Spiroux

1 University of Caen, Institute of Biology and Network on Risks, Quality and Sustainable Environment (MRSH), Esplanade de la Paix, 14032 Caen Cedex, France; CRIIGEN, 81 rue de Monceau, 75008 Paris, France. 2 CRIIGEN, 81 rue de Monceau, 75008 Paris, France. 3 University of Caen, Institute of Biology and Network on Risks, Quality and Sustainable Environment (MRSH), Esplanade de la Paix, 14032 Caen Cedex, France; CRIIGEN, 81 rue de Monceau, 75008 Paris, France. Electronic address: gilles-eric.seralini@unicaen.fr.

Glyphosate-based herbicides (GlyBH), including Roundup, are the most widely used pesticides worldwide. Their uses have increased exponentially since their introduction on the market. Residue levels in food or water, as well as human exposures, are escalating.

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We have reviewed the toxic effects of GlyBH measured below regulatory limits by evaluating the published literature and regulatory reports. We reveal a coherent body of evidence indicating that GlyBH could be toxic below the regulatory lowest observed adverse effect level for chronic toxic effects. It includes teratogenic, tumorigenic and hepatorenal effects.

They could be explained by endocrine disruption and oxidative stress, causing metabolic alterations, depending on dose and exposure time. Some effects were detected in the range of the recommended acceptable daily intake. Toxic effects of commercial formulations can also be explained by GlyBH adjuvants, which have their own toxicity, but also enhance glyphosate toxicity. These challenge the assumption of safety of GlyBH at the levels at which they contaminate food and the environment, albeit these levels may fall below regulatory thresholds. Neurodevelopmental, reproductive, and transgenerational effects of GlyBH must be revisited, since a growing body of knowledge suggests the predominance of endocrine disrupting mechanisms caused by environmentally relevant levels of exposure.Copyright © 2015 Elsevier Ltd. All rights reserved.

And. Gene Expression and Therapy Group, Faculty of Life Sciences and Medicine, Department of Medical and Molecular Genetics, King’s College London, Guy’s Hospital, London, United KingdomThe safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate’s reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis.

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We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect.

This misrepresentation of glyphosate’s toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations. It doesn’t matter how beautiful your theory is, it doesn’t matter how smart you are. If it doesn’t agree with experiment, it’s wrong. Feynman (Nobel Laureate, Physics, 1965) Glyphosate: The Controversy Over its SafetyGlyphosate ( N-phosphonomethyl glycine) is a small molecule (Figure ), which acts as an herbicide primarily by inhibiting the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), a key component of the shikimate pathway. Inhibition of the shikimate pathway blocks aromatic amino acid biosynthesis in plants, resulting in their death.

Glyphosate was patented as an herbicide in 1971 (US Patent No. Upon its introduction as an herbicide commercially in 1974, glyphosate quickly became the leading pesticide in the global agrochemical market. Glyphosate sales and use has increased exponentially since 1996 after the introduction of novel glyphosate-tolerant “Roundup-Ready” crop varieties (namely, maize, soybean, canola, cotton, sugar beet, and alfalfa), which are genetically engineered to be sprayed with Roundup without dying. The ubiquity of glyphosate in food, water, and air means that it is ingested on a frequent basis and regularly found in human urine at levels around 1–10 µg/L. The effects of glyphosate are well characterized at concentrations and doses causing acute toxicity, with outcomes increasing over time and in a dose-dependent manner.

Toxic effects on rat liver, measured after the administration of 60 mg/kg body weight/day of glyphosate over 2 years, formed the basis for calculating the acceptable daily intake (0.3 mg/kg bw/day) within the European Union for the period 2002–2017. However, data regarding health risks arising from ingestion of glyphosate alone at lower than the regulatory permitted daily intake, and which is relevant for human environmental levels of exposure, are far more limited and the subject of much debate.As with any controversial topic, conclusions are not only driven by facts but can also be influenced by commercial or ideological vested interests. Several reviews have been published by individuals who are consultants of companies commercializing glyphosate-based herbicides (–) to facilitate the process of glyphosate’s reapproval by regulatory agencies.

These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by independent scientists based on academia report toxic effects below regulatory limits , as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures (, ). Other authors have published reviews proposing that long-term exposure to glyphosate is responsible for many chronic diseases (cancers, neuropathies, infections, osteoporosis, etc.) (–).These diverse points of view on glyphosate toxicity has led to extreme discrepancies in the scientific community, has given rise to confusion, and thus deserves clarification. Limitations and recommendations for improvement in the regulatory assessment of the risks to humans from exposure to glyphosate-based herbicides have previously been extensively discussed (, ) and will not be detailed here.

The aim of this review is to critically evaluate the scientific evidence presented in a series of commentaries used to conclude on the role of glyphosate in the etiology of chronic diseases (–).The five commentaries by Samsel and Seneff propose a link between exposures to environmental levels of glyphosate and the development of a wide range of chronic diseases (–). In each commentary, these authors largely construct their arguments on deductive reasoning based on a logistic structure called syllogism, which is formed when two or more propositions are used in order to generate a conclusion.

Although syllogisms can help in deductive reasoning, to ensure that they are used in science in a constructive rather than a misleading way, it is necessary to ensure that the two propositions that lead to the conclusion are firmly evidence-based. We therefore evaluated the Samsel and Seneff commentaries to see whether this was indeed the case. Can Glyphosate Inhibition of Cytochrome P450 Enzymes and Aromatic Amino Acid Biosynthesis a Cause Chronic Illness?Their first commentary attempts to make a link between glyphosate ingestion and “most of the diseases and conditions associated with a Western diet” by suppression of the activity of the cytochrome P450 class of enzymes (CYP450) and amino acid biosynthesis by the gut microbiome.

The claim that glyphosate inhibits the detoxifying CYP450 enzyme system is based on inferences from studies performed on plants or with other pesticides. However, even if some studies do show inhibition of CYP450 at high levels corresponding to agricultural use concentrations (typically 10 g/L of glyphosate), they are not relevant in terms of environmental exposures to which humans are typically exposed (approximately 0.1–1 μg/kg/day). In addition, the authors fail to acknowledge the studies performed in mammals with environmentally relevant levels of Roundup , as well as studies on human cell cultures, which actually show an increase in CYP450 activity.Some studies are misrepresented and misquoted in the commentary.

For example, the authors refer to a study reporting that the liver of male and female rats exposed to Roundup in their drinking water at glyphosate equivalent levels allowed for human consumption in the US (0.7 mg/L), showed a reduction in CYP450 enzyme levels. Samsel and Seneff conclude that this reduction in CYP450 is solely due to glyphosate ignoring the fact that Roundup, which contains a large spectrum of coformulant adjuvants was administered to the animals and not glyphosate alone. It is established that coformulant adjuvants are toxic in their own right resulting in commercial pesticide formulations being more toxic than the stated active ingredient alone (, ). Thus, the coformulants may have been responsible either alone or in combination with the glyphosate in the Roundup formulation tested for the observed decrease in rat liver CYP450 levels. In addition, the data presented by Larsen and colleagues clearly show that although the global CYP450 content decreased, the activities of the CYP450 enzyme complex in female animals increased. Overall, a review of the literature shows that glyphosate and Roundup are likely to increase the activity of CYP450, disproving the conclusions of this first commentary.Samsel and Seneff also postulate that glyphosate disrupts the biosynthesis of aromatic amino acids by gut bacteria, based on a study showing a decrease in amino acid levels in a carrot cell line exposed to glyphosate.

Although it can be hypothesized that glyphosate may disturb the gut microbiome because some bacteria possess the EPSPS enzyme and shikimate pathway, and thus may indirectly affect aromatic amino acid biosynthesis, this has never been studied in a controlled laboratory animal experiment. Indeed, the patenting of glyphosate as an antibiotic to be used against a wide spectrum of microorganisms was based solely on effects in protozoa (not bacteria) and its effectiveness was dependent on the addition of di-carboxylic acids (US Patent No. At this stage, it is currently not clear whether glyphosate has an effect on the mammalian gut microbiome, especially at environmentally relevant levels of exposure. Nonetheless, some studies have shown that glyphosate and glyphosate-based herbicides such as Roundup can selectively affect bacterial populations in vitro while others have reported no adverse effects.

Given these discrepancies additional research is clearly needed to ascertain whether glyphosate-based herbicides at environmentally relevant levels of ingestion can result in disturbances in the gut microbiome of human and animal populations with negative health implications. Glyphosate Linked with Rise in Non-Celiac Gluten Sensitivity (NCGS)?The hypothesis of glyphosate-induced gut microbiome disturbances has led Samsel and Seneff in a second commentary to propose that glyphosate is the most important causal factor in the epidemic of NCGS disease. Their arguments are based on the following syllogism.

Since glyphosate could have effects on the gut microbiome and since NCGS disease is associated with imbalances in gut bacterial populations, glyphosate could fully explain the etiology of this condition. This syllogism is further extended by these authors by adding that NCGS disease patients have an increased risk of developing non-Hodgkin’s lymphoma and reproductive problems such as infertility, miscarriages, and birth defects, and thus glyphosate could also explain the rise in these latter pathologies.

Although there have been a number of studies showing an association between occupational glyphosate-based herbicide exposure and non-Hodgkin’s lymphoma and reproductive problems including birth defects , a link between typical levels of human exposure and these conditions has not been demonstrated experimentally. It is true that rates of conditions of the gastrointestinal tract such as inflammatory bowel disease have dramatically increased with the adoption of Westernized diets (consumption of processed foods, high in animal protein, processed sugars, starches, and fats). Exposure to increased levels of toxic chemical pollutants could be a crucial factor causing gut microbiome alterations and subsequent gastrointestinal disorders. However, a causative link between glyphosate and gut microbiome-associated intestinal disorders remains hypothetical but nonetheless an important area to be investigated.

Is Glyphosate Chelation of Manganese a Cause of Chronic Illnesses?In their third commentary, Samsel and Seneff create multiple syllogisms based on the fact that glyphosate can chelate manganese (Mn). At face value, there is merit in this supposition, since glyphosate was originally patented and used as a divalent cation metal chelator (US Patent No. These authors propose that the dysregulation of Mn homeostasis by glyphosate chelation could cause osteoporosis and osteomalacia (because bone mineralization depends on Mn), seizures (associated with reduced serum Mn), and prion diseases (since the prion protein, PrP, can misfold following binding to Mn instead of Cu). They also claim that large-scale environmental damage, such as the collapse of coral reefs, may in fact be due to glyphosate because coral mucus contains sulfated glycoproteins similar to chondroitin sulfate, whose synthesis is dependent on Mn.

However, the conclusions from this commentary are speculative since the effects of glyphosate on metal micronutrient homeostasis have never been characterized. Samsel and Seneff propose that glyphosate chelation of Mn can promote binding of this nutrient metal to PrP, causing it to misfold, and rendering it capable of catalyzing metal-free aggregation of this protein , which in turn could lead to prion disease. However, the sequestration of Mn by glyphosate would effectively make it unavailable to participate in interactions with other substances including proteins, making it unable to bind in place of Cu to PrP to promote misfolding and prion disease as suggested. Indeed, based on the arguments presented, chelation of Mn by glyphosate would be protective against, rather than a causative agent of, prion disease as this would prevent this divalent cation from binding to PrP.Out of the 328 references quoted in these authors’ third commentary , which are used to support their proposal of a link between Mn chelation by glyphosate and chronic diseases, only one study reports the effects of glyphosate on Mn levels in animals.

This investigation looked at a possible connection between urinary concentrations of glyphosate and Mn, and health indicators in Danish dairy cows. The results revealed a correlation between markers indicative of a disturbance in kidney function and glyphosate urinary concentration; i.e., the higher the levels of glyphosate found in the urine, the greater the indicators of kidney dysfunction. However, although Mn levels were abnormally low, they were not correlated with urinary glyphosate levels.

Although no doubt interesting additional studies are required to clarify the mechanism of the observed low levels of Mn in these farm animals. Thus, this study cannot be used to conclude on an effect of glyphosate on Mn homeostasis. The conclusions of the third commentary by Samsel and Seneff are thus unsupported by evidence. Is Glyphosate Responsible for the Steep Rise in Certain Cancers?The fourth commentary by Samsel and Seneff discusses the question of the carcinogenic potential of glyphosate. Conclusions are based on correlations between time trends in various cancers and glyphosate-based herbicide application on corn and soy crops. The reason given is that it appears that increasing cancer rates reported by the US Centers for Disease Control and Prevention from 1990 and 2010 parallel the dramatic increase in the volume of glyphosate-based herbicide application on these crops due to introduction of varieties in 1996 that are genetically engineered to tolerate being sprayed with this pesticide.

Although it is surprising to see that the trends in increased glyphosate-based herbicide use and increasing incidence of certain cancers closely overlap, conclusions on a causative link between the two ignores two fundamental facts. First, the vast increase in the use of glyphosate-based herbicides due to expansion in the cultivation of glyphosate-tolerant genetically engineered crops did not become a substantial proportion of US agriculture until the turn of the century, with 66% of the total volume of glyphosate applied in the US from 1974 to 2014 taking place between 2004 and 2014. Thus, significant increases in exposure of human populations to glyphosate have also only occurred since the year 2001.

Second, it is well established that there is always a delay or lag period between exposure to a carcinogen and formation and detection of a cancer, with this delay varying depending on the type of cancer. Thus, the fact that increases in glyphosate-based herbicide use overlap with, for example, an increase in breast cancer incidence is more indicative of an absence of a connection rather than a link between the two phenomena.

Thus, the increase in the use of glyphosate, and thus exposure to this compound, and the etiology of cancer are both out of step with the proposed link of this herbicide with cancer causation. In addition, cancer can be caused by a myriad of factors, some known and most unknown. Thus, statistical correlations of cancer incidence with exposure to a specific agent is insufficient to establish a causal link.The known biology of cancer suggests that we look further back in history to identify the causative factors that have led to the steep increase in this class of diseases starting in the mid-1990s.This fourth commentary also discusses the World Health Organization’s International Agency for Research on Cancer (IARC) classification of glyphosate as a probable (Group 2A) human carcinogen. However, this IARC categorization of glyphosate has no bearing on, and thus cannot be used to support, the principal message of this commentary, which is that the increased incidence of some cancers has paralleled the escalation in use of glyphosate-based herbicides since the mid-1990s and thus suggests a causative link. The IARC assessment and scoring of glyphosate as a Group 2A carcinogen is based on sufficient evidence of carcinogenicity in animals , limited evidence of carcinogenicity in humans (increased rates of non-Hodgkin lymphoma in farmers) , and strong mechanistic evidence (genotoxicity and oxidative stress).

Can Glyphosate Substitute for Glycine in Polypeptide Chains?In their fifth and latest commentary, Samsel and Seneff present what is arguably their most radical hypothesis regarding mechanisms of glyphosate toxicity. The core message of this publication is that glyphosate, being a derivative of glycine, can substitute for the native amino acid in proteins. Based on this supposition, it is postulated that such mis-incorporation of glyphosate in place of glycine can lead to polypeptide chain misfolding and aberrant cellular biochemistry that could lead to disease.

By this mechanism, the authors argue a link between glyphosate exposure and an extremely large spectrum of disease conditions, including diabetes, obesity, asthma, chronic obstructive pulmonary disease, pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, prion diseases, lupus, mitochondrial disease, non-Hodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease, and kidney failure. However, a number of the conceptual and experimental tenets used by Samsel and Seneff to assert that glyphosate can substitute for glycine in proteins are flawed.First, Samsel and Seneff argue that since glyphosate can potentially form N-substituted glycine polymers known as peptoids , then it can also replace glycine in regular polypeptides. However, as peptoids are laboratory creations that do not exist naturally in living organisms, it is not valid to extrapolate from these laboratory-manufactured entities to suggest that glyphosate can substitute for glycine in naturally occurring polypeptides, which are biosynthetically and structurally distinct from peptoids. In this context, it is perhaps also noteworthy that to the best of our knowledge, there are no reports of glyphosate peptoids having been generated.Second, Samsel and Seneff quote in support of their arguments results from studies conducted by scientists at DuPont, a company based in the US.

The references provided numbers 34 and 35 in Samsel and Seneff are company reports dating back to 2007, which have not been published in the peer-reviewed scientific literature and thus are unavailable for scrutiny to verify the conclusions drawn from these investigations. Nevertheless, Samsel and Seneff make the following arguments, which they claim provide strong evidence of glyphosate’s incorporation into proteins in place of glycine. First, they state that only 42% of the radioactively labeled 14C-glyphosate administered to goats was extractable from muscle from these animals and that treatment with pepsin and an additional (undisclosed) protease did not release any additional 14C-glyphosate from this tissue. In their view, this suggests that the 14C-glyphosate had been incorporated into proteins and thus was non-extractable by the methods used. In addition, they state that to more fully release 14C-glyphosate from the liver, kidney, and omental fat of goats or the eggs of chickens fed with this substance, required treatment with pepsin, which again in their view suggests that the glyphosate had been “incorporated” into proteins in place of glycine.