Wednesday, March 13, 2013

One Man’s Poison Is Another Man’s Cure

Biology concepts – toxin, poison, venom, LD50, ED50, therapeutic index

The skull and crossbones is the most recognized symbol
for poison. It originated at the entrances of Spanish
cemeteries, so it has always been associated with death.
With advent of pirate toys and play acting, the United
States proposed moving to the Mr. Yuk symbol, shown
above, a registered trademark of the Children’s
Hospital of Pittsburgh, so they are going to want to get
paid. The design was by a fourth grader from West
Virginia in 1971.
There is a dangerous chemical that is all too common in the developed and developing worlds. Colorless and odorless, this poison is responsible for thousands of deaths and millions of injuries each year. Inhaling even a small amount can be harmful and more is certainly lethal. Likewise, ingestion of too much can also be lethal. In a gaseous state, it can cause severe to lethal burns.

And yet, there is no pending legislation to eliminate this compound or restrict its use for safety’s sake. You can find out more about this deadly substance at the only research site dedicated to its control. The molecule in question goes by many complex names in order to hide its true nature; Dihydrogen Oxide, Hydrogen Hydroxide, or simply Hydric acid.

But we know it most commonly as water…. yep, water. Look again at the list of dangers associated with water above. Are any of them untrue? Too much of even a good thing can be bad for you, like in drinking too much water. But water in your respiratory track can go bad very quickly; it’s called drowning. So next time you want to same something is harmless, think twice – just how much of something is still harmless?

This is not a new concept; one scientist was contemplating the nature of poisons and medicines 500 years ago. He called himself Paracelsus (para = as good as or better than, and celsus = the great encyclopedist named Celsus). Celsus lived just before Julius Caesar came to power. He wrote one of the first comprehensive medical encyclopedias, including books on pharmacology, pathology, anatomy, and surgery. What is more, this which was just one part of his more extensive encyclopedia of all the world’s knowledge.

Paracelsus, on the other hand, was a German-Swiss natural philosopher who lived from 1493 to 1541. He really liked himself, although I am kind of glad he adopted the pseudonym…. his real name was Philippus Aureolus Theophrastus Bombastus von Hohenheim!

Paracelsus was his own greatest fan. He traveled the
world in an effort to learn everything – he missed out
humility. Here is a quote to illustrate, “Let me tell you
this: every little hair on my neck knows more than you
and all your scribes, and my shoe buckles are more
learned than your Galen and Avicenna, and my beard
has more experience than all your high colleges.”
Paracelsus is often called the “Father of Toxicology,” although he also worked in metallurgy, botany, and astrology. He pioneered the idea of medicines; substances that could be used to treat diseases rather than just trying to adjust the systems of the body, such as that great medical technique --- bleeding.

Paracelsus believed that every chemical or substance had a good side and a bad side. His most famous quote goes like this, “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous." We usually shorten this to, “The dose makes the poison.”

You can see from the water example above, Paracelsus was right - moderation in all things. How much water kills you? Well it depends on what body system it interacts with and what organism we are talking about. For drinking water, the lethal dose is about 2x105 mg/kg. This is called the LD50.

LD50 translates to the dose that will be lethal in 50% of the organisms tested at that dose. It wouldn’t be fair to test substances out on humans (although we all know folks we would volunteer for that), so most commonly the LD50’s of known poisons and toxins are given in relation to the mouse model.

This even applies to medicines, and since rats and mice differ from humans in many ways (some more than others), LD50 in humans is most often a guess, but usually a very good guess. This is why your medicines come with a dosage – take enough to help you, but not enough to kill you.

ED50 (effective dose for 50% of patients tested) is the term used for medicines that helps determine the dosage. It is the least you can take to reasonably insure that the medicine will do what you want. The goal in pharmacological development is to minimize the ED50 and maximize the LD50, so you have a big range (called therapeutic index) in which the medicine is safe. Sometimes this is calculated as the safety margin, or LD1/ED99; the dose that kills 1% of animals divided by the dose that is effective in 99% of animals.

The ratio of the LD50 to the ED50 is a drug’s
therapeutic index. The log of the dose is used on
order to produce nice curves. Here, the therapeutic
index for digoxin, used to treat congestive heart
failure, is 1.5-2. By way of contrast, for penicillin it
is more than 100. Penicillin is a safer drug ----
unless you’re allergic.
So, your medicines are just poisons under control. Sometimes we even use things that you wouldn’t think of as medicines. Take botulinum toxin A (BoNT/A) for instance; it’s a deadly poison, but that doesn’t stop people from injecting it into their foreheads to remove wrinkles! BoNT/A has also been used to treat muscular spasms in the larynx (spasmodic dysphonia) and it may be useful for chronic pain.

A new study from Rome shows that morphine + BoNT/A works better for chronic pain than morphine alone. In addition, BoNT/A keeps mice from developing a tolerance to morphine over time. It seems that even if morphine has been used for a while, administration of BoNT/A can up-regulate the morphine opiod receptors, so that the drug regains its maximum potency in the animal.  Studies like this show us that we must be careful how we use the word ”poison.”

Do you know the difference between poison, toxin, and venom? Some definitions are in order, because they are currently being used all wrong. A poison is any substance that brings about a change in a living organism. It doesn’t say a good change or a bad change, just a change. This is why I can say that medicines are poisons, and why water can be considered a poison. You would be hard pressed to find something that isn’t a poison.

Prohibition in the United States made the production,
selling, and consumption of alcohol illegal. Many turned
to wood alcohol (methanol) for the same high. For a
good description of the practices and outcomes of this
bad idea, I recommend a book called, The Poisoner’s
Handbook: Murder and the Birth of Forensic Medicine
In Jazz Age New York, by Deborah Blum.
A toxin is a poison that is produced by a biologic process. So man-made hydrofluorosilicic acid from phosphate production is poison, but the secretions from a poison dart frog’s back contain several toxins. Here is where things are being used incorrectly. Toxic waste dumps usually contain man-made chemicals that seep into the ground water or soil. But they are not toxins, they are poisons. People commonly use toxic to refer to anything that can harm a living organism – wrong, but well accepted.

Sometimes the toxin isn’t actually the toxin. For instance, many people died from methanol toxicity during prohibition. Unscrupulous producers would concoct wood alcohol (methanol) combinations and alcoholics would consume them, because they gave the same high as ethanol; but they could also kill.  

But, the methanol wasn't directly toxic until it underwent a process called toxication. The human body metabolizes the methyl alcohol to formic acid, and this is what does damage to the cells. Formate can damage the optic nerve at very low doses and cause permanent blindness. It attacks the mitochondria to stop ATP synthesis – something not compatible with continued life.

There are more definition problems; people talk about poisonous snakes and spiders. But their poisons are made biologically, so they are better described as toxins, not poisons.

Snakes and spiders provide another level of complexity. A venom is a toxin that is delivered into the flesh (subcutaneously – below the skin) by some deliver method developed by the organism. Toxins are often absorbed through the skin or mucosal surface, but venoms often cannot be absorbed, they have to be physically placed into the tissues. Poisonous snakes and spiders are better described as venomous (we will talk about exceptions to this rule as well).  Interestingly enough, many ants inject formic acid as their venom, the same chemical formed by toxication of methanol.

The Inland Taipan snake (Oxyuranus microlepidotus) is
also called the Fierce Snake.  Despite the word’s
Chinese origin, the snake is native to Australia, as are
so many things that can kill you. They can change colors
with the season to maximize heat absorption in the
winter, and are usually very shy. The only bites on record
have been to snake handlers, and an anti-venom is
available, so no deaths have been recorded lately.
So what are the most deadly organisms on the planet? The deadliest snake is the Inland Taipan snake. One bite contains enough venom to kill about 100 people; the LD50 is about 0.03 mg/kg of body weight! LD50’s for spiders aren’t as readily available, but the funnel web spider of Australia is considered very toxic, with an LD50 of about 0.16 mg/kg.

However, these pale in comparison to the most toxic organisms – and wouldn’t you know it, they are the smallest as well. In a list posted by the University of New Mexico, the top three toxins come from bacteria, as do half of the top 16! Number one is botulinum toxin, made by an anaerobic (grows without oxygen) bacterium called Clostridium botulinum – our Beverly Hills forehead flattener. Its LD50 is 0.000001 mg/kg, so you can imagine how little the doctors must use - doesn’t stop them from charging a mint for it! The toxin of C. botulinum is especially nasty as a food contaminant, since you can sterilize the food, but the premade toxin will still be active.

A close second are the shiga toxin of Shigella dysenteriae and the tetanus toxin of Clostridium tetani, each with an LD50 of 0.000002 mg/kg. The list contains plant toxins as well as marine animal toxins and spider venoms, but once again, bacteria show us who’s in charge of this planet.

Here are the three arthropods commonly referred to as daddy
long legs. The crane fly is on the left. It is an insect with no
venom what so ever. The middle picture is a harvestman. It is
an arachnid, but it is not a spider, and it is not venomous either.
You can see that its legs are attached to its only body segment.
The cellar spider on the right is a true spider. You can see it has
a cephalothorax and a large abdomen, and the legs are attached
to the cephalothorax. Everybody got that?
One last item while we are here talking about relative strengths of toxins and venoms - the daddy long leg myth. The myth says they are the most venomous spiders in the world, but their fangs are too short to penetrate human skin. Well, the brown recluse has very short fangs, and they are deadly. And just what daddy long legs are you talking about anyway?

There are three bugs commonly called daddy long legs; the crane fly, the cellar spider, and the harvestmen. Only the cellar spider is venomous, and no one has ever assessed its LD50 (except for a short segment on Mythbusters). I think the myth started because they will catch venomous spiders in their webs, and eat them. They kill something dangerous, so they must be more dangerous -the worst kind of scientific thinking. O.K., is that settled once and for all?

Next time, mammals have defenses, but it is the rare mammal that resorts to toxins.

Vacca, V., Marinelli, S., Luvisetto, S., & Pavone, F. (2013). Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice Brain, Behavior, and Immunity DOI: 10.1016/j.bbi.2013.01.088

For more information and classroom activities, see:

Poisons –

Safety margin and therapeutic index –

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