Unsafe at Any Dose?

In this post we'll see why we no longer have to take any notice of claims that GMO crops and herbicides are not causing us harm.  But first, let me put this in the context of this blog's major goal: to explain the importance of Swanson et al. and to defend it against its critics (for reference see below).

Yes, it’s high time to up-armor for the coming fight.  Ripples are already spreading across the blogosphere, but so far the only counterargument I’ve seen that went beyond the hoary old “bad journal”, “bad credentials” Monsantoite b.s. was that the authors should have separated different areas of America for statistical purposes. That’s because, if they were right, surely there should be more chronic diseases where there was heavy spraying and less where there was little or none.

 

GMO advocates never tire of repeating the mantra “The poison is the dose”—even things you eat unthinkingly every day, like table salt, can poison or even kill you if you eat too much.  Just the other day, a comment by Chris Preston on a post on the Biofortified page (http://www.biofortified.org/2015/01/medical-doctors-weigh-in-on-glyphosate-claims/#comment-1340450)  claimed “Toxicity always depends on the dose. Regulators address whether a product can be used in such a way that the dose received is below a level which may result in toxicity.”  In technical terms, all substances with toxic potential are monotonic—their toxicity may be zero at very low doses, but increases proportionately with the size of dose.

This looks like a general law, not just one for toxic substances. Surely the more you consume of anything, the greater the effect?  The more food you eat, the fatter you get.   The more alcohol you drink, the drunker you get.  Your common sense and your senses tell you that.  They also tell you that the sun goes round the earth (not vice versa), that continents can’t creep around the globe (they’re solid, lifeless rock, goddammit!), that we couldn’t possibly be kissing cousins to chimps.  But if our senses and our common sense told us how things REALLY worked, there wouldn’t be much need for science, would there?  What science does is prove that the counterintuitive thing is all too often the truth, and I haven’t even mentioned quantum mechanics.

While we’re talking about science, let me emphasize one of the most important things about it.  It moves on.  It’s always moving on.   It’s not like religion, where you must believe exactly what people believed hundreds or even thousands of years ago, or else be branded as a heretic.  If you truly believe in science, you must always be ready to change, because science is always changing, and once it’s changed, what was science yesterday isn’t science any more.  “The poison is the dose” is a case in point.

The assumption behind “The poison is the dose” is that damage from any toxic substances can be avoided if you simply make sure that people don’t get too much of it.  And the mechanics of that seem straightforward enough.  There’s a nice summary at http://www.animalresearch.info/en/drug-development/safety-testing/):  “New medicines or chemicals which may affect the health of humans are required by law to be tested on animals…Safety tests begin with acute toxicity testing, where the animals are given a single dose of the test compound. The aim of the tests is to determine the range between the dose that causes no adverse effect and the dose that is life-threatening.”

 Alas for that.  According to Vandenberg et al. (“Bisphenol-A and the Great Divide: A Review of Controversies in the Field of Endocrine Disruption” Endocrine Reviews 30.1. 75–95, 2009), “a safe dose determined from high doses does not guarantee safety at lower, untested doses that may be closer to current human exposures.”

Why not?  It’s because for any toxic substance you can plot a response curve, with a strong effect at or near the top of the curve and a weak or null effect at the bottom.  And there is not just one possible curve--here's a sample of several:

  

Note that in all the figures, low-dose is to the left of the graph, high-dose to the right. The left-hand A and B graphs are the kinds of curve once thought to be universal (and still are by pro-GMOers).  The right-hand C curve—the U-shaped curve—is very different, and probably the hardest one for GMO supporters to deal with.

That’s because of the mode of testing described above—start high, work down until effects aren’t apparent, leave what you think is a wide enough margin and announce a safe dose.  In other words, you plot only the right-hand side of the U-curve.  There’s no way you could find that, at still lower levels, harmful effects could begin again (left-hand side of the graph).  But that's exactly what the graph means.  It means that if a toxic substance has a U-curve but you like a good Monsantoite assume it's monotonic, it may very well have serious consequences that you literally cannot know about till after they've happened.

By now I’m sure GMO defenders will be saying. “Well, what’s the so-called scientific evidence for all this?  Some rubbish published in a pay-for-play journal with a 0.something impact factor, I’ll bet.”  Well, sorry, guys.  “Endocrine Reviews has the highest Impact Factor ranking of the 89 journals in the ISI category of endocrinology and metabolism. Of the total 5,684 surveyed by ISI, EDRV's Impact Factor ranking is #20.”  (source: ResearchGate, but you can also consult the original ISI lists.) The journal’s impact factor is 19.36, and the paper itself has been cited in 537 other journal articles and books.  We’re not talking junk science now; we’re talking Gold Standard in Endocrinology.

Move on another three years, and the same journal publishes “Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses” (Vandenberg et al., Endocrine Reviews 33.3. 378-455 (2012)).   This is right in our ball-park because it specifically includes glyphosate in its list of non-monotonic dose-response curve substances that cause substantive harm:

Chemicals by chemical class      Nonmonotonic effect                       Cell type

Glyphosate-based herbicide        Cell death, aromatase activity       HepG2 liver

(Round-Up)                                 ERβ activity                                   cells

Note that this paper has 564 citations, even better than the previous one, especially since they cover only a two-year period.  It includes nearly 850 citations of supporting work.

Fallback position for GMOers:  “This stuff’s very controversial, you’re cherry-picking data, good science says the opposite”.  Well, six years ago (quite a while in science at nowadays speeds) Laura Vandenberg wrote:  “Although scientific inquiry is a dynamic give-and-take among researchers with different opinions and viewpoints, the so-called controversies surrounding low-dose effects and NMDR curves should be put to rest, given that they now affect public health decisions [My italics, DB].  These phenomena have been demonstrated time and again for a sufficient number of endocrine-related endpoints, and they no longer merit being considered ‘controversial’ topics.”  In other words, this is the new orthodoxy in toxicology.

So what has all this got to do with Swanson et al.?  Well, first and foremost, it gets them off the “why no data by area” hook.  If glyphosate has a low-dose effect, then there is no reason to expect people in high-spraying areas to have more chronic diseases, and therefore no point in separating data from different states or regions.  

But the work on response curves goes much further than that.  As Vandenberg et al. point out at the end of their 2012 paper, “The concept of nonmonotonicity is an essential one for the field of environmental health science because when NMDRCs occur, the effects of low doses cannot be predicted by the effects observed at high doses.”  This means that when GMO advocates tell us that low doses of glyphosate are harmless, their claims no longer have any valid scientific evidence.  To the contrary, the knowledge that glyphosate is non-monotonic and an endocrine disruptor makes it all the more probable that it does cause substantive harm.   What’s the next step towards proving this?  Well, how did people first find evidence that tobacco caused lung cancer?  Through epidemiological studies and correlations!

 

The tobacco comparison is a story that deserves its own post, and will get it.  For now, it’s sufficient to note that this is the importance of Swanson et al.  Through epidemiology, the paper builds a prima facie case for supposing that glyphosate could indeed cause the rise of certain chronic disease conditions in America.  Given that we now know what toxicology can and can’t prove, Swanson et al.’s claims can no longer be dismissed with blanket denials--they must be further investigated.  And however that investigation turns out, we’ll still be able to tell GMO defenders that their claims of pesticide safety aren’t worth the paper they’re written on.

Reference:  “Genetically engineered crops, glyphosate and the deterioration of health in the United States of America” by Nancy L. Swanson, Andre Leu, Jon Abrahamson and Bradley Wallet,  Journal of Organic Systems, 9(2), 2014 (http://www.organic-systems.org/journal/92/JOS_Volume-9_Number-2_Nov_2014-Swanson-et-al.pdf).

Opening the First Offensive

Word of Swanson et al. has begun to trickle into the blogosphere, so I've decided to open the first offensive (I'll try not to be too offensive!).  My statisticians are taking their own sweet time evaluating its stats, but the hell with it, let's roll.

I'm opening with a pre-emptive strike on what might look at first sight to be a weak spot in their paper.  But when I looked into it I learned stuff that amazed me.   That "weak spot" turned out to be the very reverse--a key to something new (but no longer controversial!) in REAL science that the GMO pseudo-scientists haven't begun to cotton on to, even though (or maybe because) it makes nonsense of their claims that GMOs have been proven safe.  And that's only a foretaste of what's to come, which will include 'Seralini and Hauser: Two Very Different Academic Scandals' and 'The Hidden Connection between GMOs and Climate Change'.

Stuff you won't read anywhere else, plus a free induction into the GMO Hall of Shame for the first commentator who says, "Ha-ha, that's because you make it all up!"

Response to Professor Folta.

Here is my response to Professor Folta's response (at http://kfolta.blogspot.com/2015/01/vani-haris-kooky-response-to-critical.html)

Dr. Horta’s words are in standard script, mine in italic.

_______________________________________________________________

Over at The GMO Smoking Gun, Professor Emeritus Derek Bickerton has prepared a response to my criticism of Vani Hari's letter to grad students.

My blog is smokinggmogun.blogspot.com, not GMO smoking gun. Failure to get this right has misled at least one of Dr. Folta’s readers already.

I would be disappointed too if I believed the nonsense.

My piece was not intended as an endorsement of everything Vani Hari has written, and indeed I have never read anything by her except her letter. I am as aware as Professor Folta that a lot of anti-GMO propaganda is as short on facts as it is long on indignation.  But then so is a lot of pro-GMO propaganda.  My disappointment stemmed solely from the fact that, in a piece with “a zillion hits”, I had expected something better than Professor Folta's critique.  Now he has graciously admitted its shortcomings, we can put this issue to bed.

EXHIBIT A

TACTIC: FALSE ATTRIBUTION OF INTENTION+FALSE ACCUSATION

Of course the first resort of those that don't have science-- try to discredit a scientist by immediately linking them to a company that has a negative image to many.

I use terms like Monsantoite indiscriminately with things like “pro-GMOer” or “GMO supporter” simply as a descriptor for anyone who supports the policies of Monsanto and similar firms.  In common usage, the suffix “-ite” refers to someone who supports particular actions or policies—like “Reaganite” means someone who supports the policies of Ronald Reagan.  Do you deny that you support Monsanto’s policies?  If I’m wrong about that, I’d be delighted to admit it. 

He's wrong in that "the current system in the United States" ... "considers most chemicals innocent until proven guilty."  That is the biggest lie I've heard all day.

Whether the statement is true or false is irrelevant, since I neither wrote nor endorsed it.

EXHIBIT B

TACTIC: EVADING THE REAL ISSUE

Anyone that knows anything about clinical trials can think of many instances where trials ended because of evidence of toxicity.  This is why they are tested for tolerance and side effects.  We understand how molecules work, can make predictions, and then carefully test them.  Chemical compounds that are acceptable for use on food must be re-tested and re-registered if they are used for other applications in agriculture!  There is incredibly stringent oversight. 

This is where virtually all pro-GMO writing misses the point.  Clinical trials may be as stringent as you wish--I don’t for one moment suggest the contrary.  But of their very nature they are and can only be concerned with immediate harm—rashes, digestive upsets or whatever symptoms occur within a short time-period of direct exposure.  There’s no way any test of this nature can say anything about any long-term cumulative effects acting over a period of years or even decades (like those of tobacco for instance—I was diagnosed with emphysema forty years after I gave up smoking).  The only way to reveal such effects is through epidemiology (just like the tobacco-lung cancer connection was first revealed), and even then epidemiology, alone, can’t prove those effects. 

As for your blanket dismissal of 1800 papers, I wonder how many of these you have actually read.

I will say nothing here about the Swanson et al. paper because it would take days.  If you’re prepared to answer my counterarguments, just keep reading smokinggmogun.  Explaining the significance of that paper was, after all, one of the main purposes for which the blog was created.

EXHIBIT C

TACTIC: PRETENDING SOMETHING CONTRADICTS SOMETHING WHEN IT DOESN’T.

The authors of this work note in the Abstract and Introduction that all food additives must be tested and shown to be safe by the FDA and/or manufacturer.  It says it right in the first sentence:

“In the United States, chemical additives cannot be used in food without an affirmative determination that their use is safe by FDA or additive manufacturer.”

I will ignore for now the obvious conflict of interest when that determination is made by the additive manufactures.  As I pointed out above, the main point is that ALL such tests can do no more than detect IMMEDIATE harm, and as the harm that anti-GMOers are complaining about is not immediate but long-term, this sentence is irrelevant.  Before citing the abstract, Dr. Folta would have been wise to take notice of the take-home message in its last sentence: “A program is needed to fill these significant knowledge gaps by using in vitro and in silico methods complemented with targeted in vivo studies to ensure public health is protected.” (My emphasis)

In other words, the FDA itself admits that its database lacks “significant knowledge”. What stops Dr. Folta from admitting as much?

EXHIBIT D

TACTIC: FALSE ACCUSATION

I interpreted Hari's comment as an explanation from on-high, which is probably correct, as she refers to Ph.D. graduate students as "Future Science Students in Training".  It is a reminder of her arrogance. 

As the students’ original letter shows, Ms Hari’s form of address was NOT “a reminder of her arrogance”.  Here’s how they opened it.

“Greetings Ms. Hari,

We are writing to you as a group of students, scientists-in-training if you will.”

Okay, so all she really did was to clumsily or carelessly mangle their self-description.  Big deal.  

EXHIBIT E

TACTIC: IRRELEVANCE

There is no evidence that the EPSPS enzyme, the gene that encodes it, or the Bt protein have consequences outside their targets at levels encountered.  Zero.

I never stated anything about these two examples.

EXHIBIT F

Next. This is really boring.

For the first time I wholeheartedly agree with Dr. Folta.  So I’ll skip ahead to his two most egregious errors and then close.

ERROR 1: SELF-CONTRADICTION.

Between 1992 (where there were no GM crops) and 2011 (where 90% of soy, corn, cotton, sugar beets and canola are resistant to herbicide) there OF COURSE will be an increase in glyphosate use!  

But A FEW LINES EARLIER THERE WAS THE FOLLOWING EXCHANGE:

“Ms.Hari: An even bigger problem with GMO crops is they are being used primarily to increase the pesticide…
 Dr.Folta: Actually decreased pesticide use, Vani.”

In other words, pesticide use decreases when that suits his argument but increases when it doesn’t.

ERROR 2: CLAIMING I SAID THE OPPOSITE OF WHAT I SAID

The reason Hari and Bickerton combine insecticides and herbicides as "pesticides" is so they don't have to admit that insecticide use is decreasing. That's kinda deceptive, but common.

Either Dr. Folta didn’t read what I wrote or he deliberately misrepresented it.  I didn’t admit insecticide use is decreasing?!  I wrote

 “So it is logically possible for insecticide use to decrease while herbicide use is increasing (or vice versa of course).  And that is exactly what is happening, and what inevitably must happen with GMOs.  The logic is simple.  Insects attack plants directly, weeds indirectly (by simply competing for water and nutrients).  Therefore, you can put insecticidal genes into plants (those of Bacillus thuringiensi, for example) and thus decrease the need for spraying.”

In other words, I not only admitted that insecticide spraying can be decreased with GMO crops, I even explained WHY it can decrease, as well as (subsequently) why it MUST increase with herbicides.  And far from “combining insecticides and herbicides as pesticides”, I carefully and explicitly distinguished the three terms.  It’s the Monsantoites in general (not just Dr. Folta) who confuse the terms so that they can wriggle out of admitting that HERBICIDE use is increasing.

Can misinterpretation go further than this?
_______________________________________________________________________

I had hoped for a serious debate on GMOs and their possible shortcomings.  I could still be convinced if anyone came up with arguments that were both cogent and civil.   

Alas, Dr. Folta’s response is neither.  One cannot conduct a civil debate with someone who uses expressions like “That is the biggest lie I've heard all day”, “do I need to really waste my time on this?”, “Okay, I have to do something else tonight”, “Duh!”, “What a stupid, stupid, comment”, or “a cheap facsimile of the real thing”.  One cannot conduct a cogent debate with someone who carefully avoids dealing with points made, while doubling down on previous blanket assertions and dismissing without serious discussion any work that disagrees with his position.

GMO defenders in general (not just Dr. Folta, it would be unfair to single him out) should take note that if they preach only to the choir, they will soon find that their congregation, those as yet uncommitted or uncertain what to believe, have all left.  In other words, they are seriously damaging their own cause.   You cannot influence people by treating them like idiots—you just alienate them and ratchet up the polarization another notch.

I therefore see little point in continuing this particular debate.  However, in subsequent posts on my website, which I re-emphasize is not the GMO anything but smokinggmogun.blogspot.com, I will defend Swanson et al. in a lot more detail, and will welcome any pertinent comments Dr. Folta cares to make.