Naturally Toxic Crowdsourcing

Among a typically mad summer of academic activities, I am nervously trying to finish a chapter on naturally-occurring toxins for a drug metabolism book. Indeed, this entire chapter will be a science-based rebuttal to the timeworn but misled statement, "Natural is safe." So far, I've focused on naturally-occurring toxins that are metabolically activated by the liver such as the aflatoxins from Aspergillus spp. and pyrrolizidine alkaloids from a litany of herbal medicines such as comfrey and teas such as Jamaican bush tea made from Senecio. These two classes of compounds are acutely toxic to the liver because they are metabolized to highly-reactive nucleophiles. With long-term exposure, both classes are liver carcinogens.

From TW Kensler et al., Translational strategies for cancer prevention in the liver. Nature Reviews Cancer 3: 321-329 (2003).

I've also talked a bit about α-amanitin, the RNA polymerase II poision from Amanita phalloides and other Amanita species. Here, I mentioned the treatment of such poisoning with extracts of milk thistle in an intravenous form available in Europe. This 2009 case in California is a great example. But let me ask you: what naturally-occurring toxins would you like to know about? They don't necessarily have to be metabolically activated. Some interesting aspects about their absorption, distribution, or excretion are a plus. For example, I feel compelled to cover E. coli toxins, particularly those due to the recent O104:H4 outbreak, as most recently discussed by Superbug writer, Maryn McKenna. But I want to be sure that I'm not missing anything. The crowdsourced suggestions of the hivemind are greatly appreciated below.

Author: David Kroll

Share This Post On


  1. I once read a mystery novel where water from a vase of chrysanthemum was used to poison someone. Perhaps the chemical culprit was the pyrethrins some mums produce? Not sure that could have killed someone, though… a mystery novel favorite is hemlock, which I’d like to know more about

    • DrR, I’d be interested to know the cause of death in the chrysanthemum poisoning. They have two classes of compounds: the pyrethrins, as you mention, and a sequiterpene lactone, arteglasin-a. The pyrethrins affect sodium channels (and at least one report of a calcium channel) and cause death in insects due to cholinergic hyperactivity. However, people are less sensitive to this effect because we hydrolyze the pyrethrins quite well – unless the prep has piperonyl butoxide, a cytochrome P450 inhibitor that is sometimes added to pyrethrins. However, that would not be in chrysanthemum tea.

      Arteglasin-a can cause severe contact dermatitis and asthma attacks if inhaled, probably due to haptenization via its epoxide moiety. So, the culprit in your novel could be either. These metabolic issues would make chrysanthemum a good addition to the chapter. Could you let me know the name of the book where you read this?

      Hemlock poisoning is due to coniine, a neuromuscular nicotinic receptor antagonist with the deceptively simple structure, 2-propylpipieridine. As a piperidine, it stinks.

      Thanks for the good suggestions!

      • I believe the book was Anne Perry’s ‘Weighed In The Balance’. I read it years ago, I’ll have to dig it up to confirm. This is such a fun project! Look forward to reading more.

  2. David: I was always partial to cone snail venom, just due to its amazingly fast systemic effects, plus the fact that it’s usually produced from strangely kinked-up amino acid macrocycles.

    I’m also a big fan of the natural toxins used by tribal hunters…maybe the alkaloids from frog skin? I also always wanted to know more about poisons found in hemlock teas.

    Let us all know when the book is published!

    • See Arr Oh, in a case of the dose makes the poison, a synthetic version of cone snail venom ω-conotoxin is sold as ziconitide (Prialt). Another case of a poison giving rise to a drug as John Beutler describes below. Zicontide is an inhibitor of voltage-gated calcium channels used for chronic pain syndromes that don’t respond to anything else but it has to be given by intrathecal infusion.

      I know about some of the frog toxins such as the pumillotoxins. I believe that some frogs also make one or more pyrrolizidine alkaloids.

      Good suggestions!

  3. The obvious ones I’d think of would be botulism toxin and ricin. My other personal favorites (as in, they scare me the most) are all inophores that act on H+, so that they become metabolic uncouplers. The scariest ones are of course synthetic (i.e. FCCP, CCCP) but there are some such as Gramicidin and Nigericin that are biologically-derived.

    • Ricin is cool (scary cool, of course) because of its potency in inhibiting ribosome function but also because it has cellular internalization sequences. It can be metabolized by peptidases but it’s just so potent that it has to be completely metabolized to be inactivated.

      Botulinum toxin is, again, another poison-turned-drug. But not just for cosmetic purposes. It has efficacy against migraines that are resistant to triptan therapy.

  4. Cyclopamine is a good story, a teratogen to livestock, now the basis for a drug candidate. Cardiac glycosides. Ibotenic acid/muscimol from Amanita muscaria. Don’t think there are major metabolism stories in those that I know of, though. The Senecio alkaloids and aflatoxins are about as good/bad as it gets. Amanita toxins not metabolism but enterohepatic cycling increases toxicity.

    • Great suggestion about cyclopamine, John. I saw Ervin Epstein talk at AACR in April about the Genentech/Roche/Curis cyclopamine-based hedgehog inhibitor, GDC-0449. Pretty impressive stuff so far.

      Good point about enterohepatic recycling of Amanita toxins. I had forgotten that.

      Thanks so much, John!

  5. “Indeed, this entire chapter will be a science-based rebuttal to the timeworn but misled statement, “Natural is safe.”” Wonderful, look forward to it!

  6. There’s the case of Germander extracts used as weight loss supplements in Europe. They can also be quite hepatotoxic, owing in part to metabolic activation of components. Evidently some still make a tea from germander for various indications.

    • ‘belle, thanks so much for the germander reminder. Turns out that many plants have prohepatotoxins. I’ll probably have to devise a table for them. Just like germander, I still see teas made from comfrey being sold in herbal catalogs and online. Not a good idea to drink but a good idea to put in this chapter. Thanks!

  7. Saxitoxins are pretty interesting. The cause of paralytic shellfish poisoning, they can be a real pain for coastal seafood industries.

  8. How about algal toxins in seafood (domoic acid, saxitoxins,brevetoxins, ciguatoxins, cyanotoxins, okadaic acid) or freshwater ponds, lakes and water sources (cyanotoxins)?

    • Glen and Mol, good points about the algal/marine toxins. Both of your comments were stuck in my moderation queue so you didn’t see each other’s at the time your wrote here.

      This interesting PDF on saxitoxin from the University of Alaska Fairbanks describes how some shellfish can metabolize the dinoflaggelate toxin to more or less toxic species. I had no idea that it was a problem as far north as Alaska.

  9. Hey David,
    I thought about you this past week when I was in NY for a family event and needed to, ahem, depilitate my legs. My preference is waxing and i went looking for my favorite brand, with no luck. Instead, I found Nads Body Hair Removal Strips. The label said, “contains natural beeswax” and the excess wax removal wipes contain “desensitizing kava”.

    Well, a week later, my legs are still itchy from the intense, red rash. Needless to say they looked really, really pretty under my party dress.

    Now, I don’t known if it’s an allergic reaction to the kava. doubt it. (I actually chewed the stuff when I was a volunteer in the Pacific), or if it was to the prunus amygdalus dulcis (sweet almond), calendula oil, bisabolol parfum, or the coco-caprylate caprate… or the other ‘natural’ ingredients. Or maybe it was the beeswax…

    Sigh. Itchy.

  10. How about cyanide containing compounds found in bitter almond, that peach pit cancer cure in mexico, and kasava?

    Most people thinking “natural” wouldn’t think cyanide

  11. Hi David,
    Thanks for an awesome post. I hope my comment is not coming a tad too late. As I was going over some of the suggestions, i couldn’t help but think about some people I know back home who “we” were told had neurolathyrism.
    I remember my dad telling me( I am originally from Ethiopia) and after cycles of drought, because of lack of access to their regular staple, people( especially in the north) shift their diet to legumes that are sturdy and grow in water-scarce environments. I think one of these legumes( Lathyrus Sativus), after heavy ingestion and specially if combined with milk( I don’t know what the association is) potentially causes paralysis. Growing up, I remember seeing these people with a distinct kind of waddling gait and being told they “were crippled by the Guaya plant”( Guaya is the local name for the seed). I think that is one good example that “natural” is not always safe. What do you think?


  1. Legislation to protect men from PDE5 inhibitors | Terra Sigillata - [...] been rather quiet here as of late, Dear Reader. Between my new day job and trying to finish my…