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There’s Toxicity, And There’s Toxicity

This is a neat article at Bloomberg about the production of botulinum toxin (BTX, aka Botox). This is a drug that has some rather special handling involved:

A baby-aspirin-size amount of powdered toxin is enough to make the global supply of Botox for a year. That little bit is derived from a larger primary source, which is locked down somewhere in the continental U.S.—no one who isn’t on a carefully guarded list of government and company officials knows exactly where. Occasionally (the company won’t say how frequently), some of the toxin (the company won’t say how much) is shipped in secrecy to the lab in Irvine for research. Even less frequently, a bit of the toxin is transported by private jet, with guards aboard, to the plant in Ireland.

Now, all drugs have biological activity, or they wouldn’t be drugs. But some of them are definitely more active than others, and BTX is at the far end of the scale. To give you the idea, on a mg-per-kilo basis, I believe that its fatal dose is at least five orders of magnitude lower than Sarin nerve gas, a fact that will definitely make an industrial safety director sit down and think about career options. There are quite a few wildly toxic peptides and proteins, since they’ve had plenty of time for evolution to sharpen the spear points, but to the best of my knowledge, botulinum is the winner – read on.

It’s hard to rank these things exactly. Venoms are usually mixtures of several nasty constituents, for one thing, and there aren’t many cases where all the components have been tested as pure substances. Route of administration is a big factor – venoms get injected, which is generally bad news, but this doesn’t happen under very controlled conditions, to put it mildly. And rankings of dangerous species are helpful for real-world risk analysis, but don’t reflect the underlying toxicities. I have read, for example, that Maricopa harvester ant venom (LD50 120 micrograms/kilo in mice, i.v.) is worse than that of the black mamba on a weight basis, which makes me glad that they’re so small (although, to be sure, you’ll run into a lot more of them simultaneously than you will black mambas). The worst animal venom is believed to be that of some species of marine cone snail, with a lethal dose in humans of around 30 micrograms/kilo, although box jellyfish venom is probably in the same class). Here’s a table with some collected values under different conditions.

In the non-venom protein toxin world, the most well-known is ricin, but that’s another case where the definitions get tricky. Ricin, as isolated, is often not very clean – fortunately – and even when purified is still a mixture of several proteins, with Ricin D as the worst of the lot. At their worst (via inhalation), ricin toxins are down in the single-digit microgram/kilo range, which is very bad. There are many others in this group (amatoxin comes to mind, down in the 100 microgram/kilo range), which normally would be considered very dangerous indeed, but not when you’re competing with ricin and botulinum.

In general, small molecules can’t quite get down to those levels of toxicity. Anatoxin A is one that comes to mind as being particularly awful (its alternate name of VFDF, or Very Fast Death Factor, is certainly a tipoff), and tetrodotoxin is not to be messed around with, either. Trying to rank these is similarly difficult, because you have species differences, those route of administration differences, and so on. Amatoxin is probably a bit worse than tetrodotoxin (estimated lethal oral dose in humans of the former is 100 micrograms/kilo; LD50 in mice for tetrodotoxin is in the 300 micrograms/kilo range). Anatoxin-A is in a very similar range. There may be some marine toxins that beat these (I’m all ears), but in general, I don’t think that small molecules can compete with the true horrors.

It gets trickier, though, when you’re just talking about potency, rather than out-and-out toxicity. Those toxin numbers above are for lethal doses, and far smaller ones will produce physiological effects. That takes you into the territory of small molecules like LSD, famously potent although not particularly toxic. The dose of LSD needed to produce a noticeable effect is variable, but is generally agreed to be at or below 0.2 micrograms/kilo. Now that’s potent (and that’s why Albert Hoffman’s coworkers were skeptical when he reported his accidental exposure to it). This is the most biologically potent small molecule I’m aware of (activity 200 nanograms/kilo is nothing to mess around with, in my book) – I will be glad to hear about other contenders in the comments section.

But back to botulium, now that we have the range of things. The LD50 for it in humans is estimated at about 2 nanograms/kilo i.v., 10 nanograms/kilo by inhalation. The amount that causes noticeable effects is far lower (in fact, I’ve had difficulty this morning figuring out just how much toxin is in a typical cosmetic injection). As you can see, that beats everything out there, and thus the precautions at the Allergan plant. There is no way whatsoever that I would consider handing this substance in any sort of concentrated form, and “concentrated” runs down to such ridiculously miniscule amounts that it’s best just to stay away in general. It is, fortunately, not that easy to produce or purify (Allergan is holding a number of trade secrets in this area), and as the article mentions, no company has made a successful run at a Botox biosimilar yet, despite its sales of billions of dollars per year. There’s nothing else like it. And that’s a good thing.

84 comments on “There’s Toxicity, And There’s Toxicity”

  1. anoano says:

    can Botox be considered homeopathic drug?

    1. Sal says:

      I imagine the production of the stuff resembles homeopathic preparations.

      1. Isidore says:

        Hardly homeopathic. The LD50 is 2 ng/kilo and 2 ng of the toxin is a little over 1 fmol, which is about 600 million molecules. I have no idea what the dose is for cosmetic or therapeutic treatments, but if it is, say, 1000 times less than the LD50 it would still amount to ~600,000 molecules per kilo or about 40 million molecules for an adult.

        1. Chester says:

          Botox is sold in 100 unit vials, and each vial is diluted and dosed such that each 0.1 mL injection contains 4 units. I found a reference saying that 100 units of Botox contains 0.73 ng of botulinum toxin. Based on that, it seems that each injection contains 117 million molecules of botulinum toxin.

          1. Isidore says:

            I was off by a factor of 13, so the LD50 is about 8 billion molecules and a botox injection consists of ~1 billion molecules. Wow, not much margin of error here!

          2. Jason says:

            FWIW, a human LD50 is around 3800 Units (1 Unit is a mouse LD50). So a 100 Unit vial is only 1/38th of a human LD50. For cosmetic purposes, only part of a vial is used.

    2. Derek Lowe says:

      Not at all. If you have an active ingredient with a dose-response curve (less compound, less effect) then you are not talking homeopathy. Homeopathy is where less compound, plus more water-shaking, actually is supposed to make things *stronger*. Which is ridiculous. And according to homeopathic principles, you would give something like botulinum to cure paralysis, too.

      1. milkshaken says:

        few years back, there was a case of a plastic surgery doctor who thought he could make extra buck from botox injections, by not using the approved drug but buying the active substance from a lab supply company, and making his own solution. He must have made some kind of decimal error, because the two women he injected and himself all ended up in ICU – they were paralyzed and on ventilator for something like a month because the effect is very slow to wear off.

        1. Patrick says:

          One (Alma Jane Hall, his girlfriend and employee) was paralyzed for 4-5 months. She still suffers physiological symptoms 13 years later.

          We work with BoNT routinely – in our hands, the mouse LD50 is 0.4 ng/kg. Since it is a select agent, the oversight, auditing and tracking by the biosafety office is nontrivial. My favorite part is that the CDC exempt quantity is 1 mg of toxin…

    3. Barry says:

      To be “homeopathic” the response would have to go up as the concentration went down. Botox follows a perfectly normal (albeit shifted) dose/response curve.

  2. GutDecipher says:

    What about Ligand Efficiency metrics? I want atom economy in my toxins!

    1. Barry says:

      LD50 is already expressed in mass, not in moles, so the ligand efficiency is already rolled into the math.

  3. Anon says:

    I am wondering how the “voodoo magic” works in Haiti, where it is popular. The guy who goes into coffin takes some kind fish or portion loaded with tetradotoxin/saxitoxin, and once the drug wears off, people show up alive. They may not be chemist or toxicologist, but their experience pays off!

    1. Derek Lowe says:

      The state of the literature on this topic is confused, to say the least. It runs all the way to “never been actually used”.

      1. MoMo says:

        E. Wade Davis described this in his book The Serpent and the Rainbow. Villagers exact Haitian justice by dusting the doorway of the perps home with puffer fish extract containing tetrodotoxin. Said perp crosses threshold, goes into a state of suspended animation, and the villagers bury him in box until just enough of his frontal lobe is killed off and he or she is let out.
        Sounds feasible to me, and a good way to keep criminals at bay.

        1. L Crocker says:

          Yes, but a lot of scholars including experts on toxins have called his account into question. There is a reason why you won’t find Davis’s book cited in the bibliography of anthropologists and related scholars working on Vodou in Haiti. As one prominent scholar put it, Davis’s book had “As much fiction as field work.” (see: C Arthur and M Dash, Libete: A Haiti Anthology (Kingston, Jamaica: Ian Randle, 1999), at 315)

          When the powders Davis brought back were tested, they did not have significant amounts of the chemicals he claimed and toxicologists found no evidence they would have produced the results Davis says he saw. See: T Yasumoto and CY Kao, see note 9 above. See also CY Kao and T Yasumoto, “Tetrodotoxin in ‘Zombie Powder’” (1990) 28(2) Toxicon 129-132.

          While it is true that there are zonbi ko kadav in Ayiti (the kind of zombie where the personality-soul is believed to be removed leaving behind a husk of a person that is easily controlled) no other scholar has ever witnessed one being made. It is a threat made for violating the most fundamental social ethics and/or of violence from someone like the infamous dictator Papa Doc. You don’t need toxins to explain how a community that was ravaged by a particularly brutal chattal slavery and then brutal dictators could develop a folklore about your soul being chained to a master who can force you to do hard labor.

          1. MoMo says:

            Yes, the story is well known, but there are 2 things wrong with this – Cao’s methods were called into question and the “prominent scholars” are a couple of editors who compile others work.

            Wade Davis is a serious scientist and awarded many accolades for his work in Ethnobotany and, other cultures, and world travel. Cao’s paper cant even be found in Toxicon and probably didn’t even use LCMSMS.

            Now the only Zombies encountered are those on the streets of all cities including Cambridge, in suspended animation while staring at cell phones.

          2. Anon says:

            @MoMo
            Kao and Yasumoto’s letter in the Toxicon is still available: https://doi.org/10.1016/0041-0101(90)90330-A
            It certainly strongly questions the amount of TTX that was reportedly found in the zombie powder (in only one of six samples tested.) It makes a neat story, but there is basically no convincing evidence that TTX plays a significant role in zombification. This story at least seems to be a case where the cart was put before the horse

  4. pete says:

    I’ve read claims that a *single atom* of radioactive plutonium inhaled and deposited into the lung can result in almost certain lung cancer. The idea being the locally absorbed ionizing “hit” due to intense alpha emission will in time absolutely generate carcinogenic founder cells.

    Is it true? How do you prove that ? (And is it true for different plutonium radionuclides ?) — Dunno. But, if true, and from the standpoint of relative toxicity, then that’s gotta take the cake in “Tox-World”.

    1. SirWired says:

      That is not correct. If it were true, nuclear tests involving plutonium-based bombs would have wiped out much of the world population. The Fukushima disaster would have decimated Japan. You get the idea…

      As far as intensely dangerous radioactive substances go, plutonium is not especially dangerous. You can even ingest small amounts and survive for many decades.

    2. road says:

      Sounds like nonsense to me. A single atom will only produce a single alpha decay which should only be possible of causing at-most a single mutation. The likelihood that a single mutation would be carcinogenic is close to zero.

      1. pete says:

        I take your point but isn’t there successive a chain of emitters formed as plutonium decays — until you get to something stable ?

        1. Mr. Eldritch says:

          Plutonium-239 (the main isotope for reactor fuel and weapons material) has a half-life of 24,100 years. You will be exceptionally unlucky if your single inhaled plutonium atom decays at all; so worrying about dealing with the decay products is pretty much irrelevant.The other isotopes you might encounter, Pu-240 and Pu-238, have half-lives of 6,560 and 88 years respectively.

          (So that latter might actually decay; but Pu-238 decays into U-234, with a half-life of 246,000 years. So we still don’t need to worry about side product radiation from our single atom)

          Basically, any given atom of plutonium is going to lead to either zero, or one if you’re really unlucky, decays in your lifetime.

          There IS a hypothesis that small “hot particles” of radioactive material (quite a bit bigger than single atoms) might be a really serious problem, for basically exactly the same reasons you cited; so that’s probably what you’re thinking of. But as far as I can tell, it is still a hypothesis, and a fairly controversial one at that.

          1. pete says:

            Thanks and ok then. I’ll just sit down now.

    3. Vader says:

      “I’ve read claims that a *single atom* of radioactive plutonium inhaled and deposited into the lung can result in almost certain lung cancer. ”

      You need to select your reading material a little more carefully.

      As others have pointed out, a fair amount of plutonium got into the atmosphere during the era of atmospheric testing, and yet the earth was not rendered lifeless.

      This is not to say that plutonium is not really nasty stuff, nor to deny that a really small dose greatly elevates cancer risk if inhaled as fine particulates. But “one atom” is hysteria.

      1. scott lloyd says:

        There is or was a group of los alomas scientists who were exposed to Pu and had detectable levels of Pu in there urine the rest of there lives. most ofthem were young when exposed and lived to old age I just cant remember if any are still alive now because of age.

        1. AlphaGamma says:

          The UPPU club (named because they had plutonium detectable in their urine). Several were alive in 2015, as far as I can tell- their mortality rate was 50% lower than the national average.

          There’s also Albert Stevens, who holds the record for highest accumulated radiation dose survived by a human. He was injected with 131 kBq of plutonium without his consent in 1945. He had been chosen for this experiment because he had been diagnosed with terminal stomach cancer, but it turned out to be a curable ulcer. Stevens died of heart disease 20 years later, aged 79, having received an accumulated dose of 6400 rem.

          1. tangent says:

            What. the. hell.

            I see the guy who led this experimentation died himself of leukemia at 49, which it’s hard to be sad about.

    4. Sf. says:

      I can find the source of confusion. Not a single atom – a single radionucleid.

      These things are the border of macro/microscopic; pieces of dust micrometers big. They contain alpha radiation sources, which, while mostly harmless in the environment due to short range of the alpha particles, become lethal when inhaled, causing either perforation of the intestine if caught in the digestive tract, or lethal lung damage if inhaled with air.

  5. Mzspectrum says:

    I think polonium is the closest? Microgram quantities kill large adults.

    1. Wavefunction says:

      It gets tricky when it comes to poisons and especially radioactive poisons since one has to distinguish between acute and chronic toxicity. For instance, polonium has high acute toxicity while strontium-90 has high chronic toxicity. The amounts required to produce the two kinds might not be the same. You start getting into interesting territory once you get into discussing chronic toxicity; for instance, spread over a large amount and a long period of time, few substances can beat the chronic toxicity of cane sugar.

      1. Ted says:

        Agreed. I do a lot of work on Aflatoxin, and it generates a host of maladies at a wide range of exposures. 10 – 20 mg/kg to kill you outright (aflatoxicosis is high on the list of terrible ways to go…), but the TD50 for liver cancer is down at single digit µg/kg/day… and of course, acute but less persistent exposures expand the sliding scale.

        -t

      2. Kofiman says:

        Dose makes the poison, again and again. Mercury would be a much more straightforward chronic poison that doesn’t require massive doses to produce toxic effects. Or in this case, loose correlations with arguable statistical effects.

        1. BJ says:

          Depends on what it’s compounded with. Elemental mercury is not all that toxic. One woman tried to kill herself by injecting 10 ml. (135 g) She survived with no apparent long term effects.

    2. Anon says:

      Yea, the agent Alexander Litvinenko and the poison umbrella tip killing of Georgi Markov come to my mind.

    3. Project Osprey says:

      Mad as it sounds Polonium-210 is present in tobacco smoke

      1. anonymous says:

        Is your tobacconists a subsidiary of the FSB?

        1. Scott says:

          No, tobacco naturally fixes polonium out of the ground and air.

          What should scare the everliving daylights out of you is that polonium is radioactively hot enough to emit Cherenkov radiation in air. Uranium? Nah, new fuel rods won’t even glow underwater. Plutonium? Well, spent fuel rods do glow underwater, but as to whether that’s from the Plutonium or some other interesting radioactive is something I don’t know.

          But polonium is obscenely ‘hot’. The only way you’d see Cherenkov radiation in air with uranium is if you had a critical mass actively fissioning!

          And I’d be willing to bet that Klapotke et al look at the Botox and other biotoxin makers and say, ‘no way, no how!’ (For that matter, I’d be interested in seeing what’s on Klapotke’s “Things I Won’t Work With” list…)

  6. SirWired says:

    Don’t forget the tetanus toxin required to manufacture everybody’s once-a-decated tetanus booster! I think that runs at about 2.5ng/kg; nearly as toxic, and I bet the annual amount required is a bit higher.

  7. APAJ says:

    The LD50 of 1-2 ng/kg is actually the “conservative” estimate of toxin B, apparently the lesser of all evil sub-types. The University of Barcelona (see link) has data indicating 0.2 ng/kg could do the trick too, depending the precise definition of botulinum. But ‘a sniff’ will certainly do it.

    1. Sky says:

      Can you please provide a citation for the Barcelona research ? I found biological war research that indicated 3 picograms caused botulism in 40. Percent of the mice and 30 pg was the LD50. The better question about the sick mice is what would happen after the botulism ? Recovery or eventual fatal outcome?

  8. shanedorf says:

    I was working for a major CRO when Allergan came to us asking about conduct of GLP animal studies to support this development program. Senior management said : ” No way are we bringing THAT into our facility !”
    Somebody else at another CRO said “yes” to the botulinum and the millions that followed.

  9. myma says:

    “a bit of the toxin is transported by private jet, with guards aboard”
    Now there is a chain of custody.

  10. NJBiologist says:

    I wonder if Thomas Klapötke reads about stuff like this and thinks, “man, those guys are nuts!”.

  11. Alex says:

    Question for those who have worked in the natural products space: do you ever worry that the products you’ve come across might be an unknown toxin with super low potency? I’m surprised it’s not more common when people are testing thousands of novel microbes and compounds, I can’t find any literature on the safety of unknowns in natural products research. Does basic sterile technique basically always protect you with any risks?

    1. Ted says:

      Absolutely. I worked in a lab developing synthetic methods for large scale production of camptothecin variants. In some cases, we knew some of the known intermediates were not particularly hazardous because of their poor bioavailability (that’s why people were making variants in the first place). But in other cases, we had to rely on common sense: novel intermediates with structural commonalities (for camptothecin, closed ring lactones with planar conjugated arenes) are likely to behave with the same mechanism of action, but with unknown potency.

      A generation earlier, chemists in those same labs were working on novel prostaglandins – highly potent compounds with unknown mechanisms and potencies. They had incidents…

      Sterile technique is different from cytopotent compound handling. Nowadays, Safebridge has developed pretty good standards for uniform handling of these sorts of compounds.

      -t

      1. aairfccha says:

        Glove boxes and remote handling like in the nuclear industry?

      2. JAB says:

        Back in the 80’s we made 44 grams of esperamicin A1, one of the enediynes, for BMS. My recollection is that the phase I dose in humans was 15 micrograms/kg. I figured that we could kill every mouse on the planet with that much material. Needless to say, this drove the pharmaceutical analysts and formulation people completely nuts, having to detect a tiny amount in serum. Unsurprisingly, the compound failed phase I due to toxicity. The saving grace in working with this compound was that it was extraordinarily unstable – we dunked glassware in bleach and the compound was gone in an instant.

    2. FormerNatProdChemist says:

      As a former natural products chemist trained in the 90’s I was always amused to read about the compounds published in the 50’s to 70’s where the LD50 and the taste were published in the characterization of the molecule. I have no idea what my cytotoxic marine natural products tasted like, and I’m fine not knowing to this day.

    3. a. nonymaus says:

      It’s not just natural products that can have unexpected toxicity. Bicycloheptadiene dibromide is an example: http://pubs.acs.org/doi/abs/10.1021/ja01467a058

      1. HGMoot says:

        I was afraid we would bring up such examples… probably better not to.

        1. Rhenium says:

          Good to know though, otherwise I would have though it an interesting lead…

    4. Molecular_architect says:

      I spent the better part of a decade working with palytoxin. The LD50 in mice is 0.045 µg/kg by IV. At one point in time, I had over 2 g or pure palytoxin on hand. Once we had developed an immunoassay for the compound, we began wiping down lab surfaces and analyzing for palytoxin. The initial results were scary! After that, we instituted meticulous cleanup with bleach following all operations with the toxin. (We also had demonstrated that bleach was an effective decontamination procedure). This was just one of many toxins that I’ve played with over the years, including botulinum and anthrax lethal factor. Fun times!

  12. Chrispy says:

    One of my first graduate labs had a compound handling exercise. We had a number of things to weigh out and were warned that they were quite toxic: be careful!

    At the end of the day the instructor shut off the lights and turned on a black light. One of our compounds was highly fluorescent, and it was everywhere. Tracked all over the ground, on the balances, everywhere. It was a real eye-opener.

    I have heard that if you recrystallize a compound in a lab that you will forever be able to recrystallize it in that lab, as microscopic seed crystals will be present from then on. (That is also supposed to be why older, bearded chemists are better at recystallizing.)

  13. Imaging guy says:

    Just read Wiki page on botulinum toxin. What I find surprising is that this toxin which is a protein dimer of molecular weight of 150 KDa (similar to IgG antibody) can enter the neuron, leaves the synaptic vesicles into the cytoplasm and finally engage its supposed targets, SNARE proteins. [If the toxin is inhaled, it probably has to go through two additional cell layers (lung epithelial cells and endothelia cells of the capillaries) before reaching the bloodstream.] Just think of what you can do if you were able to deliver inhibitory therapeutic antibodies and replacement proteins into the cytoplasm.

    1. Ted says:

      Maybe you can get the Mohawks to help you patent botulinum fusion proteins for targeted delivery of therapeutic antibodies…

      :^)

      -t

    2. Anon says:

      What this stuff really needs, is an active protein transduction domain, to make it a bit more bioavailable and thus potent.

      And a pair of anthracene “wings” to make it airborne.

    3. Druid says:

      Botulism is a “food”-borne disease, so clearly enough BTX is absorbed to kill. Possibly it has to be biosynthesized inside the intestine and it might not survive the acid in the stomach (the primary purpose of that acid is such protection). But it is a useful rule of thumb that ~1% of anything in solution can be absorbed – high molecular weight, peptides and proteins, etc – maybe through Peyer’s patches, or through small lesions in the gut wall. In the old days before knowing better, we tried and failed to get another %. Those big old renin inhibitors, MW 1000 … So the safe oral dose of botulin is probably 100x the safe IV dose as far as central toxicity is concerned, though there may be local effects before then.
      That ~1% bioavailability is a real tease, and a lot of time has been wasted on experiments on mAbs for example. Anyone else had similar experiences?

      1. Wile E. Coyote, Genius says:

        The interesting thing about botulism is that some species (vultures) are immune.

        1. Druid says:

          Thank you, that is interesting. It makes sense for a carrion eater.
          Lipopolysaccharide from e coli is > 1 miilion x more potent in man than in mouse, which may be why I like my drugs tested in people. 🙂

  14. Fil says:

    I developed chromatography methods to detect anatoxin-a in Brasil back in the days. The brasilians had a bad habit of re-using lab gloves inorder to save money. After a few times taking the gloves off and on it was hard remembering which side was out to begin with. I am glad I am still alive after the time spent in Sao Paulo 🙂

  15. Eric A Johnson says:

    The article in Bloomberg Business Week regarding the development of Botox has many factual errors. The original batches of Botox were made by Schantz and Johnson at the University of Wisconsin, and we still make batches in an CDC approved high security laboratory. Allergan acquired batches from our laboratories in the late 1980’s. Allergan clearly did not develop this technology.

  16. Barry says:

    Back when he was still at Pittsburgh, one of Sam Danishefsky’s grad students was hospitalized. Apparently he had synthesized a very potent inhibitor of acetylcholine esterase that was known to the U.S. military, but unpublished. I don’t know if the exposure was thought to be transdermal or by inhalation or by insufflation, but it sounds like he came close to death although he was working in a fumehood.

  17. BernYeeIris says:

    You all forget about Karen Wetterhahn, the Dartmouth professor who died in after she came in contact with 2 drops of dimethyl mercury. That is probably more toxic than botulinum toxin anyday.

    1. Semichemist says:

      I’m not sure how legit the sources are, but I’m seeing several references of the LD(50) of dimethyl mercury as approx. 50 micrograms/kg. Which would make botulinum toxin roughly 25,000 times as toxic.

      1. skeptic says:

        The interesting (and sad) aspect of the Wetterhahn case is that the dimethyl mercury went right through the gloves she was wearing. BoNT won’t do that.

    2. aairfccha says:

      A drop is still a quantity visible to the unassisted eye…

  18. Ken says:

    Like an idiot, I clicked all the wiki links in the original article. Anyone know how long before some three-letter-agency pays me a call?

    1. Steven says:

      The MWA has already left a method of contact in your bedroom.

  19. CoxTH says:

    I believe that most “natural” poisons have such high toxicities, because they have some kind of enzymatic activity. BTX cleaves SNARE Proteins, Ricin cleaves a glycosidic bond in the ribosome, etc. The point is that one single molecule of toxin can disable a huge amount of important molecules in the cell. Compare that to most small molecule drugs that either work by competitive antagonism or by covalently binding to their target. Are there any small molecule drugs with catalytic activity?

    1. Barry says:

      Several Oncology programs targeting the kinase activity of Raf were bedeviled by small-molecule inhibitors of B-Raf that perversely increased signaling through C-Raf. These never became drugs, but they were small molecules with (indirect) catalytic activity.
      Kim Janda works for years on small-molecule transition-state analogues that might provoke the expression of catalytically-active antibodies that would cleave cocaine in circulation. No drug came of it.

    2. Design Monkey says:

      Offhand – bleomycin, works like a pseudoenzyme. Also oxime AChE reactivators theoretically could do catalytic cycles, though likely that is not at all significant in real use.

    3. sgcox says:

      That is the idea with PROTACs – convert inhibitors or even simple binders into catalytical destroyers.

  20. John Campbell says:

    Maitotoxin has an LD50 of 50 ng/kg in mice apparently (i.v. or i.p. I think)
    https://en.m.wikipedia.org/wiki/Maitotoxin
    In terms of producing a physiological response, olfaction takes some beating. Geosmin, a simple terpene, is detectable at 5 ppt. Trichlorophenol gives an off-taint to chicken meat at 2 ppb.
    I haven’t got a handle on the detection limit for thioacetone but it sounds pretty low: https://en.m.wikipedia.org/wiki/Thioacetone

  21. David Edwards says:

    One of the lessons I’ve learned – in no small part from Derek here, incidentally – is that metabolisms are all about the right molecules, in the right place, at the right time, and in the right quantity. It isn’t just the “wrong” molecules (e.g., cyanides, carbon monoxide, or any of the more hideous substances in his “Things I Won’t Work With” section) that can cause trouble. The “right” molecules can become horribly wrong, if they turn up at the wrong place, or in the wrong quantity.

    Oxygen is a vital respiratory gas for obligate aerobes such as us, but oxygen can wreak havoc if it gains access to molecules that should NOT be oxidised. Hence the presence of numerous antioxidants such as superoxide dismutase in obligate aerobes, to keep that vital but potentially wayward oxygen under something resembling control. And, of course, at a suitably distant point in time, oxygen was a toxic waste product for many single celled life forms then extant, most of which were probably wiped out once cyanobacteria started changing the planet’s atmosphere substantively.

    I suspect that quite a few biochemists regard oxidative damage, and the ability of organisms to prevent or repair it, as being significant limiting factors on lifespan. So even if you avoid excessive exposure to sunlight, have a diet that doesn’t propel you into type 2 diabetes in later life, don’t smoke or drink, your need for oxygen is probably going to cut you down anyway – the other items in that list simply accelerate the process. Aerobes with inefficient antioxidant pathways will be cut down more quickly, but I don’t suppose the average fruit fly worries unduly about this. 🙂

    1. NJBiologist says:

      “The “right” molecules can become horribly wrong, if they turn up at the wrong place, or in the wrong quantity.”

      Yup–toxicologists call this hormesis. It usually shows up in discussions of essential vitamins and trace minerals, but oxygen is also a good example.

  22. Anonymous says:

    I knew someone who started working on the anthrax problem just after the anthrax terrorism events in 2001. They developed an improved rapid method for culturing and detecting anthrax (so it could be genetically IDed and sourced, I think). They did their research in a regular safety cabinet in a regular biology lab (BL1, I guess) because they were using some weakened form of anthrax that was, almost, harmless; something they had worked with for many years, many times before. The NIH or CDC liked their method, they got some kind of Presidential Award for serving the security needs of the nation and they got a headline or two. Well, that blew the top off of things at the university! They called in HazMat and every government agency to investigate anthrax and clean up the lab. There were other professional consequences.

    (Anthrax is an intact organism that can reproduce itself. It is not a small molecule, enzyme or single molecular entity. Anthrax toxin itself is a mix of three proteins. But why synthesize it when the bug can do it for you?)

    Even though that anthrax strain wasn’t highly toxic, it had some unanticipated toxic consequences.

  23. vinod says:

    Hello, a dumb question: What is the difference between “toxin”, “venom” and “poison”? I tried to search the Internet, but didn’t get any clear cut responses. For example, it says that Tetrodotoxin is both – a venom and a toxin! I do realize there’s a difference, but what?
    Secondly, I’ve read somewhere that marine organisms produce the deadliest toxins on the planet. Is it true?

    1. z says:

      Generally, “toxin” is something bad for you – a more precise definition is surely possible but this should do.

      “Venom” is a toxin specifically produced by animals and injected (fangs, stinger, hollow spines, etc) into the bloodstream or tissue to be affected.

      “Poison” is ingested toxin, and could come from a natural source (nightshade, fugu), or a mineral (lead), or it could be synthetic.

      1. NJBiologist says:

        From the glossary in the back of Hayes’ Principles and Methods of Toxicology, a toxicant (call it a toxin) is “an agent that can result in the occurrence of a structural or functional adverse effect in a biological system”. (Adverse gets defined as alteration of function or altered ability to respond to environmental challenges–but this typically is a judgment call.)

  24. Chemystery says:

    The poison arrow toxin batrachotoxin is pretty toxic (it is a steroidal alkaloid) – “According to experiments with rodents, batrachotoxin is one of the most potent alkaloids known: its subcutaneous LD50 in mice is 2 µg/kg.[6] ” (from Wikipedia – https://en.wikipedia.org/wiki/Batrachotoxin)

  25. Rich Rostrom says:

    So why are donkeys immune to botulism?

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