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 botulinum, 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.