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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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April 30, 2013

Is Glyphosate Poisoning Everyone?

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Posted by Derek

I've had a few people send along this article, on the possible toxicological effects of the herbicide glyphosate, wondering what I make of it as a medicinal chemist. It's getting a lot of play in some venues, particularly the news-from-Mother-Nature outlets. After spending some time reading this paper over, and looking through the literature, I've come to a conclusion: it is, unfortunately, a load of crap.

The authors believe that glyphosate is responsible for pretty much every chronic illness in humans, and a list of such is recited several times during the course of the long, rambling manuscript. Their thesis is that the compound is an inhibitor of the metabolizing CYP enzymes, of the biosynthesis of aromatic amino acids by gut bacteria, and of sulfate transport. But the evidence given for these assertions, and their connection with disease, while it might look alarming and convincing to someone who has never done research or read a scientific paper, is a spiderweb of "might", "could", "is possibly", "associated with", and so on. The minute you look at the actual evidence, things disappear.

Here's an example - let's go right to the central thesis that glyphosate inhibits CYP enzymes in the liver. Here's a quote from the paper itself:

A study conducted in 1998 demonstrated that glyphosate inhibits cytochrome P450 enzymes in plants [116]. CYP71s are a class of CYP enzymes which play a role in detoxification of benzene compounds. An inhibitory effect on CYP71B1l extracted from the plant, Thlaspi arvensae, was demonstrated through an experiment involving a reconstituted system containing E. coli bacterial membranes expressing a fusion protein of CYP71B fused with a cytochrome P450 reductase. The fusion protein was assayed for activity level in hydrolyzing a benzo(a)pyrene, in the presence of various concentrations of glyphosate. At 15 microM concentration of glyphosate, enzyme activity was reduced by a factor of four, and by 35 microM concentration enzyme activity was completely eliminated. The mechanism of inhibition involved binding of the nitrogen group in glyphosate to the haem pocket in the enzyme.
A more compelling study demonstrating an effect in mammals as well as in plants involved giving rats glyphosate intragastrically for two weeks [117]. A decrease in the hepatic level of cytochrome P450 activity was observed. As we will see later, CYP enzymes play many important roles in the liver. It is plausible that glyphosate could serve as a source for carcinogenic nitrosamine exposure in humans, leading to hepatic carcinoma. N-nitrosylation of glyphosate occurs in soils treated with sodium nitrite [118], and plant uptake of the nitrosylated product has been demonstrated [119]. Preneoplastic and neoplastic lesions in the liver of female Wistar rats exposed to carcinogenic nitrosamines showed reduced levels of several CYP enzymes involved with detoxification of xenobiotics, including NADPH-cytochrome P450 reductase and various glutathione transferases [120]. Hence this becomes a plausible mechanism by which glyphosate might reduce the bioavailability of CYP enzymes in the liver.
Glyphosate is an organophosphate. Inhibition of CYP enzyme activity in human hepatic cells is a well-established property of organophosphates commonly used as pesticides [121]. In [122], it was demonstrated that organophosphates upregulate the nuclear receptor, constitutive androstane receptor (CAR), a key regulator of CYP activity. This resulted in increased synthesis of CYP2 mRNA, which they proposed may be a compensation for inhibition of CYP enzyme activity by the toxin. CYP2 plays an important role in detoxifying xenobiotics [123].

Now, that presumably sounds extremely detailed and impressive if you don't know any toxicology. What you wouldn't know from reading through all of it is that their reference 121 actually tested glyphosate against human CYP enzymes. In fact, you wouldn't know that anyone has ever actually done such an experiment, because all the evidence adduced in the paper is indirect - this species does that, so humans might do this, and this might be that, because this other thing over here has been shown that it could be something else. But the direct evidence is available, and is not cited - in fact, it's explicitly ignored. Reference 121 showed that glyphosate was inactive against all human CYP isoforms except 2C9, where it had in IC50 of 3.7 micromolar. You would also not know from this new paper that there is no way that ingested glyphosate could possibly reach levels in humans to inhibit CYP2C9 at that potency.

I'm not going to spend more time demolishing every point this way; this one is representative. This paper is a tissue of assertions and allegations, a tendentious brief for the prosecution that never should have been published in such a form in any scientific journal. Ah, but it's published in the online journal Entropy, from the MDPI people. And what on earth does this subject have to do with entropy, you may well ask? The authors managed to work that into the abstract, saying that glyphosate's alleged effects are an example of "exogenous semiotic entropy". And what the hell is that, you may well ask? Why, it's a made-up phrase making its first appearance, that's what it is.

But really, all you need to know is that MDPI is the same family of "journals" that published the (in)famous Andrulis "Gyres are the key to everything!" paper. And then made all kinds of implausible noises about layers of peer review afterwards. No, this is one of the real problems with sleazy "open-access" journals. They give the whole idea of open-access publishing a black eye, and they open the floodgates to whatever ridiculous crap comes in, which then gets "peer reviewed" and "published" in an "actual scientific journal", where it can fool the credulous and mislead the uninformed.

Comments (130) + TrackBacks (0) | Category: The Scientific Literature | Toxicology


COMMENTS

1. George Brownfield on April 30, 2013 7:44 AM writes...

Awesome. How dare you deflate a conspiracy theory with facts ;-)

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2. Credible on April 30, 2013 7:51 AM writes...

So I can expect to see this on CNN or Fox next week...

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3. In vivo Veritas on April 30, 2013 8:09 AM writes...

Stephanie Seneff! What an embarrassment she must be to MIT. She actually was a passable language/cognition scientist, but she's gone off the rails. I guess she's tenured, or she would be long gone.

I love her caveat on her home page about her recent spate of publications:

"Note: Entropy is an Open Access journal that is willing to publish novel hypotheses regarding biochemical and biophysical phenomena, which can help the community break out of its current straitjacketed research paradigm. The papers below, many of which were published in Entropy's Special Issue on Biosemiotic Entropy: Disorder, Disease, and Mortality, cover several topics relating environmental toxins to disease, as well as the revolutionary concept that endothelial nitric oxide synthase (eNOS) synthesizes sulfate as well as nitric oxide. The papers were subjected to rigorous review by experts who were not beholden to industry influence. These papers collectively explain how widespread cholesterol sulfate deficiency throughout the body is behind most modern diseases and conditions."

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4. The Iron Chemist on April 30, 2013 8:25 AM writes...

"Straitjacketed research paradigm?" "Biosemiotic entropy?" Somebody whip out the crackpot index.

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5. anon the II on April 30, 2013 8:42 AM writes...

I'm wondering if your post on glyphosate was prompted by a trip to the midwest. When I visit my in-laws in Iowa, the discussion often turns to the miracle of Round-up and Round-up ready crops. And, the coming horror of Round-up resistant weeds and how that happens is discussed. If nothing else, a lot of people who don't believe that dinosaurs ever existed are seeing evolution in action.

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6. Marcelle on April 30, 2013 8:47 AM writes...

"Exogenous semiotic entropy" is going to be my new excuse for everything. Or the name of my new band...

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7. Rebecca Gavin on April 30, 2013 8:57 AM writes...

Another humorous and enlightening point is that Entropy is a pay for publication journal. The authors actually paid to have their paper published in this sad excuse for a scientific journal. I can't seem to find where I read it, but one science blogger said that Senoff actually has "published" eight papers in a special issue of Entropy, and that the approximate cost of that, to her, is around $9,000.

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8. MTK on April 30, 2013 9:15 AM writes...

It's incredible to me how much people generally fail to recognize the importance of dose and exposure to toxicity. The arguments for aspartame toxicity always point out how bad phenylalanine or methanol is without ever considering dose and exposure particularly relative to other ingested foods.

If it's bad, it's bad!

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9. Vader on April 30, 2013 9:36 AM writes...

@MTK #8 --

I would be happy to encourage folks who think this way to eliminate all phenylalanine from their diet and that of their children.

But then I'm kind of ruthlessly Darwinistic that way.

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10. Algirdas on April 30, 2013 9:49 AM writes...

@Rebecca,

just have a look at TOC of the special issue (man, this one really puts 'special' into 'special issue'):

http://www.mdpi.com/journal/entropy/special_issues/biosemiotic_entropy

I count 7 articles with Senoff as an author.

As to the cost - that is nothing surprising, and, by itself, does not indicate that MDPI is a predatory publisher. Content hosting costs money, as do staff salaries. PLOS One charged us US$1000+ for an article last year.

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11. Tamar Haspel on April 30, 2013 9:56 AM writes...

Derek -- Thanks for the dope on reference 121. I wrote the Huffington Post piece you link to, and I didn't catch it.

The paper irritated me not only because it was crap, but because it seemed to be written in such a way as to attempt to bamboozle the non-scientist -- lots of big words, lots of references. Being a non-scientist, there's nothing I dislike more than being bamboozled, so I'm glad to see an actual, genuine scientist explaining it clearly.

So thanks.

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12. TB on April 30, 2013 9:58 AM writes...

Check out reference 259 in the Samsel and Seneff paper and contrast what they say it found with what it actually found. Even a first year grad student would know they couldn't get away with this.

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13. sven on April 30, 2013 10:20 AM writes...

Seneff is an electrical engineer. She thinks Alzheimer's is caused by sunscreen and the flu vaccine! See this by Seneff:
http://www.spacedoc.com/recipe_alzheimers_disease

"The elderly are greatly encouraged to renew their flu shots every single year, and I think this is another major factor that is steadily increasing their risk to Alzheimer's disease. This is mainly due to the aluminum contained in the flu shot."


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14. Dan on April 30, 2013 10:20 AM writes...

I can't speak to the quality of this review, but surely inactivity against a panel of cytochromes doesn't prove glyphosate is safe for chronic ingestion?

Just wondering about the possibility they're acting like cranks but still have a point. I guess this would require an incredibly tedious point-by-point debunking.

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15. Curious Wavefunction on April 30, 2013 10:21 AM writes...

I think you doom yourself to a state of disorder the moment you name your journal "Entropy".

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16. Scarodactyl on April 30, 2013 10:26 AM writes...

@Curious WaveFunction: Be that as it may, you're also guaranteed long-term growth.

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17. Dave on April 30, 2013 10:30 AM writes...

Flu vaccines contain Aluminum? I knew that they contained Mercury:

http://en.wikipedia.org/wiki/Thiomersal

Dave

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18. Sleepless in SSF on April 30, 2013 10:41 AM writes...

The Seneff article is nothing compared to the comments on Tamara Haspel's HuffPo article. Some days I don't know whether to pound my head on the desk or weep for the future of the human race.

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19. Boris on April 30, 2013 10:55 AM writes...

#17 - the adjuvant used in most vaccines is aluminum hydroxide or aluminum hydroxy phosphate.

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20. Boris on April 30, 2013 10:55 AM writes...

#17 - the adjuvant used in most vaccines is aluminum hydroxide or aluminum hydroxy phosphate.

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21. Boris on April 30, 2013 10:55 AM writes...

#17 - the adjuvant used in most vaccines is aluminum hydroxide or aluminum hydroxy phosphate.

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22. RM on April 30, 2013 10:59 AM writes...

Rebecca Gavin@7 - From a purely cynical point of view, it's $9,000 well spent. She's now the darling of the anti-pesticide & anti-GMO crowds. Even if her current career goes belly-up, she's almost guaranteed to be able to land a job at some think tank or specialty "research organization", assuming she's content to turn the crank on the "pesticides are killing us" promotion machine. She also stands a good chance of being a media darling to fill the "reputable scientist who says pesticides are bad" chair on a he-said she-said featurette.

It certainly worked for Andrew Wakefield. (hat tip to Ben Goldacre)

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23. Mike F on April 30, 2013 11:24 AM writes...

Interesting read Derek, I had not heard of this controversy before. It goes to show how wrapping an argument around selected data and tenuous connections can make almost anything sound plausible. Thanks for untangling the web.

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24. sven on April 30, 2013 11:38 AM writes...

I am Machiavellian on this one. Let Seneff publish all she wants. The more publications in writing out there the easier it is for everyone to finally discredit these antiScience people. These people can then be connected directly to mainstream opinion news blogs who publish it, like huffingtonpost.

This then discredits the well-known antiAgScience agenda of huffingtonpost. farmers and science then win.

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25. CMJ on April 30, 2013 11:38 AM writes...

Hmm...Smells like something that would translate well into a NewScientist article...

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26. CMJ on April 30, 2013 11:39 AM writes...

Hmm...Smells like something that would translate well into a NewScientist article...

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27. ptm on April 30, 2013 12:06 PM writes...

Clearly you lot have already been poisoned and cannot comprehend the gravity of the situation. Your only hope now is to embrace exogenous semiotic entropy!

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28. Dave on April 30, 2013 12:23 PM writes...

Speaking as a toxicologist who teaches risk assessment: great blog Derek.

Pesticides are a magnet for scientific misinformation. What most people fail to realize is that any "chemical" (and many "things") can be a pesticide. It's the claims that are made that determine if a product is a pesticide.

Several years ago, a consumer products company sold a vegetable wash to remove pesticides. However, it also said the wash removed bacteria, which was a pesticidal claim. As a result, the wash itself was a registered pesticide, i.e., it was a pesticide used to wash pesticides off fruit. (in reality, it was just a simple soap)

Even simple fabric pillow/matress covers that control beg bugs or mites are considered "pesticides". If it has an EPA registration # on it, it's a registered pesticide.

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29. The Iron Chemist on April 30, 2013 12:24 PM writes...

@27: I don't know. I think endogenous semiotic entropy's the way to go.

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30. Hap on April 30, 2013 12:39 PM writes...

If your peers are the people who publish in Entropy, what exactly does that say about you?

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31. Dave on April 30, 2013 12:45 PM writes...

Speaking as a toxicologist who teaches risk assessment: great blog Derek.

Pesticides are a magnet for scientific misinformation. What most people fail to realize is that any "chemical" (and many "things") can be a pesticide. It's the claims that are made that determine if a product is a pesticide.

Several years ago, a consumer products company sold a vegetable wash to remove pesticides. However, they also said the wash removed bacteria, which was a pesticidal claim. As a result, the wash itself was a registered pesticide, i.e., it was a pesticide used to wash pesticides off fruit. (in reality, it was just a simple soap)

Even simple fabric pillow/matress covers that control beg bugs or mites are considered "pesticides". If it has an EPA registration # on it, it's a registered pesticide.

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32. Anonymous on April 30, 2013 12:46 PM writes...

What are you all- Shrills for the Glyphosate Industry?

The paper in question may be suspect to bad scientific interpretation and full of crap, but study the toxicological effects of the beast and its metabolites (over 900 references) and you will find it has significant toxic effects in most and a wide variety organisms up the food chain.

And Toxi Dave, get real.

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33. barry on April 30, 2013 12:57 PM writes...

thank, Derek!
Debunking this pseudoscience is an important intellectual exercise and an important service to the uneducated public.
Monsanto has much to answer for. But Glyphosate replaced a shelf-ful of dangerous persistent herbicides with one that is not persistent in the environment and which is remarkably safe in mammals. That's a big win, of which Monsanto should be proud.

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34. Anonymous on April 30, 2013 1:02 PM writes...

Monsanto should be proud? Are you brain damaged #33? And there are still plenty of nasty herbicides in all your foods. Go lookk up chemicals found in orange and grape juice. Guess what? You wont find any publications here because no one studies the obvious. Then go to European viniculture journals. Viola! Plenty are studied over there!

Its a cover up that we are poisoned by agricultural chemicals.

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35. anonimous on April 30, 2013 1:25 PM writes...

#34 "Go lookk up chemicals found in orange and grape juice."


Yep, both of these got DHMO in them! more than 1% by weight, if I'm any judge of these things.

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36. A Non-Mousse on April 30, 2013 1:29 PM writes...

I love it when, whenever presented with actual evidence, the rabble accuses us of being shills for one company or another (the accusation itself made obviously without evidence). It's about the best way to signal an end to the conversation.

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37. regioisomer on April 30, 2013 1:32 PM writes...

Yes, DMHO - nature's deadliest chemical. Millions die every year after ingesting it....

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38. ClutchChemist on April 30, 2013 1:32 PM writes...

#34,

Obviously you are anti-agrochemicals and mostly likely anti-GMO's as well. We are not going to change your mind in a blog comments section. My question is, do you have any better options for feeding the ever-growing population of the world? It is a fact that most of the arable land in the world is - guess what? - already being used for farming. That means we have to either (a) produce more food from the same amount of land using agrotechnological advances or (b) stop population growth by selectively killing babies. Neither are easy, but which one of those seems more reasonable? I'll take (a).

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39. Anonymous on April 30, 2013 1:54 PM writes...

Stop with the DMHO bullshit and I am not anti-chemical or anti-GMO. But forcing glyphosate and not using more modern rechniques of crop and livestock rotation is core to the problem.

But isnt science and especially chemistry supposed to warn us of chemicals that are deleterious in the environment and food supply? It works in Europe, but why not the good ol' USA?

Its because the lobbyists and their companies control the US food supply and its use of deleterious chemicals en masse.
The real problem is most scientists do not stand up against such exposures as you are all sycophants and drones of mass consumption.

And you are threatened by such statements contrary to your belief systems.

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40. NUchemist on April 30, 2013 2:08 PM writes...

#39 Anonymous - you obviously have under-developed critical thinking skills

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41. Jim on April 30, 2013 2:20 PM writes...

@39 anonymous:

Paint with broad brushes much?

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42. Anonymous on April 30, 2013 2:26 PM writes...

Critical Thinking?

A majority (>98%) of the scientific papers on glyphosate and AMPA come from countries other than the US.

How come no US scientists study the compound?

How's that for broad brushes?

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43. A Non-Mousse on April 30, 2013 2:39 PM writes...

#42: if that is the case, how about providing links to five papers based on all those non-US studies that document demonstrable harm caused by glyphosate using statistically sound and rigorous experiments? Five is all I ask for. Let's see you walk the talk.

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44. Hap on April 30, 2013 2:39 PM writes...

Pot? Is that you?

Either one of you, actually.

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45. Anonymous on April 30, 2013 2:47 PM writes...

Well, as soon as I found out all the chemicals that they put in my orange juice and drinking water, I quickly switched to grain alcohol distilled from organically grown crops. I feel much better now.

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46. sven is not an anonymous name on April 30, 2013 3:20 PM writes...

#39 Anonymous..
You think we should use more modern techniques in agriculture? Roundup IS modern farming. What you mean by modern? I am sure you want to use 100 year old organic. But of course.. pesticides like copper sulfur dust are used today for "organic". Would you rather have me (a farm owner) use more atrazine which is harsher? Atrazine has significant carry over. Europe uses a lot of chemicals harsher than Roundup. They have to use pesticides other than glyphosate since they have very little Roundup-ready crops.

You really need to get more modern. Even 1950 would be an improvement for you. You are obviously playing among the grown ups here.

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47. Shaun on April 30, 2013 3:25 PM writes...

I am not educated enough to get on either side of the toxicological argument about glyphosate. I do have enough common sense to know that we have to stop using these chemicals, which includes fertilizers. The issue of long term health damage to human is a moot point. In my opinion. The way we pour NPK salts and the other assorted chemicals onto our farmland, desertification is inevitable. Do a little research on how "dead" our farmlands are as far as soil microrganisms.

Another point, Roundup is great, but it seems that mother nature wins in the end. There are weeds that survive glyphosate. Or am I wrong? My understanding is that we now have "superweeds" which include pigweed, ryegrass, and marestail and they laugh at glyphosate. I mean, I am not a scientist but I remember some of my AP high school science, it's called selective pressure. Right? I would love to be wrong about this, but I am pretty certain it's true. I am from a farming family and I pay attention at Christmas dinner.

I don't have an iron in this fire except that I want my children, and their children, to not have to deal with a polluted world. We should deal with it now.

When people engage in this "my science is better than your science" I just want to barf. So many smart people, so much energy wasted, so much damage being done to our environment and water supply but everyone is too busy being blind to the real dangers. I say the only danger about Monsanto is that smart people are wasting a bunch of time attacking this single issue, when there are much much larger issues we could use their brainpower on.

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48. ars-chemia on April 30, 2013 3:44 PM writes...

I read the comments over at HuffPo also and it can make one despair for our future.

If one breaks down "endogenous semiotic entropy" it really makes no sense.

Endogenous = coming from outside of the organism, ok there.

semi