Thursday, December 30, 2010

What Can Modern Toxicology Tell Us About Food Toxins and Food Intolerances?

by Chris Masterjohn

"The dose makes the poison." — Paracelsus (1493-1541)
"What is food to one is bitter poison to others." — Lucretius (ca. 99 BC -- ca. 55 BC)

This post will be the first in a series of posts on food toxins and food intolerances.  As an introduction, I'd like to review some of the recent advances in our understanding of toxicology, to see how a basic understanding of toxicology might be able to shed some light on the toxicity of foods.

Although the sayings attributed to Paracelsus and Lucretius above may seem contradictory, taken together they capture two central concepts of modern toxicology.  Some drugs, for example, are just inherently toxic at high enough doses.  Reactions to these drugs are called type 1, type A, or "intrinsic" adverse drug reactions.  Other drugs only produce toxicity in suscpetible individuals.  Reactions to these drugs are called type 2, type B, or "idiosyncratic" drug reactions.  Some authors call them "bizarre" drug reactions (1).  Idiosyncratic reactions are estimated to account for 13% of all drug-induced liver injury (2) and somewhere between 5% and 20% of all adverse drug reactions (1).

In reality, the separation of drugs into some that produce "intrinsic" toxicity and others that produce "indiosyncratic" toxicity is probably an illusion.  For example, acetaminophen (e.g., Tylenol) is the drug most commonly responsible for intrinsic drug reactions, but over a third of people develop clear signs of liver toxicity when taking the maximal dose allowed on the label, while nearly a fifth of people tolerate the dose with complete impunity (3). 

One review (4) recently argued that all drugs have a therapeutic curve and a toxicity curve, but with drugs whose toxicity is usually called "idiosyndratic" the toxicity curve just lies much further away from the therapeutic curve:

Figure from Roth, R.A. and P.E. Ganey, Intrinsic versus idiosyncratic drug-induced hepatotoxicity--two villains or one? J Pharmacol Exp Ther, 2010. 332(3): p. 692-7.

In the case of the intrinsic reaction, shown at the top, the therapeutic (left) and toxicity (right) curves are fairly close together, so that toxicity predictably develops at a high dose.  However, as indicated by the arrow, individual susceptibility can shift the toxicity curve leftward so that it overlaps with the therapeutic range.  This would allow, for example, someone to develop toxicity taking Tylenol at an approved dosage.

In the case of the idiosyncratic reaction, shown at the bottom, the therapeutic (left) and toxicity (right) curves are very far apart.  Since the liver toxicity curve lies to the right even of the lethal dose, liver toxicity never develops under normal conditions.  However, once again, individual susceptibility can shift the toxicity curve leftward so that it overlaps with the therapeutic range.  This allows the "idiosyncratic" or "bizarre" reaction to occur.

In other words, these aren't two types of reactions, but they are two principles that are important in any toxic reaction: how dangerous the toxin is, and how susceptible the person is.

Food toxicities and intolerances also clearly involve both principles.  On the one hand, celiacs predictably improve in the majority of cases by removing gluten from their diets and many non-celiacs benefit as well.  On the other hand, many people eat grains, beans, peanuts, salicylates, oxalates, glutamates, amines, polyphenols, barbecued meat, bacon, and every other potentially toxic food and food chemical with impunity until they die at a ripe old age, sometimes over the age of 100.

What, then, contributes to this individual susceptibility?

Let's turn again to modern drug toxicology and see what we find. 

Here are a few of the well studied factors that contribute to individual susceptibility:

Nutritional Status.  Acetaminophen causes toxicity in part by causing a massive 90% depletion of glutathione, the master antioxidant and detoxifier of the cell.  (See my related blog post, "The Biochemical Magic of Raw Milk and Other Raw Foods: Glutathione.")  The standard treatment is N-acetyl-cysteine, a highly bioavailable form of the amino acid cysteine, which our cells use to make glutathione.  It is especially effective at mitigating the toxicity of acetaminophen when provided during the first ten hours of toxicity (5).

Intestinal Flora. In the 1970s and 1980s, researchers provided compelling evidence that the mechanism by which galactosamine, carbon tetrachloride, and halothane produce liver toxicity is by causing the movement of endotoxin from the gut into the bloodstream (6).  If they added endotoxin, the toxicity increased.  If they provided any number of materials that "mop up" endotoxin in the intestine, without adding any additional endotoxin, they could prevent the toxicity of these chemicals.  Nowadays, researchers are investigating the role of endotoxin in priming a person to idiosyncratically react to the antidepressant chlorpromazine, the antihistamine ranitidine, the antibiotic trovafloxacin, and several NSAIDs.  Endotoxin is a component of the cell wall of gram-negative bacteria.  Many stressors can temporarily increase the transport of endotoxin across the intestinal barrier, while probiotics decrease the levels of endotoxin in the intestine.

Genes.  C57BL/6 mice are used for many experiments.  Although researchers often make additional genetic modifications to these mice, they are actually already genetically defective: they have a genetic deficiency of the enzyme that converts the B vitamin niacin from its NADH form to its NADPH form, which is needed to recycle glutathione (7).  Researchers have further used these mice to create a deficiency of the maganese-dependent enzyme superoxide dismutase, which, like glutathione, is critical to the cell's natural antioxidant defense system.  These mice suffer from poor mitochondrial function as a result.  They develop toxic reactions to flutamide (7) and troglitazone (8), two drugs that are considered "idiosyncratic" and are otherwise difficult to use to produce toxicity in animals.  About one in 5,000 people have a similar genetic mutation, although many people may have poor mitochondrial function for nutritional, lifestyle, and other reasons.

Immunological Reactions.  About a fifth of idiosyncratic liver toxicity is associated with immunological signs and symptoms such as eosinophilia (an increase in a certain type of immune cell in the blood), rash, fever, and autoimmune  antibodies or antibodies to drug-modified proteins; when these occur, they generally occur within one to six weeks after beginning the drug (9).  Some authors argue that the immune system could confuse "self" and "nonself" when toxic drugs form complexes with proteins, causing the immune system to recognize the protein itself as toxic (10).  Others argue that the immune system does not have anything to do with recognizing "self" or "nonself" but instead recgonizes "danger," and that it is tissue damage that causes the immune system to come along and clean up the mess, including cleaning up our own proteins when they are damaged or spilling out where they don't belong (11).  The role that these immunological reactions play in toxicity, whatever their cause, remains obscure.

This is not a comprehensive list of factors that affect drug toxicity, but it contains some of the most important kinds of factors, and gives us a clue what types of things to look for when understanding why some foods are toxic.

Here's a brief outline of some of the factors that are most likely to be involved in food toxicity and food intolerance:
  • The intrinsic toxicity of the food. 
  • Proper preparation of the food to neutralize the toxins.
  • Genetic, and perhaps epigenetic, variations in the activities of enzymes and other proteins that activate the toxin, detoxify the toxin, transport the toxin, or mount an immunological response to the toxin.
  • Variations in intestinal flora, including bacteria that degrade the toxin or bacteria that counteract the body's detoxification mechanisms.
  • Secretion of sugars such as mannose into the digestive system that bind to lectins (such as gluten) and protect against their toxicity.
  • Secretion of IgA antibodies into the intestinal tract, which bind to undigested food particles and protect against their toxicity.
  • Variations in nutritional status, including nutrients involved in modulating the immune response, supporting detoxification mechanisms, and protecting the integrity of the gastrointestinal tract.
How these factors should be expected to affect the toxicity of wheat, other grains, beans, oxalates, amines, salicylates, and various other foods and food toxins will be the subject of upcoming blog posts.

Stay tuned!

Read more about the author, Chris Masterjohn, PhD, here.


1. Pirmohamed, M., Pharmacogenetics of idiosyncratic adverse drug reactions. Handb Exp Pharmacol, 2010(196): p. 477-91.

2. Holt, M. and C. Ju, Drug-induced liver injury. Handb Exp Pharmacol, 2010(196): p. 3-27.

3. Watkins et al., Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):87-93.

4. Roth, R.A. and P.E. Ganey, Intrinsic versus idiosyncratic drug-induced hepatotoxicity--two villains or one? J Pharmacol Exp Ther, 2010. 332(3): p. 692-7.
 5. Hinson, J.A., D.W. Roberts, and L.P. James, Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol, 2010(196): p. 369-405.

6. Lind, R.C., et al., The involvement of endotoxin in halothane-associated liver injury. Anesthesiology, 1984. 61(5): p. 544-50.

7. Kashimshetty, R., et al., Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity. Toxicol Appl Pharmacol, 2009. 238(2): p. 150-9.

8. Ong, M.M., C. Latchoumycandane, and U.A. Boelsterli, Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities. Toxicol Sci, 2007. 97(1): p. 205-13.

9. Pachkoria, K., et al., Genetic and molecular factors in drug-induced liver injury: a review. Curr Drug Saf, 2007. 2(2): p. 97-112.

10. Pessayre, D., et al., Mitochondrial involvement in drug-induced liver injury. Handb Exp Pharmacol, 2010(196): p. 311-65.

11. Li, J. and J.P. Uetrecht, The danger hypothesis applied to idiosyncratic drug reactions. Handb Exp Pharmacol, 2010(196): p. 493-509.


  1. Chris, Congratulations and Thanks.

    I use the Paracelsus reference, but did not know that Lucretius had enunciated something similar.

    I also try to judge whether a cause is a trigger or predisposing condition.

    Stimulus response curves for therapy and toxicity are a beautiful description of effects.

    Great post.

  2. This is great information, thanks! I'm very interested in food intolerance because I have some issues that I know are absolutely related to food. Figuring out how to fix them has been a challenge.

    Your post outlines what irritates me most about so-called modern medicine. Doctors seem to believe that a treatment should be applied equally to all patients and if something "strange" occurs then they throw their hands up in the air and give up, even if the treatment has caused major problems. Worse, they will accuse the patient of being a hypochondriac as a defense mechanism rather than admitting their ignorance. Medicine is going to remain in the dark ages until methods are devised for personalizing treatment for each unique individuals rather than treating everyone the same.

  3. You should join the Polar Bear Swim Club after this promised plunge.

  4. Hey Leon, thanks! I think the two were saying something quite different, but they are very complementary.

    Dave, thanks, and you're welcome! Regarding medicine, right on. I hope the future posts prove useful.

    ...AL, what?


  5. More posting glitches.
    You're tackling an adventurous subject; so obviously got what it takes to defy fear and go where only the Polar Bear club dares.

  6. Maybe you'll include the potential damage modern people risk by taking mega-doses of supplements. Something being good for you doesn't mean more is better.

    Glutathione we make from cysteine, glycine and/or glutamic acid. In it's nucleophile way it saves us from reactive oxygen species.

    Quercetin is a flavenoid that neutralizes our naturally produced hydrogen peroxide. Marketing has people buying quercetin since they believe more anti-oxidants is better.

    The byproduct of that anti-oxidation reaction leaves a quercetin compound. It goes on to bind to our circulating glutatione's thiol group (a sulphur, carbon and hydrogen formation). That end product takes glutatione out of play for other toxicological use.

    That rump quercetin is a fast acting and
    tenaciously binding thing. If we are low in glutathione it snags other thiol proteins in us. In the process it makes a cell's
    membrane more permiable to that cell's detriment.

    A rise in the % of free calcium occurs in the cell cytosol. Briefly put, that is not good. Since key sulpher pathway enzymes depend on that filched thiol there is a risk for localized catechol-amine toxicity.

    When a thiol is peeled off of a
    mitochondrial protein the enzyme NAD(P)H de-hydrogenase underperforms. This depresses the mitochondrial energy reduction/redux fluctuation; and that's not desireable. Even more sinister is the provoked increase in Ca++ loose in the mitochondria that you don't want.

  7. Hi ...AL

    I agree quercetin supplementation is probably not a good idea. Thiol-binding isn't necessarily bad though, at the right dose. In modest doeses, this should stimulate Nrf2 pathway activation and increase antioxidant defenses via transcription. At high enough doses it should produce something that looks like acetaminophen toxicity. Eat quercetin-rich foods is probably a good idea.

    And yeah, I'm not afraid of writing about food intolerance. Even if the topic can get a little emotional sometimes.


  8. Lectin glyco-proteins, like wheat germ agglutinin (soybean agglutinin another common one) block the intestinal ion-ophore mucus secretion by underlying goblet cells. Micro-villi exo-cytosis repair of intestinal epithelial cells is not going forward. They need Ca++ to run a key part of a bio-chemical reaction or damage to the site persists.

    Lectins shut down this repair very quickly on contact; I've heard within a minute. And of course, big bad evil sugar at that same shut down site reverses the inhibition of repair in +/- 5 minutes.

    Bring on the studies of cultures that favor a sweet desert after their main meal. Sudents of dietary habits see people eat sugar and interpret the significance as they are taught "nutritionally".

    P.S. I agree: no taboo on quercetin

  9. @AL,

    I would like to get your opinion about an article I saw that recommended supplementing pyrroloquinoline quinone for repair and actual generation of mitochondria. Is there a way to communicate with you without hijacking Chris's blog?

    The article is at and yes, they do sell a supplement containing PQQ.

  10. Might-o'chondri-ALJanuary 1, 2011 at 3:22 PM

    Toxi-co-logic (pun?)implies intrinsic and idiosynchratic pathways share genes. The up/down regulation makes for pathological changes.

    A noxious, or chemo-actived, pathway intrinsicly messes with a cell membrane. Chemicals alter membrane polarity and signal pathways get distorted. Genes go on to under/over express and the cell suffers.

    A toxic idiosynchratic pathway works by signaling downstream cascades. Cancer's steps are an extreme example of this toxicology.

    about pyrroloquinoline quinone: I've no special insight - maybe Chris does

  11. Absolutely off-topic but I had posted this over at the WAP blog regarding D/A amounts.

    I had recently tracked my dietary intake for 3 days and my average A intake was 19167 IU (RAE of 2336.57, if it matters). I take a 5000 IU vitamin D at least 6 days out of 7 and my last blood test showed a serum D level of 80.17ng/ml. Can you see any need for me to take additional A?


  12. My, my. These details on quercetin are very much the opposite of what I've been hearing.

    Recent studies have suggested that quercetin is the only thing apart from strenuous exercise that seems to cause mitochondiral proliferation. It certainly increases VO2Max, and in endurance-stressed athletes it prevents suppression of the immune system (ie prevents the "post-marathon flu").

    It stops the proliferation of cancer cells, at least in vitro, and there is some evidence that it acts to restore the mitochondrial function of cancer cells (cancer cells normally suffer mitochondrial dysfunction and rely primarily on glycolysis for cellular energy).

    The hype I've been hearing about quercetin isn't because of its antioxidant function.

  13. BTW, as long as you're going to be talking about wheat, do you have any reflections on this seeming paradox--

    I have encountered a few people in health food stores who claim to be violently gluten-intolerant...but who eat seitan with no adverse reactions, totally unaware that seitan is wheat gluten in its purest form.

    Now, this might simply mean that there are a lot of people out there whose reaction to gluten is all in their minds.

    But it also might mean that a lot of people who are classed as gluten-intolerant in fact have no problem with gluten, but instead have a problem with with something else in the wheat--something that is removed when the gluten flour is exhasutively washed to concentrate the protein.

    Any thoughts?

  14. Chris, this statement has me intrigued.

    "Secretion of IgA antibodies into the intestinal tract, which bind to undigested food particles and protect against their toxicity."

    Is this the method by which our bodies attempt to protect us against gluten?

    I don't understand the difference between people who tolerate gluten differently. Based on your snippet, I'm wondering if a big difference between them might be their bodies success in "neutralizing" the gluten in the intestine via IgA.

    Can you direct me to any further reading to help me understand why it is that different people seem to tolerate gluten differently?

  15. Might-o'chondri-ALJanuary 3, 2011 at 2:41 PM

    3rd attempt, problem-O posting here more than elsewhere....

    The "quercetin paradox" of improved mitochondrial function involves the home-stasis between apoptosis (cell "suicide") and phagocytosis (cell "house cleaning"). Necrosis, a distinct toxicological event, is different from these.

    Pharmacolgy tritrates doseages by body weight and observes age related contra-indications. Genetic vulnerability to the "law" of unintended consequences is my concern about supplements.

  16. Might-o'chondri-ALJanuary 3, 2011 at 6:51 PM

    Cancer paradoxical resilience is unique. Yes, those cells have mitochondria - but their glycolysis (carbon cleaving)is their hallmark.

    Cancer cells practise anaerobic glycolysis and trend to hypoxia (low oxygen)inside. It means they cleave carbon in their cytosol, make a bit of ATP (energy) and pass a few NADH to their mitochondria for more sparse ATP net energy gain. People with advanced cancer lose weight (sure, the cancer bulks up)because anaerobic glycolysis is a waste of energy.

    Aerobic glycolysis is more a mitochondrial boon. An initial step of carbon cleaving in the cytosol still occurs. Then it does more efficient ATP generation in the mitochondria ( freed "radical" oxygen species are spun off in the mitochondrial processes).

    Cancer cells' anaerobic energy metabolism spares their mitochondria damage from big load of reactive oxygen species. If , something "restores" mitochondrial function in them the organelle would then get "hit" with free radicals.

    Cancer cell(s ?) in a lab may go into apoptosis and fragment it's (their ?) DNA. In the body the histone in a cancer cell's chromatin (chromatin = packaging protein and DNA wrapped around histone)seems to have epigenetic "memory". The histone does an acetylation trick that brings the cancer DNA back from the brink.

  17. can you expand on the comment you left over at leangains about the adrenals and your patients experiences with regulating them. i am a year in IF sometimes with a smaller than 8hour window and i still have unregulated BG readings. i was wondering how you would go about repairing this.

    macros wise?
    3hr eating windows?


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