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| This is relevant, I promise. Image from xkcd.com |
I've chosen this journal article because I saw some blog posts about it spreading around Facebook recently, though I think this all started back in February. I am not going to dignify these blog posts with link backs. I will, however, summarize the contents; if you want to find the original post I'm sure you won't have any trouble.
The other reason I chose this article is that this is, in a way, a topic near to my heart. My PhD thesis was on spreading glyphosate resistance in the agricultural pest Amaranth. All that time in the lab left me with a lot of expertise to share regarding glyphosates biochemistry and utilization, and also with the distinct idea that agriculture is both really important to human health and a really misunderstood science (by the general public, I mean). People all over the internet are talking about GMOs and Monsanto, but there seems to be a lot more hysteria than science. I'd like to see that start to change. Starting with this: is there research showing that there are negative health effects for humans from the consumption of crops treated with glyphosate?
As I said in the beginning of this post, this topic choice started with a blog post spreading on Facebook, specifically one by the blogger Sarah from The Healthy Home Economist. Sarah holds a BA in Economics and an MA in Government Administration; sounds like a smart woman, but not a scientist. Around 2002 she decided to use her experience with the government to work on nutrition activism, but to date does not claim to have received any formal training in nutrition or any similar health-related fields.
In her post Sarah describes anecdotal experience that "gluten" sensitivity/intolerance is often inconsistent in individuals. Some types of wheat, often those sourced outside the US, do not aggravate some people's symptoms. (I put gluten in scare quotes, because as we talk about this we are going to be looking at the possibility that it's not the gluten per se that's causing problems). She says that she long thought that the USDA was lying about the fact that there is no GMO wheat in the US human food supply, and that these GMO wheat cultivars (breeds) were the ones that made people sick.
Before I continue with her argument, I'm going to stop here and make sure we're all on the same page about what a GMO crop is, and what it isn't. GMO is an acronym for "genetically modified organism"; but from a legal/regulatory perspective it's meaning is more specific than that. GMOs are modified by using transgenic techniques. An example will make this easier to follow: Round Up Ready (TM) cotton is a GMO developed by Monsanto. Round Up's active ingredient is glyphosate; glyphosate is toxic to most plants. It would make a great herbicide if only it didn't also kill the crops. To fix this crop-killing problem Monsanto found a species of algae that was resistant to glyphosate and studied it. They found the gene that made the algae resistant and they then copied that gene's sequence and added it to the genome of cotton. This is transgenics: adding genes to an organism (cotton) from a totally different type of organism (algae). There is another major technique for crop improvement that is not considered GMO, but still require a lab: marker assisted breeding. This is, really, the same as traditional breeding, hybridization, and grafting techniques that humans have been using since the dawn of agriculture, but with one major upgrade. Rather than waiting for the plant to mature (could be a long time if we're working with fruit trees) and then judging the plant and making a guess which cross would result in even better plants, breeders send leaves to the lab for genetic analysis. They then uses the information about the genetics of the plant to make breeding choices. This results in faster and better cultivar development and does not use any transgenics. Avoiding transgenics, particularly with food crops, is of real benefit to breeders because of the heavy regulations most governments place of the growth of transgeneic crops. In the US the crops must pass inspection by the USDA, FDA, and EPA. Such crops must pass testing for allergens or human toxins (the DNA inserted is considered safe, but any proteins produced by the plant as result of it's new DNA must be shown to be safe just like any other food additive.), as well as testing to show that the new traits will not escape into the wild (this is the reason for Monsanto not wanting farmers to save and resow seeds, it's not just greed). Cultivars derived from marker assisted technologies, as they do not contain foreign DNA, are exempt from these regulations, making them cheaper and easier to bring to market. However, these non-GMO cultivars may also posses traits such as herbicide resistance or pest resistance.
Back to Sarah's work, she says that she recently found out that glyphosate has been increasingly used to kill all the wheat in a field before the combine comes through because dead wheat is easier to harvest than live wheat. She shows some statistics showing that diagnoses of Celiac's and use of glyphosate in wheat show a similar upward trend from 1990 to 2009. Based on this, and the Entropy article, she concludes that "gluten" sensitivity is actually glyphosate poisoning.
So what did the authors of the Entropy article find out about glyphosate's link to "gluten" sensitivity?
The short answer is nothing. This is a review article, so rather than do novel research and present the findings, this article is about all the research that other scientists have done. There's nothing inherently wrong with review articles, they can be an important part of pulling large amounts of work together into a cohesive idea of how the world works. So let's go with the long answer. Because this is a long paper I'm going to add some of my own thoughts/information based on following the author's citations as we go, I'll mark those in purple.
These researchers begin by introducing glyphosate. It is a herbicide introduced in the 1970s, and rose in prominence in the 1990s as GMO glyphosate-tollerant crops were brought to market. They say that glyphosate is used both in weed control and for crop "dessication" (killing) prior to harvest. Glyphosate kills plants by inhibiting the function of the protein EPSPS, which is part of the metabolic pathway that makes the aromatic amino acids phenylalanine, tyrosine, and tryptophan. Humans, like all mammals, do not have this metabolic pathway; we must get aromatic amino acids from our diets. This has led to the conclusion that glyphosate is completely non-toxic to humans. It has been found that if you allow a mammal to consume glyphosate, about 2% will be metabolized and the other 98% will be excreted as urine via the kidneys. They claim that, while no studies have shown acute toxicity of glyphosate in mammals, one 2012 study showed chronic kidney dysfunction after life-long exposure in rats. This paper was REDACTED in January of 2014, before the Entropy paper was published, the authors do not note this. The researchers conclude the introduction by saying that the rest of the paper will describe research showing how inhibition of CYP enzymes (we'll get to what those are in a bit) and disruption of symbiotic bacteria may be the cause of negative effects of glyphosate exposure (of which they have no evidence).
To bolster their assertion that glyphosate exposure is problematic researchers describe some data from biochemical tests of glyphosate resistant and sensitive plants. In these studies it is shown that, after exposure to glyphosate, the glyphosate sensitive plants have decreased levels of aromatic amino acids (makes sense), and several other amino acids, and increased levels of ammonia. They suggest that the increased ammonia is the result of increased Phenylalanine ammonia-lyase activity (In plants, this enzyme is the first step of converting phenylalanine into various polyphenolic defense compounds; i.e. this is part of the stress response of a very unhappy plant. So, again this makes sense.). The authors suggest that it is possible that increased ammonia or polyphenols could cause the plant toxicity from glyphosate, but this isn't true. All the papers they cite are old (late 70s - early 80s, back when glyphosate was a brand new herbicide); newer research has shown that it is amino acid starvation, potentially accelerated by a stress response that consumes amino acids, that causes plant death. The authors also add that even glyphosate resistant plants still have some trouble with glyphosate exposure due to glyphosate binding to divalent cations, such as magnesium, and preventing them from being used by the plant or available to the human that eats the plant. However, the paper they cite tested ion transport in glyphosate sensitive plants. They have no evidence this is true in resistant plants; this could be related to plant stress.
Continuing with the idea that glyphosate is problematic, the authors describe some studies about the gut bacteria of cows and chickens. They say that these studies show an increase in dangerous bacteria and a decrease in symbiotic ones as a result of animal feed contaminated with glyphosate. Then on to humans, they bring up the redacted study on rats again before describing Round Up toxicity. It's important to specify Round Up, because the herbicide contains not only glyphosate but also surfactants (soaps) to aid in plant absorption of glyphosate. These surfactants have been shown to have toxic effects in animals, including humans. The authors cite a study showing that, while glyphosate does not effect bacteria, Round Up does. (Which is in contrast to the paper that claims glyphosate does kill bacteria. The authors do not attempt to resolve this incongruity)
In the next section the authors describe glyphosate's potential links to "gut dysbiosis", autism, and colitis. They start with the assertion that, "it is now well established that autism spectrum disorder (ASD) is associated with dysbiosis in the gut"; however, they only cite two papers (it takes more than two papers to call anything "well established" in science), and while both of these papers suggest a link between gene expression, gut bacteria, and gastrointestinal symptoms in autistic children, neither of them conclude the directionality that the authors are claiming (ie gut bacteria weirdness causes changes in gene expression and/or tummy trouble). The authors then suggest that excess ammonia in the blood generated by gut bacteria via Phenylalanine ammonia-lyase (PAL) as a result of glyphosate exposure may be causing the problems with the gut bacteria. But there's a problem here, the study linking PAL with glyphosate exposure was done in glyphosate-sensitive plants where PAL is part of the plants response to stress and glyphosate causes stress. PAL genes are quite rare in bacteria, only identified in a few species so far. As for colitis, the authors acknowledge that current research suggests that the increasing rate of colitis is due to increasing C. difficile infection, thought to be the result of excess antibiotic use (largely in agriculture). But they then suggest that glyphosate may be to blame. Their line of evidence for this is that C. difficile infections are more common in formula-fed infants and that some formula-fed infants would be fed soy-based formula that could be contaminated with glyphosate (really, that's the entirety of their "evidence". Not even a citation).
The next section is about the link between glyphosate and sulfate transport and phenol synthesis. They claim that these changes could be associated with autism and then go on to describe evidence for these changes. Frankly, they flip-flop between talking about autistic kids, plants, and bacteria so fast I have no idea what they are on about. It sounds to me that they are suggesting that glyphosate competes with phenolic compounds for sulfate groups, but, unlike the phenols, does not deliver the sulfates to the blood stream. This results in decreased sulfate absorption from the gut. They have no direct citations for this, they merely suggest this could be happening based on the electrochemical properties of the various compounds and some evidence of reduced blood sulfate in autistic kids and those suffering from colitis.
Finally we get back to the CYP enzymes mentioned at the beginning. CYPs or cytochrome P450 enzymes are a large class of enzymes that contain iron and oxidizes things. Many different things: drugs, toxins, hormones, etc. CYPs are often involved in plant resistance to herbicides, by oxidizing them for transport out of the plant. The authors show research that suggests very small amounts of glyphosate can inhibit the activity of the CYP that turns testosterone to estrogen humans, and a CYP found in plants. They suggest that because glyphosate is an organophosphate much like many insecticides, it may be contributing to honey bee colony collapse. They suggest glyphosate's contribution to colony collapse is due to it's (potential) inhibition of CYP enzymes needed to resist other pesticides that bees should be resistant to. Glyphosate is an organophosphate, which is simply an organic compound with a phosphate double bonded to an oxygen somewhere in it, but so is DNA, RNA, and many other biologically important molecules. This class of compounds does also contain many toxic compounds. However, most of the research into colony collapse suggests that it is neonicotinoid insecticides, not organophosphates, that are responsible. Neonicotinoids are, as the name suggests, compounds similar to nicotine and represent majority of popular insecticides.
The next section moves on to obesity and it's potential link to glyphosate. The authors pull this story together from several of the previous sections. They start by pointing out that serotonin has an important role in satiety signaling and that it is synthesized from tryptophan. They then suggest that the agricultural use of glyphosate depletes tryptophan from crops/food, and the contamination of our diet with glyphosate reduces the amount of tryptophan we get from our gut bacteria. They suggest this leads to low serotonin, and thus over eating, and thus obesity. One of their major arguments here is that the beginning of the obesity epidemic coincides with the beginning of glyphosate's agricultural use. The problem is, glyphosate is only applied to Round Up Ready crops, and as these plants have the glyphsate-resistant algae gene do not suffer inhibition of aromatic amino acid biosynthesis. These crops would not have less tryptophan than organic crops (and many of the best plant-based dietary sources of tryptophan are not crops that are sprayed with glyphosate). As for the gut bacteria, that has not been shown to be a major source of tryptophan for humans.
In addition to obesity, the authors suggest that glyphosate contamination is also responsible for anorexia. They hypothesize a process by which fat helps regulate sulfate metabolism (which they suggest could be perturbed by glyphosate), and that insufficient fat can result in either weight gain or inflammatory bowel disease. This "tummy trouble" then leads to anorexia nervosa. This, they suggest is working together with a potential glyphosate induced tryptophan deficiency. The evidence presented for this is that mice fed a tryptophan deficient diet have more sever colitis-attack-like "tummy trouble" after being fed dextran sodium sulfate than mice on a normal diet. This seems to be completely ignoring the fact that "anorexia nervosa" is a mental disorder that focuses on control and an obsession with body size/shape and that inflammatory bowel disease is ruled out as the cause of not-eating before that diagnosis is given. Also, there is no research suggesting that dextran sodium sulfate has anything to do with colitis in humans. It is used in studies on mice because it causes lesions of the bowel that look very similar, but the mechanism is unknown and thus so is the link to human colitis.
The length of this is getting out of hand and I've pretty much explained the primary logic of this paper: glyphosate messes up tryptophan and sulfate bioavailability. This causes lots of problems. So far the authors have implicated glyphosate in autism, colitis, obesity, and anorexia nervosa. In the last few sections of the paper they add several more: vitamin D deficiency, disseminated intravascular coagulation, Alzheimer's, Parkinson's, metabolic disorder, multiple sclerosis, liver disease, low sperm count, premature birth, preeclamsia, cancer, and cachexia (muscle wasting as a side-effect of chronic disease).
Since this is a review, everything I've related here is the author's conclusions from the available data. But, for their final take-home conclusion let me quote them,
"this paper presents an exhaustive review of the toxic effects of the herbicide, glyphosate, the active ingredient in Roundup®, in humans, and demonstrates how glyphosate’s adverse effects on the gut microbiota, in conjunction with its established ability to inhibit the activity of cytochrome P450 enzymes, and its likely impairment of sulfate transport, can remarkably explain a great number of the diseases and conditions that are prevalent in the modern industrialized world. Its effects are insidious, because the long-term effects are often not immediately apparent. The pathologies to which glyphosate could plausibly contribute, through its known biosemiotic effects, include inflammatory bowel disease, obesity, depression, ADHD, autism, Alzheimer’s disease, Parkinson’s disease, ALS, multiple sclerosis, cancer, cachexia, infertility, and developmental malformations. Glyphosate works synergistically with other factors, such as insufficient sun exposure, dietary deficiencies in critical nutrients such as sulfur and zinc, and synergistic exposure to other xenobiotics whose detoxification is impaired by glyphosate. Given the known toxic effects of glyphosate reviewed here and the plausibility that they are negatively impacting health worldwide, it is imperative for more independent research to take place to validate the ideas presented here, and to take immediate action, if they are verified, to drastically curtail the use of glyphosate in agriculture. Glyphosate is likely to be pervasive in our food supply, and, contrary to being essentially nontoxic, it may in fact be the most biologically disruptive chemical in our environment.
What are my conclusions?
This is garbage, and these scientists should be ashamed of themselves. The crux of almost every one of their connections between glyphosate and some disease is temporal. By that I mean glyphosate was introduced in the late 1970s, it was used at low levels because it killed everything (not usually the goal of agriculture), then in the 90s Round Up Ready crops were introduced and glyphosate use started to grow. Quickly. The Round Up Ready crops were adopted by farmers because they made weed control much easier and cheaper; and they were told that glyphosate use was much better for the environment and human health.
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| Glyphosate use by year and crop in the US. Image and Data from USGS.gov |
All of the diseases discussed in this review have also been increasing since the 1970s. Many of these diseases, particularly cancer and Alzheimer's, are diseases of old age and are thus likely the result of the baby boom (born 1945-'65) getting old. Much like the comic I started with, the correlations are incidental.
The "infertility" described in the article was actually measured as decreased birth rate. The Pill was introduced in 1960, and has been increasing in use since. Now almost every woman has used it at some point. Since they measured birth rate and not rate of treatment for infertility controlled for age, we can not disentangle changes in family planning practices from decreased fertility. I suspect that the declining average family size over the last 40 years has less to do with glyphosate and more to do with contraception access.
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| Changes in birth rate, contraception use, and abortion rate in South Korea. Image from Marston C and Cleland J, "Relationships between contraception and abortion: a review of the evidence", International Family Planning Perspectives, 2003, 29(1):6-13. via The Guttmacher Institute |
The obesity epidemic kicked off in the 80s, but there is still a lot of debate regarding why (and novel chemicals in our environment do have the potential to be involved). If you watch the GIF you can see that the South leads the charge on increasing obesity; however, glyphosate use is highest in the Mid-west. So this, also, seems like a very unlikely direct causative relationship.
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| Image from Wikipedia |
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| Image and Data from USGS.gov |
A lot of what is presented in this paper seems to stem from a fundamental misunderstanding of metabolism and of glyphosate. Which isn't really all that surprising when you investigate who it is that wrote this paper. Anthony Samsel's affiliation, as given in the paper, is "independent scientist and consultant", he isn't working for any university or research institute. Which I can't say anything against, I'm not working for a university and I'm a real scientist. However, his linked in profile doesn't give any information about his formal education, but his prior work suggests that he is not a biologist or biochemist. As for his co-author, Stephanie Seneff, she is a computer scientist who specializes in artificial intelligence at MIT. So, Dr. Seneff is likely a very smart woman, but no biochemist. But a smart scientist knows when she's out of her depths, so why was this written? (As I said, glyphosate is my jam and these two don't know what they're talking about). The research was "funded" by the Qmulus Project (scare quotes because reviews are cheap), which is database mining project. And published in Entropy which is an "international and interdisciplinary open access journal of entropy and information studies published monthly online by MDPI". So, not a biology journal, which means that the reviewers of this article would also not be biologists (but rather computer scientists, physicist, or maybe statisticians, if anyone at all). MDPI is Multidisciplinary Digital Publishing Institute which is based in China and considered by most scientists to be a predatory open access publishing journal; this means that they will publish almost anything if you are willing to pay the publication fees. Basically they are charlatans and internet trolls who got together and made a business plan. I think our authors are in on it. We've all been trolled.
To wrap this up I'd like to go back a bit and set the record straight about glyphosate. It was a great discovery that has done a lot to advance modern large scale agriculture while protecting the environment. It's a nice ideal to have all our food come from small organic farms, but it just isn't reasonable. There is not enough land to feed 7 billion people without using modern intensive agriculture. At this point we really are dependent on it. We need to figure out a way for intensive agriculture to be sustainable and at first it looked like glyphosate and Round Up Ready crops could be the answer. Glyphosate was a great herbicide, in the 70s it killed every type of plant, it didn't accumulate in the soil (many soil microbes ate it), and it wasn't toxic to human or other animals or insects. It allowed farmers to use low- and no-till techniques that saved the soil from erosion, allowed natural fertilization via composting, protected beneficial soil microbes, and saved on diesel fuel (less driving the tractor around). It was so great that the only bad thing about it was that it couldn't be used all season and once the crops sprouted other, more toxic, herbicides had to be used. In the 90s Monsanto found a solution: Round Up Ready crops. Farmers loved them. Unfortunately, as farmers used more and more glyphosate the weeds started to evolve resistance. Now so many weeds are resistant that farmers are having to switch back away from glyphosate to the old methods of weed control that are even harder on our environment. If you're worried about what glyphosate in your food is doing, try looking into the herbicides it's being replaced with: dicamba and glufosinate.
Here's a blogger who knows what's what: http://ultimateglutenfree.com/2014/02/does-glyphosate-cause-celiac-disease-actually-no/
References
Samsel, Anthony, and Stephanie Seneff. "Glyphosate’s suppression of cytochrome P450 enzymes and amino acid biosynthesis by the gut microbiome: Pathways to modern diseases." Entropy 15.4 (2013): 1416-1463.
The retraction notice for the retracted paper about glyphosate and rats: http://www.sciencedirect.com/science/article/pii/S0278691512005637
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