBH degradation are known and the principal breakdown products (AMPA, formaldehyde)could be toxic to a variety of non-target organisms. Continued long-term use of GBHs could pose a threat to soil health and fertility [47, 49], withpossible adverse effects on crop productivity.Low levels (50 ppb) of glyphosate have been shown to have significant negative effects on the aquatic invertebrate Daphnia magna [50]. Whenmeasured against the U.S. EPA’s Maximum Contaminant Level of 700 ppb, or the Canadian short-term (27,000 ppb) and the long-term (800 ppb)freshwater aquatic standards [51], one quickly sees how the regulatory eco-toxicological risk levels set for glyphosate are orders of magnitude too high.Myers et al. Environmental Health  (2016) 15:19 Page 4 of 13Section IWith respect to glyphosate-based herbicides, we are cer-tain of the following:GBH Use, exposure, presence1. GBHs are currently the most heavily appliedherbicides in the world.Trends in the volume and intensity of GBH useshave been rising sharply since the mid-1990s, in stepwith global adoption of genetically engineered,glyphosate-tolerant crops [10, 52, 53]. Use of GBHsis likely to continue increasing if Roundup Readyglyphosate-tolerant maize, soybeans, cotton, canola,alfalfa and sugar beet are approved for planting inregions not now dominated by such cultivars.2. GBHs contaminate drinking water via rainwater,surface runoff and leaching into groundwater,thereby adding drinking water, bathing, andwashing water as possible routine exposurepathways [48, 54, 55].3. The half-life of glyphosate in water and soil islonger than previously recognized. In field studies,the half-life of glyphosate in soil ranged betweena few days to several months, or even a year,depending on soil composition [56]. Studies haveshown that soil sorption and degradation ofglyphosate exhibit great variation depending onsoil physical, chemical, and biological properties.The risk of long-term, incremental buildup ofglyphosate contamination in soil, surface water,and groundwater is therefore driven by highlysite-specific factors, and as a result, is difficult topredict and costly to monitor.4. Residues of glyphosate and its principlemetabolite AMPA are present in nearly allsoybeans harvested from fields planted withRoundup Ready soybeans [13, 16]. The intensityof glyphosate use has trended upward on mostGE Roundup Ready crops. In addition,applications are now being made later in the cropcycle on GE crops. In addition, wheat, barley andother grain, and some vegetable crops aresprayed very late in the crop season to acceleratecrop death, drying, and harvest operations. Forthese reasons, average residue levels on and insome harvested grains, oilseeds, and certain othercrops are substantially higher than they were adecade ago and, as a result, human dietaryexposures are rising.5. The emergence and spread of glyphosate-resistantweeds requires farmers to spray additionalherbicides, including older herbicides posingdocumented environmental and public healthrisks and/or newer, more costly herbicides toavoid crop yield losses and slow the spread ofthese weeds [37]. This is particularly problematicin grain and row-crop fields planted for severalyears with Roundup Ready GE crops. In the U.S.,contending with resistant weeds has already increasedtotal herbicide use per acre by approximately 70% in soybeans, and 50 % in the case of cottoncompared to herbicide rates on these crops inthe mid-1990s when GE varieties were firstintroduced [10].Section IIWe estimate with confidence that:1. Glyphosate provokes oxidative damage in rat liverand kidneys by disrupting mitochondrial metabolism[57–59] at exposure levels currently considered safeand acceptable by regulatory agencies [4, 25, 26].Therefore, the ADI governing exposures to GBHs isoverestimated. Adverse effects impacting otherendpoints are less certain, but still worrisome andindicative of the need for more in-depth research(see following sections).2. Residues from GBHs may pose higher risks tothe kidneys and liver. Metabolic studies in avariety of laboratory and farm animal speciesshow that levels of glyphosate and AMPA inkidney and liver tissues are 10- to 100-fold (ormore) higher than the levels found in fat, muscle(meat) and most other tissues3. Increases in thefrequency of serious, chronic kidney disease havebeen observed among male agricultural workers insome regions in which there is a combination ofheavy GBH use and ‘hard’ water [60, 61]. Thesepossible adverse effects of GBH exposure on kidneyand liver warrant a focused, international researcheffort.3. There are profound gaps in estimates of worldwidehuman GBH exposure. Glyphosate and AMPA arenot monitored in the human population in theUnited States, despite the 100-fold increase in use ofGBHs over recent decades. In circumstances wherethere is substantial uncertainty in a pesticide’s dietaryrisk, the EPA is presumptively required by the U.S.Food Quality Protection Act (FQPA) of 1996 toimpose an added safety factor of up to 10-fold inthe setting of glyphosate’s cRfD. Such uncertaintycan arise from gaps in the scope and quality of apesticide’s toxicology dataset, or uncertainty inexposure assessments. Considering the uncertaintiesregarding both GBH safety and exposure, theEPA should impose a 10-fold safety factor onglyphosate, which would reduce the EPA chronicMyers et al. Environmental Health  (2016) 15:19 Page 5 of 13Population Adjusted Dose (cPAD) to 0.175 mg/kgbw/day. [Note: the U.S. EPA adopted the newterm cPAD to designate a chronic ReferenceDose for a pesticide that had been lowered bythe Agency as a result of the application of anadded, FQPA-mandated safety factor. Virtually allFQPA safety factors have reduced chronicReference Doses by 3-fold or 10-fold].4. Nevertheless, imposing a 10-fold decrease inglyphosate’s chronic Reference Dose, as seeminglycalled for in current U.S. law, should only beviewed as an interim step in the reassessment ofglyphosate toxicity and risk, and re-adjustment ofglyphosate uses and tolerances in food. Consider-able work on glyphosate and GBH toxicity, mech-anisms of action, and exposure levels must becompleted before the U.S. EPA can credibly con-clude that GBH uses and exposures are consistentwith the FQPA’s basic safety standard, namely thatthere is a “reasonable certainty of no harm” fromongoing, chronic exposures to GBHs across theAmerican population.Section IIICurrent models and data from the biological sciencespredict that:1. Glyphosate and GBHs disrupt endocrine-signalingsystems in vitro, including multiple steroidhormones, which play vital roles in the biology ofvertebrates [21, 22, 24, 62]. Rat maternal exposure toa sublethal dose of a GBH resulted in male offspringreproductive development impairment [21]. As anendocrine-disrupting chemical (EDC), GBH/glyphosatecan alter the functioning of hormonal systemsand gene expression patterns at various dosagelevels. Such effects will sometimes occur at low,and likely environmentally-relevant exposures.Contemporary endocrine science hasdemonstrated that dose–response relationshipswill sometimes deviate from a linear increase inthe frequency and severity of impacts expected asdose levels rise [19, 63].2. The timing, nature, and severity of endocrine systemimpacts will vary depending on the levels and timingof GBH exposures, the tissues exposed, the age andhealth status of exposed organisms, and other bioticor abiotic stressors impacting the developmentalstage and/or physiology of the exposed organism.Exposures can trigger a cascade of biological effectsthat may culminate many years later in chronicdegenerative diseases or other health problems.Exposures leading to serious complications later inlife might occur over just a few days to a month inshort-lived animals, and over a few days to severalmonths in humans.3. The study used by the EPA to establish the currentglyphosate cRfD used gavage as a system ofdelivery, as recommended by OECD guidelines forprenatal developmental toxicity studies, which in alllikelihood underestimates both exposure andtoxicity [64]. This conclusion is derived from twoconsiderations: (i) gavage bypasses sublingualexposure, and thus overestimates the portion of thechemical subjected to first pass metabolism in theliver, and (ii) gavage stresses the experimentalsubjects inducing endocrine effects that can lead toartefacts including, crucially, a reduction in thedifference between control and experimentalgroups.4. The incidence of non-Hodgkin’s Lymphoma (NHL)has nearly doubled in the U.S. between 1975 and2006 [65]. GBHs are implicated in heightened risk ofdeveloping NHL among human populations exposedto glyphosate occupationally, or by virtue ofresidence in an area routinely treated with herbicides[66]. A causal link between GBH exposures andNHL may exist, but has not been rigorously studiedin human populations.5. Uncertainty persists over the doses required to causemost of the above endocrine-system-mediatedeffects. Some published data indicate that doseswell within the range of current human exposuremay be sufficient [22, 25], whereas other studiesdemonstrating distinct, adverse impacts have exploredhigh doses and exposures that are unlikely to reflectany real world levels of ingestion. Additional in vivostudies are needed at environmentally relevant dosesto distinguish the combination of factors likely to giverise to endocrine-system-driven morbidity andmortality. Nevertheless, the epidemiological datadescribed above provides evidence of heightenedcancer risk in human populations at levels ofexposure actually experienced in humanpopulations.6. Glyphosate is a chelating agent with potential tosequester essential micronutrient metals such aszinc, cobalt and manganese [67, 68]. This propertyof GBHs can alter the availability of thesemicronutrients for crops, people, wildlife, pets, andlivestock. These micronutrient metals are enzymaticcofactors, so their loss has the potential tocontribute to a number of deleterious effects,especially on kidney and liver function [69].Section IVExisting data suggest, but do not empirically confirm, awide range of adverse outcomes:Myers et al. Environmental Health  (2016) 15:19 Page 6 of 131. Multiple studies on GBHs have reported effectsindicative of endocrine disruption [21–24]. Based onknowledge from studies of other endocrinedisruptors, the developing fetus, infants, andchildren are most at risk. Effects following GBHexposure may not be immediately apparent, becausesome adverse conditions caused by early-life exposureonly manifest in later stages of development and/or inadulthood. These include both acute diseases andchronic health problems. In addition, proving linksbetween chronic disease and exposures to GBHs ismade more difficult by the fact that people areroutinely exposed to complex mixtures ofglyphosate and other toxic chemicals.2. The action of glyphosate as an antibiotic mayalter the gastrointestinal microbiome invertebrates [33, 70–72], which could favor theproliferation of pathogenic microbes in humans,farm animals, pets and other exposed vertebrates.3. Increased incidence of severe birth defects inArgentina and Paraguay in areas where GE RoundupReady crops are widely grown may be linked to theability of GBHs to increase retinoic acid activityduring fetal development [23]4. Glyphosate-contaminated soybean feeds used in the porkindustry have also been associated with elevatedrates of gastrointestinal-health problems and birthdefects in young pigs [32]. Related impacts havebeen observed in poultry [33].4. Some developmental studies in rats undertaken atrelatively high levels of exposure suggest possibleGBH-induced neurotoxicity through multiplemechanisms [73]. Replication of these studies usingdoses relevant to human exposures should be ahigh priority. Further work on GBH-inducedneurotoxicity should be conducted to test whetherglyphosate can act as a disruptor of neurotransmitterfunction given its similarity in structure to glycine andglutamate5.5. GBHs may interfere with normal sexualdevelopment and reproduction in vertebrates.Experiments with zebrafish with dosing of GBH inthe upper range of environmentally-relevantcontamination levels, show morphological damageto ovaries [74].6. A recent report demonstrates that environmentallyrelevant concentrations of commercially availableGBHs alter the susceptibility of bacteria to sixclasses of antibiotics (for example, either raise orlower the minimum concentration needed to inhibitgrowth) [75]. Furthermore, GBHs can also inducemultiple antibiotic-resistance phenotypes in potentialhuman pathogens (E. coli and Salmonella entericaserovar typhimurium). Such phenotypes could bothundermine antibiotic therapy and significantlyincrease the possibility of mutations conferringmore permanent resistance traits. Since GBHs andantibiotics are widely used on farms, farm animalsmay be exposed to both, with a concomitantdecrease in antibiotic effectiveness and increase inthe diversity of newly resistant bacterial phenotypesthat might find their way into the human population.Risk assessors have not previously considered thefinding that herbicides might have sublethal adverseeffects on bacteria, but this should be considered infuture risk assessments.Section VUncertainties in current assessments persist because:1. A steadily growing portion of global GBH use isapplied in conjunction with multiple otherherbicides, insecticides, and fungicides. Herbicideand other pesticide active ingredient safety levels arecalculated for each active ingredient separately,despite the fact that tank mixes including two tofive, or even more active ingredients account for asignificant portion of the volume of pesticidesapplied. Regulators do not require further testing ofsuch mixtures, nor do they conduct any additionalrisk assessments designed to quantify possibleadditive or synergistic impacts among all herbicidesapplied, let alone the combination of all herbicides,insecticides, fungicides, and other pesticides appliedon any given field.2. The full list of chemicals in most commercial GBHsis protected as “confidential business information,”despite the universally accepted relevance of suchinformation to scientists hoping to conduct anaccurate risk assessment of these herbicideformulations. The distinction in regulatory reviewand decision processes between ‘active’ and ‘inert’ingredients has no toxicological justification, givenincreasing evidence that several so-called ‘inert’adjuvants are toxic in their own right [42].Moreover, in the case of GBHs, the adjuvants andsurfactants, which include ethoxylatedtallowamines, alkylpolyglycosides or petroleumdistillates in most commonly used commercialformulations, alters both the environmental fateand residue levels of glyphosate and AMPA inharvested foodstuffs and animal feeds. They do soby enhancing the adhesion of glyphosate to plantsurfaces, as well as facilitating the translocation ofapplied glyphosate from the surface of weed leavesinto sub-surface plant tissues, where it exerts itsherbicidal function and where rainfall can nolonger dissipate the glyphosate.Myers et al. Environmental Health  (2016) 15:19 Page 7 of 133. The vast majority of GBH-toxicology studies usedfor regulatory assessments lack a sufficient range ofdose levels to adequately assess adverse impacts thatmight be initiated by low, environmentally-relevantexposures6. Most toxicology studies examine only ahigh dose between the LD50 (the dose required to kill50 % of treated animals) and the maximum tolerateddose (a dose that has high toxicity but does not kill),and then typically two lower doses (allowing for theidentification of the Lowest Observed Adverse EffectLevel [LOAEL] and the No Observed Adverse EffectLevel [NOAEL]). Environmentally relevant doses arerarely examined [63]. A further complication arisesspecifically for endocrine disrupting chemicals: thereare theoretical and empirical findings concluding thatone cannot assume any no-impact exposure thresholdfor endocrine processes that are already underwaybecause of endogenous hormones [76].4. Residues of GBHs in plants are often present inconjunction with: (a) residues of systemic seedtreatments, especially neonicotinoid insecticides (forexample, clothianidin and thiamethoxam) and theiradjuvants (such as organosilicone surfactants), (b)residues of systemic insecticides and fungicidesapplied during the season, and (c) Bt endotoxins inthe case of GE, insect-protected Bt cultivars. Suchmixtures and combinations are never tested, andthus it is unknown how GBHs might interact withthese other agents.5. Large-scale and sophisticated biomonitoring studiesof the levels of glyphosate, its metabolites, and othercomponents of GBH mixtures in people have notbeen conducted anywhere in the world.Biomonitoring studies should include measurementof glyphosate residues, metabolites, and adjuvants inblood and urine to obtain meaningful insights intointernal contamination levels and thepharmacokinetics of GBHs within vertebrates7.6. Adequate surveys of GBH contamination in foodproducts have not as yet been conducted on alarge scale, even in the U.S. The first and onlyin-depth USDA testing of glyphosate and AMPAresidues in food targeted soybeans, and occurredonce in 2011 [13]. Of the three hundred samplestested, 90.3 % contained glyphosate at a meanlevel of 1.9 ppm, while 95.7 % contained AMPAat 2.3 ppm. In contrast, the next highest residuereported by USDA in soybeans was malathion,present at 0.026 ppm in just 3.7 % of samples.Thus, the mean levels of glyphosate and AMPAin soybeans were 73-fold and 83-fold higher thanmalathion, respectively. Residues in animalproducts, sugar beet, pre-harvest treated wheat,corn silage, and alfalfa hay and sprouts areunknown, but likely much higher, given the series ofrecent requests by Monsanto to increase tolerancelevels in a range of foods and animal feeds [12].7. There is no thorough, up-to-date governmentsurvey of glyphosate and AMPA residues in U.S.grown Roundup Ready GE soybeans, normanufactured foods that contain soy-basedingredients. However, changes in the rate of GBHapplications on many other crops, and/or thetiming of applications, have clearly increasedresidue levels in some circumstances. In particular,GBH uses late in the growing season as apre-harvest desiccant have become more common.Such applications speed up the drying of crops inthe field, so that harvest operations can becompleted before bad weather sets in. Suchharvest-aid uses are popular, especially in wet years,on wheat, canola, and other grain farms in somehumid, temperate climates, such as in the UK andnorthern-tier states in the US. While pre-harvestuses have only modestly increased the total volumeof GBHs applied, they have significantly increasedthe frequency and levels of residues in harvestedgrains, and have required GBH registrants to seeksignificant increases in tolerance levels. Theseresidues are also contributing to dietary exposuresvia a number of grain-based products, as clearlyevident in data from the U.K. Food StandardAgency’s residue testing program [14].8. Glyphosate residues are generally uncontrolled forin the standard rations fed to animals inlaboratory studies. GBH residues can often befound in common laboratory animal chows usedin feeding studies, thus potentially confoundingthe results of GBH toxicity tests [77]. Out of 262pesticide residues analyzed in 13 commonly usedrodent laboratory diets, glyphosate was the mostfrequently found pesticide, with concentrationsreaching 370 ppb [78]. Therefore, GBH residuesshould be accounted for in animal chows used incontrols for GBH studies.9. The limited data currently available on glyphosatepharmacokinetics in vertebrates are insufficient topredict transport and fate of glyphosate indifferent mammalian tissues, organs and fluids inthe body, and to determine whether or wherebioaccumulation occurs, although animalmetabolism studies point strongly to the kidneyand the liver.Section VIThe following recommendations are offered to furtherimprove our predictive capability regarding glyphosaterisks:Myers et al. Environmental Health  (2016) 15:19 Page 8 of 131. Scientists independent of the registrants shouldconduct regulatory tests of GBHs that includeglyphosate alone, as well as GBH-productformulations. [Note: in the latest glyphosateregulatory assessment process by the GermanFederal Institute for Risk Assessment, thedescription and assessment of studies was providedby the Glyphosate Task Force, a group of 25agrochemical companies that combined resources tojointly apply for renewal of registrations for thisherbicide within Europe. By way of contrast, inorder to avoid conflicts of interests, the GlyphosateTask Force was restricted to a role of observer to theevaluation of data by independent scientists at therecent WHO IARC evaluation of glyphosate’scarcinogenic potential].2. Epidemiological studies are needed to improveknowledge at the interface of GBH uses, exposures,and human-health outcomes.3. Biomonitoring studies examining referencepopulations like the U.S. CDC’s NHANES programshould examine human fluids for glyphosate and itsmetabolites.4. More comprehensive toxicity experiments areneeded including those using “two hit” studydesigns, which examine early life exposures to GBHsfollowed by later-life exposures to chemical or otherenvironmental stressors.5. Because GBHs are potential endocrine disruptors,future studies should incorporate testing principlesfrom endocrinology.6. Future studies of laboratory animals should usedesigns that examine the full lifespan of theexperimental animal, use multiple species andstrains, examine appropriate numbers of animals,and carefully avoid contaminating GBH and otherpesticides within control feeds and drinking water.7. GBHs should be prioritized by the U.S. NationalToxicology Program for safety investigations,including tests of glyphosate and commoncommercial formulations.Section VIIImplications1. The margin of safety between typical glyphosate andAMPA exposure levels and the maximum allowedhuman exposures has narrowed substantially in thelast decade. The margin may well have disappearedfor heavily exposed segments of the population insome countries, especially where glyphosate andAMPA are present in drinking water. In addition,farmworkers and rural residents may incur relativelyhigh dermal absorption and/or exposures via drinkingwater. We conclude that existing toxicological dataand risk assessments are not sufficient to infer thatGBHs, as currently used, are safe.2. GBH-product formulations are more potent, ortoxic, than glyphosate alone to a wide array ofnon-target organisms including mammals [42, 43],aquatic insects, and fish [44]. As a result, riskassessments of GBHs that are based on studiesquantifying the impacts of glyphosate aloneunderestimate both toxicity and exposure, and thusrisk. This all-too-common shortcoming hasrepeatedly led regulators to set inappropriately highexposure thresholds (cRfDs, ADIs).3. The toxicological data supporting current GBHregulatory risk assessments are out-of-date andinsufficient to judge the impacts of contemporaryglyphosate and AMPA exposure levels on thedeveloping mammalian fetus, the liver and kidneys,and reproductive outcomes in humans and a varietyof other animals [3, 25].4. Most toxicological studies using advanced, moderntools and experimental designs within moleculargenetics, reproductive, developmental,endocrinological, immunological and otherdisciplines have been undertaken in academic andresearch institute laboratories, and results have beenpublished in peer-reviewed journals. Regulators havenot incorporated, formally or indirectly, suchresearch into their risk assessments. Rather, they relyon unpublished, non-peer reviewed data generatedby the registrants. They have largely ignoredpublished research because it often uses standardsand procedures to assess quality that are differentfrom those codified in regulatory agency datarequirements, which largely focus on avoiding fraud[79]. Additionally, endocrine-disruption studyprotocols have not been codified by regulators8.5. While the German Federal Institute for RiskAssessment, rapporteur for the European FoodSafety Authority’s current reassessment ofglyphosate, claimed to have examined more than900 scientific studies published in peer-reviewedjournals, most of the studies were deemed of limitedvalue, and hence had little influence on the outcomeof their assessment. Studies were classified of ‘limitedvalue’ based on degree of adherence to traditional,toxicology protocols and ‘validated’ endpoints, ratherthan scientific rigor and relevance in understandingthe mechanisms leading to adverse health outcomes.Had the German Institute used scientific quality andrelevance in identifying useful studies, instead ofrelying on similarity to outdated methodologies and/or controversial evaluation criteria [80] (such as theKlimisch score), we are nearly certain that they wouldMyers et al. Environmental Health  (2016) 15:19 Page 9 of 13have concluded that published studies collectivelyprovide strong evidence in support of at least athree-fold reduction in the glyphosate E.U. ADIand consequently a 15-fold reduction in the U.S.cRfD [3, 21, 25, 26].ConclusionsGBH use has increased approximately 100-fold since thefirst decade of its use in the 1970s. It is now the world’smost heavily applied herbicide. Major increases in its useresulted from widespread adoption of Roundup Readycrops that were genetically engineered to be tolerant toglyphosate. Applications of GBHs have also expanded inaquatic, estuarine, rangeland, and forest habitats.Initial risk assessments of glyphosate assumed a lim-ited hazard to vertebrates because its stated herbicidalmechanism of action targeted a plant enzyme notpresent in vertebrates. In addition, because GBHs killnearly all actively growing plants, farmers had to applyGBHs early in the year, before crop germination orpost-harvest, and so it seemed unlikely that therewould be residues in harvested crops and the food sup-ply. However, these assumptions ignored the possibilitythat glyphosate and its metabolites might act via otherpathways, including those present in vertebrates, aswell as the profound consequences of major increasesin the area treated and volume applied, coupled withchanges in how and when GBHs are used by farmers(e.g., on GE, herbicide-tolerant crops, and as a pre-harvest desiccant to accelerate harvest).Evidence has accumulated over the past two decades,especially, that several vertebrate pathways are likelytargets of action, including hepatorenal damage, effectson nutrient balance through glyphosate chelating actionand endocrine disruption. Other early assumptionsabout glyphosate, for example that it is not persistentin the environment, have also been called into question,depending upon soil type. In addition, the predictionthat glyphosate would never be present widely in sur-face water, rainfall, or groundwater has also been shownto be inaccurate.Existing data, while not systematic, indicate GBHs andmetabolites are widely present in the global soybean sys-tem and that human exposures to GBHs are clearly ris-ing. Tolerable daily intakes for glyphosate in the U.S.and Germany are based upon outdated science.Taken together, these conclusions all indicate that afresh and independent examination of GBH toxicityshould be undertaken, and that this re-examination beaccompanied by systematic efforts by relevant agenciesto monitor GBH levels in people and in the food supply,none of which are occurring today. The U.S. NationalToxicology Program should prioritize a thorough toxico-logical assessment of the multiple pathways nowidentified as potentially vulnerable to GBHs. The urgencyof such work was reinforced in March 2015 when theIARC concluded glyphosate is a probable humancarcinogen.We are aware of current limits on, and demands for,public funding for research. In the absence of govern-ment funds to support essential GBH research, we rec-ommend that a system be put in place through whichmanufacturers of GBHs provide funds to the appropriateregulatory body as part of routine registration actionsand fees. Such funds should then be transferred to ap-propriate government research institutes, or to anagency experienced in the award of competitive grants.In either case, funds would be made available to inde-pendent scientists to conduct the appropriate long-term(minimum 2 years) safety studies in recognized animalmodel systems. A thorough and modern assessment ofGBH toxicity will encompass potential endocrine disrup-tion, impacts on the gut microbiome, carcinogenicity,and multigenerational effects looking at reproductivecapability and frequency of birth defects.Endnotes1The E.U. ADI was calculated based on observed kid-ney (hepatorenal) effects in rat chronic toxicity studies.The “No Observable Adverse Effect Level” (NOAEL)was 31 mg/kg/day, and the “Lowest Observable AdverseEffect Level” (LOAEL) occurred at a dose of 60 mg/kg/day (determined then to be the LOAEL). A standard100-fold safety factor was applied in converting the E.U.-set NOAEL to the ADI of 0.3 mg/kg/day. The new ADIrecommended by the German regulators of 0.5 mg/kg/day is based on teratogenic effects in rabbits. TheNOAEL was considered to be 50 mg/kg/day. Independ-ent scientists argue that the 2002 determination was notbased on the most sensitive species or dataset, as is re-quired by regulatory authorities. See ref 14. Antoniou M,Habib MEM, Howard CV, Jennings RC, Leifert C,Nodari RO, Robinson CJ, Fagan J: Teratogenic effects ofglyphosate-based herbicides: divergence of regulatory de-cisions from scientific evidence. J Environ Anal Toxicol2012, S4:006.2The EPA issued an updated registration review ofGBHs in 1993. Studies dating from the early 1970sthrough mid-1980s dominated the reference list accom-panying the chapter setting forth the EPA’s estimate ofGBH human health risks.3Table B.7.3-8 in the document “Renewal AssessmentReport, Glyphosate Residue Data” (Vol. 3, Annex B.7,Dec. 18, 2013, RMS: Germany, Co-RMS-Slovakia) pro-vides an overview of the levels of glyphosate and AMPAmeasured in the meat, milk, and eggs from several live-stock species, as well as in the fat, meat, kidney, andlivers of the animals. In most cases the levels reported inMyers et al. Environmental Health  (2016) 15:19 Page 10 of 13liver and kidney exceed those in other tissues by several-fold, and the levels in kidney exceed those in liver by 3-fold to over 10-fold.4Retinoic acid signaling plays a key role in guiding em-bryonic development, affecting the expression of mul-tiple genes in a variety of cell types. Altered retinoic acidactivity causes birth defects (see 58. Duester G: Retinoicacid synthesis and signaling during early organogenesis.Cell 2008, 134(6):921-931.5Glutamate is a common vertebrate neurotransmitterreleased by neurons into the synapse, and is importantfor learning and memory (for a review, see 59. Mel-drum BS: Glutamate as a neurotransmitter in the brain:review of physiology and pathology. J Nutr 2000, 130(4SSuppl):1007s-1015s. Glyphosate’s structural similarity toglutamate creates the potential for interfering with thiskey signaling process.6“Environmentally relevant” exposures to GBHs arethose that fall within the documented exposure levelsarising from the way GBHs are typically used.7Pharmacokinetic studies project and monitor thelevels of a chemical absorbed by an organism (via inges-tion, inhalation, dermal absorption, or some other routeof exposure), how the chemical is distributed throughoutthe body to specific tissues (measuring the concentra-tions in different organs and in the blood), how thechemical is metabolized (including which metabolitesare produced, and whether the presence of these metab-olites and their relative abundance is dependent on routeof exposure), and finally, how a compound is excreted(e.g., in feces or urine). Pharmacokinetic studies providea valuable link between estimates of exposure, toxicitystudies, and estimates of human risk.8The process of establishing testing protocols forendocrine-mediated impacts has been underway in theU.S. since 1997, in response to a mandate in the 1996Food Quality Protection Act to consider such effects inassuring a “reasonable certainty of no harm” for preg-nant women, infants, and children. Seventeen years later,the EPA remains years away from codifying a new bat-tery of tests capable of identifying the risk of low-dose,endocrine-disruption driven effects.Abbreviations2,4-D: 2,4-Dichlorophenoxyacetic acid; ADI: Acceptable daily intake;AMPA: Aminomethylphosphonic acid; Bt: Bacillus thuringiensis;cPAD: Chronic Population Adjusted Dose; cRfD: Chronic reference dose;EPSPS: 5-enolpyruvylshikimate-3-phosphate synthase; EU: European Union;FQPA: US food quality protection act of 1996; GBHs: Glyphosate-basedherbicides; IARC: International Agency for Research on Cancer;LOAEL: Lowest Observed Adverse Effect Level; NOAEL: No Observed AdverseEffect Level; US EPA: United States Environmental Protection Agency.Competing interestsJohn Peterson Myers received support from the Broad Reach Fund, theMarisla Foundation and the Wallace Genetic Foundation for this work.Michael Antoniou received support from the Sustainable Food Alliance,Breast Cancer UK, The Sheepdrove Trust (UK) and the Safe Food Institute(Australia). He is also serving as an expert witness on behalf of the State ofVermont (U.S.A.) in a case involving the labeling of food products containingingredients from GE organisms.Bruce Blumberg is a named inventor on several patents related to nuclearreceptor function and testing (US 5,861,274; 6,200,802; 6,815,168; 6,274,321;6,391,847; 6,756,491; 6,809,178; 6,984,773), some of which generate royaltyincome. He has received grant support from the U.S. National Institutes ofHealth, National Science Foundation, American Heart Association, State ofCalifornia, and the Swedish Environmental Agency FORMAS. He receivesoccasional research gifts from Advancing Green Chemistry and occasionaltravel awards from professional societies in the US and elsewhere. None ofthese constitutes an actual, or perceived conflict of interest.Contributions by Lynn Carroll and Theo Colborn were supported entirely bygrants to TEDX from the Winslow Foundation and the Wallace GeneticFoundation.Lorne Everett declares no conflicts of interest. He is principle of Lorne EverettAssociates.Michael Hansen declares no conflicts of interest.Philip Landrigan declares no conflicts of interest.Bruce Lanphear served as an expert witness in California for the plaintiffs in apublic nuisance case of childhood lead poisoning, a Proposition 65 case onbehalf of the California Attorney General’s Office, a case involving lead-contaminated water in a new housing development in Maryland, and Canadiantribunal on trade dispute about using lead-free galvanized wire in stuccolathing but he received no personal compensation for these services. He iscurrently representing the government of Peru as an expert witness in asuit involving Doe Run vs Peru, but he is receiving no personal compensation.Dr. Lanphear has served as a paid consultant on a US Environmental ProtectionAgency research study, NIH research awards and the California Department ofToxic Substance Control. Dr. Lanphear has received federal research awardsfrom the National Institute of Environmental Health, the US EnvironmentalProtection Agency, the Centers for Disease Control and the US Departmentof Housing and Urban Development. He is also the recipient of federal researchawards from the Canada Institutes of Health Research and Health Canada.Robin Mesnage declares no conflicts of interest. He has received noindependent funding but has been employed by others with funding fromthe Lea Nature, Malongo, JMG, Charles Léopold Mayer for the Progress ofHumankind, Nature Vivante and the Denis Guichard Foundations, from theInstitute Bio Forschung Austria, Breast Cancer UK, the Sustainable FoodAlliance and the Committee for Independent Research and Information onGenetic Engineering.Frederic S. vom Saal declares no conflicts of interest.Laura Vandenberg declares no conflicts of interest.Wade V. Welshons declares no conflicts of interest. He is supported by theUniversity of Missouri VMFC0018 on estrogen and xenoestrogen action andby the Jenifer Altman Foundation on potential endocrine disrupting activityby glyphosate.Charles Benbrook declares no conflicts of interest. He received support forwork on this paper in a grant to Washington State University from the CeresTrust. He is the principle of Benbrook Consulting Services. He is currently amember of the U.S. Department of Agriculture AC 21 AgriculturalBiotechnology Advisory Committee. He has served as an expert witness incases involving herbicide drift and damage, and the labeling of foodproducts containing genetically engineered ingredients.Authors’ contributionsJPM recruited team members and chaired over 30 conference calls of theauthors between August 2014 and May 2015. All authors contributed to thewriting and editing, with JPM and CMB playing the lead roles. CMB addeddetailed information about changes in GBH use over time. All authors readand approved the final manuscript.AcknowledgementsThe Broad Reach Fund supported the writing and editing effort.Author details1Environmental Health Sciences, Charlottesville, VA, and Adjunct Professor,Carnegie Mellon University, Pittsburg, PA, USA. 2Department of Medical andMolecular Genetics, Faculty of Life Sciences and Medicine, King’s CollegeLondon, London, UK. 3Department of Developmental and Cell Biology,University of California, Irvine, CA, USA. 4The Endocrine Disruption Exchange,Myers et al. Environmental Health  (2016) 15:19 Page 11 of 13Paonia, CO, USA. 5L. Everett & Associates, Santa Barbara, CA, USA.6Consumers Union, Yonkers, NY, USA. 7Department of Preventive Medicine,Icahn School of Medicine at Mount Sinai, New York, NY, USA. 8Child & FamilyResearch Institute, BC Children’s Hospital, University of British Columbia,Vancouver, BC, Canada. 9Department of Environmental Health Sciences,School of Public Health and Health Sciences, University of Massachusetts –Amherst, Amherst, MA, USA. 10Division of Biological Sciences, University ofMissouri, Columbia, MO, USA. 11Department of Biomedical Sciences,University of Missouri-Columbia, Columbia, MO, USA. 12Benbrook ConsultingServices, 90063 Troy Road, Enterprise, OR 97828, USA. 13Environmental HealthSciences, 421 Park St, Charlottesville, VA 22902, USA.Received: 8 June 2015 Accepted: 6 February 2016References1. Guyton KZ, Loomis D, Grosse Y, El Ghissassi F, Benbrahim-Tallaa L, Guha N,Scoccianti C, Mattock H, Straif K, International Agency for Research onCancer Monograph Working Group ILF. 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Assessing dose–response relationships forendocrine disrupting chemicals (EDCs): a focus on non-monotonicity.Environ Health. 2015;14:42.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Myers et al. Environmental Health  (2016) 15:19 Page 13 of 13

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