A Chemical Hunger – Interlude D: Glyphosate (AKA the active ingredient in Roundup)

[PART I – MYSTERIES]
[PART II – CURRENT THEORIES OF OBESITY ARE INADEQUATE]
[PART III – ENVIRONMENTAL CONTAMINANTS]
[INTERLUDE A – CICO KILLER, QU’EST-CE QUE C’EST?]
[PART IV – CRITERIA]
[PART V – LIVESTOCK ANTIBIOTICS]
[INTERLUDE B – THE NUTRIENT SLUDGE DIET]
[PART VI – PFAS]
[PART VII – LITHIUM]
[INTERLUDE C – HIGHLIGHTS FROM THE REDDIT COMMENTS]

Glyphosate is a herbicide and all-around general weed killer that you probably know as the active ingredient in Roundup *whip cracks*

We were put onto the trail of this here varmint by Justin Mares, who pointed out that there are several reasons to be suspicious of glyphosate. We’ll start with the fact that this stuff is pretty much everywhere. “Because of its widespread use, glyphosate is in water, food and dust, so it’s likely almost everyone has been exposed,” says PBS.

Most sources say that glyphosate has a relatively short half-life in both soil and water, though apparently this “can vary widely based on environmental factors” and “values between 2 and 197 days have been reported in the literature.” Many sources downplay this contamination, emphasizing how quickly it degrades, but it does seem to end up in groundwater, as there is a whole water treatment literature about how to remove it (see also this other review paper). 

Relevant to our interpretation of the altitude mystery, one study that examined glyphosate contamination in two rivers in Mexico found that the rivers were generally (though not always) more and more contaminated as they flowed downstream.

Glyphosate was patented in 1971 and first sold in 1974, but the FDA didn’t test for glyphosate in food until 2016, which seems pretty weird. The results of these tests are publicly available — in the report from 2016, we see that they tested 274 samples of corn, 267 samples of soybeans, 113 samples of milk, and 106 samples of egg for glyphosate. No glyphosate at all was detected in the milk or eggs, but 63.1% of corn samples and 67.0% of soybean samples showed some glyphosate contamination, though none contained glyphosate levels above the limit set by the EPA. It’s clearly in some foods, though apparently less in animal products and not at especially high levels overall.

Glyphosate can affect the growth of microorganisms that rely on a specific pathway for growth, but this paper finds that most gut bacteria don’t have that pathway, and so glyphosate probably doesn’t affect their growth. On the other hand, this paper says that “54% of species in the core human gut microbiome are sensitive to glyphosate.”

There’s also some evidence that glyphosate interferes with various enzymes, at least in rats. Some of these enzymes are related to the metabolism and clearance of many drugs, and interference with these enzymes does seem to sometimes lead to negative drug interactions. This suggests that even if glyphosate doesn’t cause obesity by itself, it could potentially make people more susceptible to other compounds that do.

In addition there is at least one speculative paper arguing explicitly that glyphosate’s suppression of cytochrome P450 enzymes leads to many modern diseases, including obesity. However, we should mention that the journal that published this paper found it so weird that they added a note about “potential bias in opinions and bias in the choice of citation sources used in this article” and issued “an Expression of Concern [emphasis in the original] to make readers aware that the approach to collating literature citations for this article was likely not systematic.” Also see this pushback, and this pushback from a group funded by the American Chemistry Council, American Petroleum Institute, etc. etc.

When we look at a map, the distribution of glyphosate use in the United States matches county-level obesity data pretty darn well: 

County-Level Estimates of Obesity among Adults aged 20 and over, 2009. Map from the CDC.

Glyphosate Use in 2009, USGS. This and other maps are from 2009 to match the map above, but click through to the USGS to see use in other years.

It’s not a perfect match, but it’s pretty striking. Granted, this also looks a lot like the distribution of other pesticides, for example our old friend 2,4-D:

And Atrazine, another common pesticide:

Maps of pesticide use mostly highlight agricultural regions, regardless of the pesticide you look at. The big difference is that unlike these other pesticides, glyphosate is used more and more every year, matching the rise in obesity. Again from the USGS:

Glyphosate (interestingly, the increase seems to have stalled around 2012?):

2,4-D:

Atrazine: 

Glyphosate was developed to fight weeds in the early 1970s and was first brought to market in 1974 as Roundup. Since then, glyphosate use has increased pretty much every year, both in the US and worldwide.

This is actually a little on the late side, especially since glyphosate saw relatively limited use before the 1990s. Things really kicked in with the introduction of genetically engineered Roundup Ready crops. Roundup kills most plants, so it kills most crops too, and in the beginning the only way to use it was to spray selectively. But in 1996 Monsanto introduced Roundup Ready soybeans, which are resistant to glyphosate. Now farmers could dump Roundup on the whole field and kill everything but the soybeans. This was followed by Roundup Ready corn, canola, sugar beets, cotton, and alfalfa. These new resistant varieties led to a huge increase in glyphosate use during the 1990s and onward.

(In addition, we should note that Kuwait was already 18% obese by 1975, and it’s hard to see how glyphosate could be responsible for that.)

Round Down

There’s some circumstantial evidence that if contaminants are responsible for obesity, at least one of those contaminants is related to agriculture. As we see from the maps above, the most obese parts of America are largely farm country. If we were to suspect an agricultural chemical, glyphosate would be at the top of our list.

But there are many more signs that the main contaminants are not agricultural. If the most widely used herbicide in the United States were the cause of obesity, then we would expect agricultural workers to be especially obese, as a result of their high level of exposure. Instead, we see that the rate of obesity among agricultural workers is pretty average — sometimes slightly higher than average, sometimes slightly lower.

Agricultural workers are clearly exposed to glyphosate. One study of 48 farmers, their spouses, and their 79 children found that 60% of farmers had detectable levels of glyphosate in their urine. Farmers who wore rubber gloves had less glyphosate in their urine, and farmers who made skin contact with the glyphosate had more. A small percent of spouses and children also had low levels of glyphosate in their urine, but this mostly seemed to happen when the spouses or children helped prepare the glyphosate formulation or apply it to the fields. Despite this direct exposure, farmers are not especially obese.

Maybe glyphosate (or some other pesticide) degrades over time, or combines with something else in the environment, and ends up forming some byproduct that causes obesity? Again this seems unlikely. If some byproduct of a chemical used at farms caused obesity, you would think that the people who spend all their time at the farm would get the most exposure. There are some exceptions — farm workers probably don’t get much exposure to the antibiotics given to livestock, for example — but it seems unavoidable in the case of contaminants that are sprayed directly on fields.

Maybe eating glyphosate-laced food is different from inhaling glyphosate or absorbing it through your skin. This seems possible, given that there are some signs glyphosate might disrupt the microbiome, and this could potentially explain why farmers are not all that obese, since they’re not eating the stuff. But once again this seems unlikely, because there are major differences between obesity rates for other professions.

Motor vehicle operators, healthcare workers, and law enforcement workers are some of the professions with the highest levels of obesity. Teachers, design workers, and legal workers are some of the professions with the lowest levels of obesity. Some of these differences are very robust

This seems hard to reconcile with an account where glyphosate, or a glyphosate byproduct, causes obesity. Granted, glyphosate is used other places than just on farms. But why would truck drivers and police officers be exposed to so much more glyphosate than everyone else? How could they be exposed to more than farm workers? It’s possible that there is something about driving a truck that unlocks the harmful potential of glyphosate (or something about glyphosate that unlocks the harmful potential of being a truck driver) but at the moment this seems unlikely.

Like farmers, forestry workers also work with glyphosate. But despite this, forestry workers involved in spraying don’t show any glyphosate in their urine, despite clearly getting it on their clothes and even on their skin. It’s hard to see how law enforcement workers or truck drivers could be getting an appreciable dose of glyphosate when forestry workers who handle the stuff directly don’t seem to get any in their body. And, we can note, forestry worker is a pretty lean profession as well.

While the geographic match is pretty good in the US, the international match is mixed. We haven’t been able to find the clearest sources, but here’s a map from one paper: 

Map of estimated glyphosate intake, source.

Compared to:

If glyphosate were a major driver of obesity, we would expect Central and South America and the Middle East to be much less obese. We would expect Spain, Germany, Poland, and much of Africa to be much more obese. Food imports and differences in water treatment techniques may be able explain some of this, but it’s not an immediate hit for glyphosate. 

Direct Evidence

If you look into a potential glyphosate-obesity connection you will eventually find a 2014 paper titled Genetically Engineered Crops, Glyphosate and the Deterioration of Health in the United States of America, or sources based on it, so we need to address it here. 

This paper reports an absolutely comically huge correlation of 0.962 between glyphosate application and obesity, and similarly enormous correlations with other diseases. This correlation is implausibly large, and it is not accurate — it is the result of a common error people make when working with time series data.

A good explanation of this error can be found in Avoiding Common Mistakes with Time Series Analysis by Tom Fawcett, where he shows that adding a slight trend to two totally random, unrelated time series ends up making them appear extremely correlated despite the total lack of a relationship. In his example, the apparent correlation ends up being .96, despite the true correlation being zero. What this paper reports is not evidence that glyphosate causes obesity, it is only evidence that glyphosate use has increased since 1996 (we already knew that) and that obesity has also increased since 1996 (we already knew that too).

There is some evidence of weight loss, or at least “decreased body weight gain”, in animal studies. All these studies are in rats and mice, however, and this seems to happen only at the highest doses. When we say “highest doses”, we mean really high — in one study the highest dose was 1183 mg/kg/day, in another it was ​​3500 mg/kg/day, in a third it was 4945-6069 mg/kg/day. 

In comparison, the U.S. Environmental Protection Agency reference dose for glyphosate in humans, “or estimate of daily exposure that would not cause adverse effects throughout a lifetime”, is 2 mg/kg/day. In that study from before, the highest estimated systemic dose in farmers who were working directly with glyphosate was only 0.004 mg/kg.

This is a tiny bit of evidence for glyphosate causing weight change, but it’s 1) in animals, 2) weight loss rather than weight gain, and 3) only at doses about 1000 times higher than recommended and about 250,000 times higher than the doses found in people who work with glyphosate directly.

The best evidence for glyphosate causing weight gain that we could find was from a 2019 study in rats. In this study, they exposed female rats (the original generation, F0) to 25 mg/kg body weight glyphosate daily, during days 8 to 14 of gestation. There was essentially no effect of glyphosate exposure on these rats, or in their children (F1), but there was a significant increase in the rates of obesity in their grandchildren (F2) and great-grandchildren (F3). There are some multiple comparison issues, but the differences are relatively robust, and are present in both male and female descendants, so we’re inclined to think that there’s something here.

There are a few problems with extending these results to humans, however, and we don’t just mean that the study subjects are all rats. The dose they give is pretty high, 25 mg/kg/day, in comparison to (again) farmers working directly with the stuff getting a dose closer to 0.004 mg/kg.

The timeline also doesn’t seem to line up. If we take this finding and apply it to humans at face value, glyphosate would only make you obese if your grandmother or great-grandmother was exposed during gestation. But glyphosate wasn’t brought to market until 1974 and didn’t see much use until the 1990s. There are some grandparents today who could have been exposed when they were pregnant, but obesity began rising in the 1980s. If glyphosate had been invented in the 1920s, this would be much more concerning, but it wasn’t.

Conclusions

It doesn’t look like glyphosate can be a major contributor to the obesity epidemic. It was introduced slightly before obesity began to skyrocket, but it didn’t see much use until decades later. It seems to have arrived too late to be responsible. There may be a slim chance that glyphosate contributes in some small way to obesity, and might be responsible for some of the increase in obesity since the mid-90s, but it doesn’t look like it could have started the epidemic.

Glyphosate exposure doesn’t seem to match international patterns of obesity, and glyphosate doesn’t seem to be able to explain the variation in obesity rates by profession. If glyphosate caused obesity, we would expect farm and forestry workers to have high levels of obesity, but in fact their obesity rates are pretty average, or even below average. Finally, there’s very limited evidence of glyphosate exposure causing weight change in animals, and no evidence in humans, at least none that we can find.

To us, it doesn’t seem likely that glyphosate plays any serious role in the obesity epidemic, and it probably doesn’t play any role at all. If you disagree or have any evidence to the contrary, however, please let us know!


11 thoughts on “A Chemical Hunger – Interlude D: Glyphosate (AKA the active ingredient in Roundup)

  1. Robert says:

    From the rather short half-life of glyphosate I conclude that it cannot accumulate in the body. If so, it cannot explain why people get more obese as they age from maturity to their mid fifties or early sixties.

    In the comments on lithium you had remarked that there is data that shows people are getting more obese as they age. Then I conclude that any substance that does not accumulate in the human body cannot be responsible for the observed obesity data.

    Nonetheless, you are looking at candidates that do not accumulate in the human body. Why?

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    1. ls says:

      The suspect chemical doesn’t necessarily have to be something that accumulates in your body. I could believe that there are chemicals that make you get fatter and fatter over time, even though the amount of the chemical in your body isn’t increasing.

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    1. You’re right that would be hard. Immigrants do seem to change weights in only a couple years when they move to a new country, however, so the whole thing can’t be epigenetic. In general it doesn’t look like a phenomenon that skips a generation

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  2. Mike says:

    I’m not sure about the accuracy of the pesticide usage maps in relation to Arizona. Arizona heavily used/uses pesticides/herbicides in agriculture since they were available to the point where the Painted Rock Reservoir is basically a toxic waste dump from upstream runoff of pesticides (mostly DDT, but it’s a real mixed bag). Despite being the 2nd largest reservoir in Arizona, it’s basically unusable now (even if we did have water to put in it). The Pima and other Indian reservations are basically all around this area and upstream as well, which may or may not be coincidental.

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  3. The ending reminds me of the grandparent teenage starvation studies, like https://www.nature.com/articles/s41467-018-07617-9 – likely unrelated, but one of those crazy findings that you can’t really do anything about.

    This whole article series has been a fascinating read today, thanks for doing it. I do wonder if in the end it’s a parallel of Hickam’s dictum, where “patients can have as many causes of obesity as they damn well please”. That in general disruptions to the system tend to cause weight gain, and as the human race we’re running thousands of simultaneous overlapping experiments of exposure to random chemicals with no control group.

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  4. Simple Observation says:

    Good conclusion. A special case should be done regarding Glyphosate heavily used in eliminating coca plantations in the Andes northern basin. Again it may show some impact, but probably obesity will not show up

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