“The dose makes the poison.” This maxim is credited to Paracelsus, who is known as the father of toxicology. Another way of saying the same thing is, “Everything is poisonous. It just depends on the dose.”
The lethality of a substance is indicated by the dose required to kill. Toxicologists measure this by the LD50; that is, the dose required to kill 50% of the animals that the substance is tested in. A substance can be administered to the test animals in various ways (e.g., injected, ingested, inhaled), but we won’t worry about that for this discussion. The LD50 is given in milligrams per kilogram of body weight. So if a substance has an LD50 of 5 mg/kg in mice, it would take, on average, 0.1 mg to kill a 20 g mouse. That is a very small amount (0.1 mg is about 0.000004 oz), so this substance is a very deadly poison.
Which is the deadliest poison? Another way to frame this question is, which poison will kill at the lowest dose? There are several candidates for this dubious honor, but a strong contender is botulinum neurotoxin (BoNT), a substance produced by the bacterium Clostridium botulinum. The LD50 of BoNT is around 1 -2 nanograms per kilogram in humans. A nanogram is 0.000001 milligram.
Botulism is well-known to most people as a foodborne illness. Because C. botulinum spores are virtually everywhere, and the bacterium thrives in an environment without oxygen, cases of BoNT poisoning can arise from improper canning procedures. BoNT poisoning is a risk anytime foods are stored and allowed to spoil in a low oxygen environment – other foods implicated in botulism outbreaks are smoked meats or fish, foil-wrapped baked potatoes, and cream cheese. Thankfully, foodborne botulism is very rare in the United States, but less so in developing countries.
Botulinum toxin is a neurotoxin – that is, it exerts its toxic effect on nerve cells. Specifically, BoNT interferes with the release of a chemical from nerve cells, in an irreversible way. The chemical that is blocked allows muscular contraction – in its absence, a muscle is in a permanently relaxed state. One molecule of BoNT can disable many nerve cells, which accounts in part for its extreme toxicity. The overt indication of BoNT poisoning is a descending flaccid paralysis – meaning that muscle relaxation begins with the facial muscles and progresses downward throughout the body. When the paralysis reaches the diaphragm muscles, the person afflicted can no longer breathe, and will die without medical intervention. The mortality rate for botulism is fairly low (about 5%), as long as it is diagnosed and treated promptly. Without medical intervention, almost three out of four persons who are poisoned will die.
However, BoNT is also well-known for another reason. Marketed as Botox Cosmetic® by Allergan, it is famous as an anti-wrinkle treatment used by millions worldwide. The reason that such a deadly toxin can have such a benign effect is simple – the dose. A very dilute formulation of BoNT that tends to stay localized in the area in which it is injected, relaxes muscles just enough so wrinkles go away. The effect is not permanent, but it is long-lasting (about three to four months). However, while cosmetic usage of BoNT may be the most lucrative application, it is not the most important.
Before BoNT was approved by the FDA for cosmetic usage, it was approved for other, more serious conditions. It is a palliative for muscle spasms of many types, effective in treating eye ailments (Blepharospasm – uncontrolled eye twitching, or strabismus – crossed eyes), migraine headaches and even hyperhidrosis (excessive underarm sweating).
But BoNT is being used for even more than these approved conditions. Off-label use occurs when a doctor prescribes an approved drug for a condition for which that drug has not been approved, but is deemed effective for that condition by the prescribing physician. This practice is perfectly legal. Allergan has filed patents for over 90 such uses. Off-label uses include conditions such as enlarged prostate, oily skin, sinus and other non-migraine headaches, fibromyalgia, and nocturnal teeth grinding and jaw clamping.
Is the term “wonder drug” too strong for a substance with so many applications? Regardless, BoNT is a wonderful illustration of Paracelsus’ maxim that “The dose makes the poison.”