Viewpoint: Here’s what’s wrong with study suggesting glyphosate damages our gut health

Can glyphosate impact gut health? The Guardian reports on a team of scientists who claim to have demonstrated that it can.

One of the report’s authors, Daniele Mandrioli, at the Ramazzini Institute in Bologna, Italy, said significant and potentially detrimental effects from glyphosate had been detected in the gut bacteria of rat pups born to mothers, who appeared to have been unaffected themselves.

“It shouldn’t be happening and it is quite remarkable that it is,” Mandrioli said. “Disruption of the microbiome has been associated with a number of negative health outcomes, such as obsesity, diabetes and immunological problems.”

Beyond that, the reporting on the study is thin to non-existent. Instead, the article mostly consists of other out of context, misleading, and incorrect factoids about potentially unknown health effects related to glyphosate. It’s standard issue Guardian reportage on glyphosate, right down to the links to everything other than the actual paper they were reporting on (always a bad sign), which could be found with a few minutes of sleuthing [PDF].

A reading of the paper finds far less dramatic results and lots of problems, which we’ll get to. Here’s one thing the Guardian reporting left out, that seems worth mentioning:

No unexpected clinical signs or symptoms were observed in the experimental animals during the in vivo phase. In particular, no sign of changes in maternal behavior during lactation (nesting and nursing) were observed during the experiment. There was no clinical evidence of alterations in activity or behavior in pups.

glyphosate 5 16 18The basic story here is that they take a plausible sounding hypothesis – or at least plausible sounding to non-scientists – and conduct a statistical fishing trip through weak study design which is certain to produce “a result” which can be used as clickbait for unskilled health reporters and as agitprop by anti-biotech and anti-glyphosate activists. In this case, rather than the typical statistical fishing trip, instead, they mischaracterized and over-hyped an observation that is going to escape the notice of many health reporters.

The Ramazzini Institute has a reputation for being able to produce results that match their priors but not anyone else’s research. From Forbes contributor Trevor Butterworth:

“The problem hanging over the Splenda finding is that which hangs over the Ramazzini Institute in general: Quality control. No matter what substance the Institute tests for cancer, the results always seem to be positive, whereas other laboratories testing the same substances repeatedly fail to come up with the same findings.”

Dr. Landrigan isn’t known for his rigor of late either. Also worth noting that the Ramazzini Institute is flogging this paper prior to publication, rarely an indicator of well executed science. More often an indicator of agenda driven pseudoscience.

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The shikimate hypothesis

But is the hypothesis actually credible? Actually, not so much.

One of the reasons that glyphosate is considered to be relatively safe for humans and other mammals is that it targets a metabolic pathway in plants that mammals don’t have. The mode of action, the reason it is devastatingly toxic to plants is irrelevant to mammals. If it were toxic for mammals, it would be for a different reason than why it kills plants.

However, a new line of inquiry has popped up, that seems reasonable at first glance. That metabolic pathway – the shikimate pathway which allows plants to synthesize the aromatic amino acids phenylalanine, tyrosine and tryptophan – is also present in bacteria, including the bacteria that make up the gut flora, the microbiome that is crucial to our digestion, metabolism and other aspects of health. If residues from Roundup and other glyphosate based herbicides (GBH) are making their way into our digestive system, maybe they are inhibiting the shikimate pathway in our gut bacteria. This is what the paper aimed to test.

A number of studies have suggested that GBHs could act as antibiotics in the mammalian gut microbiome. Recent studies have raised concerns about the health effects of glyphosate on gut microbiota of farm animal when fed feed containing residues of glyphosate.

… exploring the effects of GBHs on the microbiota from early-life until adulthood in different windows of susceptibility, may give a more accurate portrayal of the microbial conditions that are involved in pathogenesis.

Possible alterations of the mammalian gut microbiota and its metabolites by environmental concentrations of GBHs in early development, starting from in utero, have never been explored in a controlled laboratory animal study. The present pilot study examines whether exposure to GBHs at doses of glyphosate considered to be “safe”, the US ADI of 1.75 mg/kg bw/day, defined as the chronic Reference Dose (cRfD) determined by the US EPA, affect the composition and diversity of the gut microbiome at early developmental stages in Sprague-Dawley rats.

Here’s the thing though, the shikimate pathway allows for the synthesis of aromatic amino acids, the digestive systems of humans – and rats – are chock full of aromatic amino acids. Gut bacteria have little to no need of producing their own. In fact, the shikimate hypothesis was given a much more robust workout in a paper published earlier this year. In that experiment, rats were fed doses of glyphosate or the commercial formulation Glyfonova®450 PLUS up to fifty times the established European Acceptable Daily Intake (ADI = 0.5 mg/kg body weight). They observed very small, short term effects of those very high doses suggesting that “sufficient intestinal levels of aromatic amino acids provided by the diet alleviates the need for bacterial synthesis of aromatic amino acids and thus prevents an antimicrobial effect of glyphosate in vivo.” (More here)

bacteria glyphosate

If you’d like to stop reading at this point, I wouldn’t blame you. For those soldiering on, we’ll look at some of the problems with the paper regardless of the fact that it wasn’t testing a credible hypothesis.

The EPA’s Acceptable Daily Intake is not the same as real world exposure levels

In the paper, they refer to the need to look at potential effects of GBH at “environmentally relevant doses”, but then end up testing the maximum levels considered to be safe. Whether the maximum exposure levels considered safe by the EPA are actually safe is a valid question to answer, but it’s not the same as testing environmentally relevant doses.

Related article:  Video: In search of the mystery glyphosate pathogen with Kevin Folta

What are environmentally relevant doses?

Alison Bernstein, a Michigan State University neuroscientist studying the role in Parkinson’s disease of epigenetics and environmental exposures, including pesticides, writes:

If we look at the Farm Family Exposure Study data summary (part of the Agricultural Health Study), 60% of pesticide applicators in the study had detectable levels of glyphosate in their urine and the average urine level for was 3.2 parts per billion (ppb). Average urine levels for spouses and children of applicators was less than 1 part per billion with only 4% and 12%, respectively, of each group having detectable exposures.

Actual exposure levels were estimated from these urine levels in this peer reviewed paper. The average exposure of 3.2 ppb for applicators corresponds to a dose of 0.1% of the RfD. Even the highest urine level of 223 ppb reported in the Farm Family Exposure Study corresponds to be only 4% of the RfD. This is equivalent to 0.004 mg/kg/day rather than the RfD of 0.1 mg/kg/day for the most highly exposed individual who didn’t take appropriate safety precautions.

Other reports, such as this one, have measured urine levels in people whose only exposures are dietary, in an effort to gauge dietary exposure levels in non-pesticide applicators. The average urine levels in this study were 0.2 ppb, with a maximum level of 1.82 ppb. Despite methodological concerns and the fact that this report has not been published in a peer-reviewed scientific journal, the levels can be informative. Using the highest level detected, the estimated dietary exposure is only 0.1% of the EFSA RfD (equivalent to 0.5% of the EPA RfD).

Using even the highest estimates of exposures, pesticide applicators are exposed to levels of glyphosate that are a very small percentage of the safe limits. Consumers are exposed to much lower levels. Measures across other studies of agriculture and dietary exposures were consistent with these results.

So, environmentally relevant doses would be 1/1000th of the ADI rather than the full ADI.

Other issues

At this point, it’s probably a bit petty to nitpick the study design after demolishing the entire premise, but there are a few issues worth noting, because they are emblematic of activist research.

The paper is poorly written. Some important things were hard, if not impossible, to figure out. Like what size are the experimental groups? There were 108 pups at post natal days 31 and 57 and 60 at day 125, the end point. As best I can tell, they were divided into six groups. But we are never told the sizes of the groups. If “N= …” appears anywhere in the paper, I can’t find it. Any way you slice it, 108 divided by 6 gives us an average group size of 18 with a 2 to 1 ratio of experimental subjects to controls, this is not an experiment with a lot of statistical power.

Asked about this paper, Alison Bernstein had this to say:

They did a metagenomic analysis of the gut microbiome using standard techniques and calculated diversity indices – also standard. Then they compared those diversity measures. This is not a case of them testing 100s of things and picking only the one. They tested things, essentially found a small change that seems to self-correct. The methods though are not reported in adequate detail, in my opinion, and I find it difficult to figure out exactly what they did. Without seeing their scripts, it’s hard to assess the methods.

Those MDS plots in Figure 2 look more like they cluster by age than anything else – in a very gestalt view, all the figures look like that to me – and remind me of this XKCD panel.

Screen Shot at PM

The results of this are relevant to setting an appropriate NOAEL (No-Observed-Adverse-Effect-Level) to be used to set safe limits. But whether this observed effect is “adverse” is unknown. The authors own report (quoted above) suggests it is not causing adverse effects. In addition, given that we know that real world exposures in the groups with highest exposures levels are orders of magnitude lower than the NOAEL and the RfD, the relevance to actual effects in current real life exposures is limited. This distinction between setting safety limits and modeling real life exposures is lost in the Guardian’s reporting – which is an odd PR push ahead of actual publication.


Not a Get Out of Jail Free Card

One last thing that should be addressed. It is a true fact that the science of the microbiome is an emerging field, with what we don’t know looming larger than what we do know. It’s a field where we should approach this issues with real humility regarding what we don’t know and what we might find out. There are those however that have seized on the uncertainty of microbiome research to insist that implausible ideas should be taken seriously regardless of a lack of evidence or credible mechanisms. Likewise, those people will use the uncertainty of microbiome science to dismiss strong evidence and analysis with some hand waving and chin stroking about “We just don’t know.”

This is irresponsible and dishonest. In this case, we have a lot epidemiogical evidence on the health effects of glyphosate from the Agricultural Health Study. And we have a lot of observational animal feeding trials. And it’s pretty clear that gut flora have access to plenty of amino acids without having to synthesize them. Insisting that there is some health effect that is still eluding our detection with some invocation of what we don’t yet know about the microbiome is not rigorous skepticism, it’s granting yourself a license to believe whatever you want despite the evidence or lack there of. It’s all too often used as a Get Out of Jail Free Card when the thing you want to believe isn’t supported by the evidence. That’s not science, that’s a cheap debate tactic.

Marc Brazeau is the GLP’s senior contributing writer focusing on agricultural biotechnology.  He also is the editor of Food and Farm Discussion Lab. Follow him on Twitter @eatcookwrite.

32 thoughts on “Viewpoint: Here’s what’s wrong with study suggesting glyphosate damages our gut health”

  1. The reporting was typical Guardian awfulness, for sure. I don’t want to address it until we can see the data that is supposed to be coming in the supplemental data, which they referred to, but doesn’t seem available now.

    What’s actually kind of amusing about this study, though: this work might end up showing that glyphosate is safe. It was hilarious to see them try to work really hard on comments that made something out of nothing–and this is their friends!

    “We think that the work is of great value. Even if preliminary results on some sperm parameters (daily sperm production, sperm count and morphology) using the Ramazzini Institute in vivo rat model did not show any significant effect, further research is needed in order to deeply investigate the possible role of glyphosate and GBHs as endocrine disruptors on other reproductive parameters in both males and females”.

    emphasis mine

    IOW–there’s no evidence, but there must be some…somewhere…if we keep torturing the data? Right??

    • I started the first draft of this piece recounting the plot of It’s The Great Pumpkin, Charlie Brown! to set up the metaphor. I cut it, this time, but it’s all I can think of with this crowd. Their faith in glyphosate’s yet undetected risks is as impressive old Linus Van Pelt’s faith in The Great Pumpkin.

      There is still a Great Pumpkin essay in the pipeline.

  2. Nice article Marc! I really enjoy the “Not a Get Out of Jail Free Card” acknowledgement. It’s important to address what we do not understand. But, often opponents use the “God of the gaps” style arguments when it comes to genetic or the microbiome.

    It’s lazy and shouldn’t be acceptable.

    • Thanks. Applies as well to epigenetics and enodrine disruptors.

      We need to exercises humility about what we don’t know, but it can’t become an excuse to believe whatever we feel like.

  3. Thank you for your article.

    However on a point of correctness I would like to point out some serious errors in it:

    Your idea to pick out the Ramazzini Institute for criticism is interesting but in fact these are Multi-Institution and Multi-University studies: including the University of Bologna (Faculty of Agriculture, Veterinary Science and Biostatistics) the Genoa Hospital San Martino, the Italian National Institute of Health, the Icahn School of Medicine at Mount Sinai in New York and the George Washington University. Are you suggesting they all have an agenda?

    Also the microbiome paper is just one of many coming out of this Pilot Study:
    The results show that GBHs – even at doses deemed safe and over a relatively short exposure time (which in human-equivalent terms correspond from embryo life to 18 years of age) – are able to alter certain important biological parameters, markers chiefly relating to sexual development, genotoxicity and alteration of the intestinal microbiome.

    Also if you had bothered to contact the journal Environmental Health, as I did, you would realize that your claim that they published before being in print is incorrect, as Environmental Health actually allowed them to do this, as the peer-reviewed manuscripts have been accepted for printing at the end of May.

    Also there has been very wide media coverage across Europe in Austria, Belguim, France, Italy and 3 of the main papers in the UK. – you suggest there has been no coverage.

    Please be less biased as I support your work.

    • Apart from your somewhat annoying pedanticism, where exactly do you come down on the specific issue under discussion because I can’t really tell from your comments?

    • Nothing you’ve pointed out shows any errors on my part.

      1. Individuals from various universities and institutions who are in partnership with the Ramazzini Institute may very well have agendas, independent of their home institutions prerogatives. That’s in part the purpose of tenure. It remains very much the case that the Ramazzini Institute has a knack for finding the health risks they are looking for despite others not finding similar effects. That’s something that readers should be aware of.

      2. Can you show me where those results are present in data in any of these three papers aside from being vaguely alluded to and promised in future publications?

      4. As you state – the manuscripts are yet unpublished. Whether they are sound science or not, this is a red flag that they are being promoted to the press ahead of publication. The pattern of papers promoted ahead of publication that are later found to be deeply flawed is clear. There is nothing wrong in pointing this out, as long as the papers were evaluated rigorously. The Guardian did no such thing.

      5. Where did I suggest that there had been so such coverage?

  4. The illustration in the Guardian is: “A French farmer sprays glyphosate herbicide produced by US agrochemical giant Monsanto on a field of corn.”

    It would pretty much surprise me that a farmer would do that in Europe… unless he wants to destroy his crop.

  5. Glyphosate is a known human carcinogen. It’s manufacturer, Monsanto, is being sued for a variety of reasons, including covering up the data on glyphosate’s carcinogenicity.

        • If glyphosate were a carcinogen, it would have demonstrated such effects in the chronic feeding studies that were conducted in order for it to be registered (approved) by the U.S. EPA and all the other world regulatory agencies that are responsible for protecting human health and environmental integrity. Furthermore, if glyphosate had produced any adverse effects at all, it would have shown up in the toxicology studies. Evidence supporting any contrived “suits” as you mentioned is lacking.

          As a sidebar, you seem inordinately fixated on Monsanto, yet fail to recognize that a very large proportion of glyphosate produced today comes from China.

  6. Thanks for the clear and detailed response to this article and paper.

    The confluence of anti-technology groups and drama seekers continues to produce an unending stream of garbage.

  7. This piece as well as the linked Hulk piece are both full of hot air and quite shallow in their research, especially regarding the importance of microbial synthesis and degradation of amino acids. To state “Gut bacteria have little to no need of producing their own” is pure impudence, perhaps more so ignorance. The fact is gut microbiota create and share the pool of amino acids in our bodies. Simply adding dietary amino acids to solve the problem created by glyphosate would never work in the real world of gut dysbiosis. The author, Marc Brazeau, is unable to accept these truths, banning me from his Facebook group page, Food and Farm Discussion Lab Forum, based on trivialities, unable and unwilling to engage in microbiome science discussion. Several papers have now demonstrated glyphosate and GBH to reduce and inhibit our most protective probiotic intestinal bacteria, allowing pathogenic overgrowth in the host.

    • Moreover, two truths must now be acknowledged:
      1) Glyphosate can and does damage gut flora balance.
      2) Shifts in gut flora balance are a cause of cancer including lymphoma. It’s time the lawyers begin to learn about this mechanism. Ample evidence exists that lymphoma is of gut microbial origin (several papers).

  8. No matter if you find anything wrong with this study taking only few minutes to search for more gives similar results.

    Argentinian study shows much higher cancer rate in the region farming with intensive use of round up

    “A multi-center study sponsored by the Health Ministry in 2012 reports
    substantial mortality differences between soybean farming villages (that
    used glyphosate) and cattle-raising villages (that do not use
    glyphosate), in Avia Terai, Campo Largo, and Napenay village, there were
    cancer deaths with frequencies of 31.3%, 29.8% and 38.9%, respectively,
    whereas in Cole-Lai and Charadai, only 5.4% and 3.1%”

    Glyphosate based- herbicide exposure affects gut microbiota, anxiety and depression-like behaviors in mice (Morocco)

    Subchronic and chronic exposure to GBH induced an increase of anxiety
    and depression-like behaviors. In addition, GBH significantly altered
    the GM composition in terms of relative abundance and phylogenic
    diversity of the key microbes. Indeed, it decreased more specifically,
    Corynebacterium, Firmicutes, Bacteroidetes and Lactobacillus in treated
    Glyphosate is the core ingredient in Monsanto’s Roundup herbicide and
    levels found in the human bloodstream have spiked by more than a 1,000%
    in the last two decades.

    Toxicity of formulants and heavy metals in glyphosate-based herbicides and other pesticides

    Co-Formulants in Glyphosate-Based Herbicides Disrupt Aromatase Activity in Human Cells below Toxic Levels.

    Glyphosate everywhere you look, whatever you eat, drink, even in a breast milk
    Regulatory long-term (2 year) toxicity studies in rodents revealed
    adverse effects of glyphosate on the liver and kidney (reviewed in [3,
    4]). These studies, however, typically do not address a wide range of
    potential adverse effects triggered by disruption in
    endocrine-system mediated developmental or metabolic processes [3, 21,
    22, 23, 24]. Studies examining low doses of GBHs, in the range of what
    are now generally considered ‘safe’ for humans, show that these
    compounds can induce hepatorenal damage [25, 26, 27, 28].

    Study Shows How Glyphosate & Aluminum Can Operate Synergistically To Destroy The Human Brain

    Glyphosate, pathways to modern diseases II: Celiac sprue and gluten intolerance

    And if you just look for a glyphosate phrase in scientific journals – there is much more but i don’t have time to waste for it anymore.

    It only takes mind open enough to check the other side of coin objectively without bias of any dogma, forgeting for a moment we know everything (because for f-k sake we don’t).

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