FUND II: 10:00 - 11:00Scribe: Paige Whitt

Friday, December 11, 2009Proof: Brittany Paugh

Dr. SmithPrinciples of ToxicologyPage1 of 7

Introduction [S1]:
Good morning folks.
Begin with cornerstone principles of toxicology.
Some of this material is self-explanatory. I do encourage you to use the handout as the primary source of information on this topic. Although I haven’t mentioned the case studies, I’ve read them and am also confident that you would have a fine understanding of the case studies based on what information is in the handout.
So I’m going to move quickly now and begin with discussion of principles and then discuss four classical examples of toxic agents of important public health concern: carbon monoxide, cyanide, methanol, and acetaminophen. Then lastly I’ll talk about toxic metals, with the most important ones being arsenic, lead, and mercury. I’ve listed on the board the antidote next to these toxic agents. For example, the antidote of carbon monoxide is breathing air (O2). Getting a person out of the environment where the carbon monoxide is present and breathing air, which contains 20% oxygen, is sufficient.
In the case of these other toxic agents, it’s possible to use a drug to block the toxic effect of the poison. With metals, there’s an important drug class known as chelators. Chelation therapy is used to hasten removal of toxic metals from body. The oldest being Calcium EDTA, which binds the metals. One of the problems of EDTA is it binds essential metals (such as calcium, magnesium, and zinc) and has to be administered with calcium to prevent cardiac arrest due to depletion of calcium.
EDTA is given only intravenously. For removing lead, which is a major public health problem in US. Millions of children suffering form lead poisoning and have high blood lead levels. To treat those children with calcium EDTA they would have to be hospitalized and it has to be given IV—that’s a considerable cost and has associated risks.
Another chelator, succimer can be administered orally. Chelators are covered at the end of the handout. Even if I don’t get to them, I’ve already called your attention to them, and you can easily find out a little more info about them by looking at the latter section of the handout.
The basic principle of toxicology is an old one. It comes from a medical writer named Pericelsis. The most famous medical writer in Rome was Celsis. This guy, Theofrostus Bombas, thought he was not quite Celsis, so he called himself Pericelsis. He’s responsible for the realization that all substances are poisonous, and it’s the dose that separates a poison from a remedy.
My own opinion is that most common medical error today is not adjusting dose for an individual. All we do for proscribing dose is look it up. Pull out an iphone and look up Medscape, and that’s all we do for prescribing doses. But doses have to be adjusted because people metabolize drugs at different rates and absorb different amounts of them, etc. Tailoring the dose is important. In regards to toxicology, we’re generally speaking not of an insufficiency of a dose, but an overdose that produces a toxic manifestation.
Title [S2]
Obviously all substances are poisonous. Death of someone in the US recently from consuming too much water without eliminating the water. Anything can be a potential poison depending on the circumstances, chiefly in this case, the dose or amount the person is exposed to or consumes.
Title [S3]
Regarding toxicology, the most important goal is to assess risks. We can’t classify things as poisonous, nonpoisonous, dangerous, or safe. Potentially any chemical substance is a poison, so we want to access risk. To do that, we need to know what the relationship is between dose or exposure and the toxic response. That’s generally straightforward for vast majority of substances, but it becomes a great problemwhen a substance produces toxicity at a very low incidence.
For example, we talked about Chloramphenicol—produces aplastic anemia at a very low incidence. So what is the risk? 1/40,000 or so cases of people administered chloramphenicol develop aplastic anemia. So that’s an assessment of risk.
But what I like to (and will) emphasize today is simply this kind of descriptive toxicology, where you expose an animal or person and access risks, that’s not what I’m going to emphasize. What I’m gong to emphasize today is mechanistic toxicology. The importance of understanding the mechanism of action of drugs or other toxic agents in order to more accurately assess risks and to develop antidotes to manage the poisoned individual and to hopefully prevent further damage to the patient by administration of an antidote. It’s most important to know a mechanism of action.
Toxic agents, just like drugs used in therapeutics, have a target in the body. They have chiefly one or a couple major targets at which they act and produce their toxic effect. Identifying that target is obviously critical for managing the poisoning and developing of antidotes.
Dose-effect [S4]
This is an example of a dose-effect. This would be used in descriptive toxicology.
It’s different only in that it’s only a quantile dose-effect here to assess the lethal dose of a toxic agent. What that means is that you simply determine if so many animals are exposed to a certain dose of a compound/chemical, how many live and how many die. It’s a quantile dose-effect as opposed to a graded one.
A graded one is where you take a drug or diuretic, and you measure the blood pressure. Diuretic causes water excretion. It reduces water volume and lowers blood pressure. You titrate the dose until you get the blood pressure at a required range.
LD50 (lethal dose 50) is used to assess toxicity of a compound.
Title [S5]
We see at the bottom: supertoxic agents like botulinum toxin (the one I manufacture in kitchen when make pickles and don’t sterilize jar correctly—anaerobic bacteria produce botulinum toxic because you seal jars real tightly.) Botulinum toxin is remarkably potent; you see 10 ng/kg is the LD50. But how many people die of botulism? I know a guy who purified botulinum toxin as part of an anti-Hitler war effort in order to develop antibodies against it. The US was concerned it would be used by Nazis as chemical warfare agent. He survived even purifying that stuff.
LD50 doesn’t tell you what the risk is, obviously, because not many people are exposed to botulinum toxin.
But here’s ethanol at the top. 8000 mg. We have a billion-fold range here. Range in potency of these various agents. Obviously ethanol kills far more people than botulinum toxin, and then there are a lot of agents in between.
Surprisingly, these iron (Ferrous) sulfate tablets that you take for anemia can be quite lethal and cause the death of children. Fortunately putting difficult to open lids on pill jars has reduced it.
Acetaminophen (such a widely used drug) is most common cause of admission to hospitals for liver failure, in which there’s no treatment other than liver transplant.
Toxicity tests in animals [S6]
There are some assumptions here regarding toxicity testing in animals.
The most fundamental assumption mentioned is that the toxic agent will be toxic to the animal by the same mechanism that it produces toxicity in people. So that’s one assumption, and that has to be verified by investigation, which is easily done.
The big problem, for example, is in accessing the risk to carcinogenic agents, where you might have to expose thousands, tens of thousands, of animals to access a risk of 1/10000, which we would consider a pretty serious risk for population of US, a few hundred million.
Therefore, we can’t afford to expose tens of thousands of animals to some carcinogenic agent to access the cancer risk. So instead we expose one hundred or fifty animals to a much higher dose and try to extrapolate the risk to a lower dose. That’s a huge problem. There’s no straightforward, scientific way to extrapolate from incidence at high dose to incidence at low dose.
So where does that leave us? We have to access the risk, do something. My preference would be to understand the biochemical molecular mechanism by which a carcinogenic agent produces cancer, and then you can evaluate early stages associated with the changes in our body/cells (or in animals) that the agent causes and have a much better scientific basis for determining the risk of exposure say to a carcinogenic agent.
Dose-related toxicity [S7]
Most toxicity is dose related, but it’s not all dose-related.
There are allergic responses, for example, which are non-dose dependent.
Most toxicity is proportional to exposure. Amount of the agent that you’re exposed to over an interval of time. That’s what we mean by exposure. Concentration over time.
Usually one or a few organs are affected. It’s not necessarily the organ or tissuewhere the agent accumulates to the highest concentration.
Many agents, remarkably specific, acting on one or a couple enzymes, and identifying what those are provides great insight into the mechanism of action and aids development of antidotes and better risk assessment.
Generally the big thing up here (brain) is the most susceptible in general to the wide spectrum of toxic agents. So CNS most likely affected in systemic toxicity, and of course that is what is affected by lead poisoning. The mental functioning is irreversibly damaged in children. Of course the brain is always undergoing such rapid development in children, and also in case you didn’t notice, it continues to change throughout life. So I’m well aware of it at my age—you may not be. It never ceases to change as a function of age, and it’s very susceptible to toxic agents.
Acute poisoning [S8]
Acute poisoning is simply a matter of emergency medicine, of course managing the patient first and foremost. You want to terminate exposure, check to make sure they are still breathing, the heart is still pumping, and provide supportive care (oxygen, for example). Have to take action quickly following the termination of exposure to get the individual to an emergency room to be diagnosed.
If the person is conscious, you have huge advantage because they can tell you what they may have ingested or were exposed to.
Lastly, you want to combat the toxicological and pharmacologic effects of the poison, but unfortunately we don’t have antidotes to many poisons. So we simply have to provide supportive care.
Decrease absorption of the poison [S9]
One of the common ways of managing poisoning is to decrease absorption of the poison.
The two chief ways of doing that are highlighted in yellow. They are gastric lavage. That means put a stomach tube down the esophagus and into the stomach and pour in some saline and then aspirate it out and get stomach contents out that way. Commonly used in hospital situations to remove overdoses of drugs and so on. So gastric lavage is very important.
Inducing vomiting is an old way and is mostly discontinued at this time. Too many contraindications, which are highlighted here.
A common agent used in addition to gastric lavage with saline is to add activated charcoal. Activated charcoal is just what you use to cook your dinner except that it is ground up into small, microscopic sized particles. They have a very high surface area and bind all variety of organic compounds. So you can add activated charcoal that you use for gastric lavage, put it down in stomach and it will bind any chemical agent that is there. Then you aspirate it out and throw it away, and that helps to remove the toxic agent from the body.
Alternatively, a way of removing say methanol from the blood would be hemodialysis. Methanol, which we will talk about in a minute, causes blindness. In cases of severe methanol poisoning, hemodialysis could be used.
Hemodialysis is useful for a number of agents, but not all. Not all toxic agents are removed by hemodialysis. For example, some mercury compounds that are sometimes used in laboratories and scientists have been exposed to and died from, they don’t benefit even from hemodialysis. It’s not a cure-all for removing any toxic agents from the blood. You have to know what your patient was exposed to to know if it would be of benefit.
CO poisoning [S10]
Carbon monoxide poisoning--leading cause of poisoning in US.
Carbon monoxide poisons 15,000 a year and kills about 500. It’s odorless, colorless, produced by faulty burning (by furnace or hot water heater, space heater). Carbon monoxide is the product of combustion when there’s an insufficient amount of oxygen. When you have sufficient oxygen, then the products of combustion are carbon dioxide and water. When insufficient supply of oxygen, get carbon monoxide. That’s why we buy the detectors.
DON’T HAVE THIS SLIDE
We go home, start cooking, tired, put TV on, leave pot on stove, burns dinner, fall asleep watching TV. If carbon dioxide leak in house from faulty furnace or something, we just pass out, we never wake up. Never is true with carbon monoxide poisoning. There’s no warning, you don’t feel like you can’t breathe, it’s a quiet death. Used to be common choice for suicide. Put exhaust into car in garage. Less common now with changes in automobiles.
Hospitals generally do not measure blood CO levels. But there is a simple finger clip device being developed.
Interesting point, this last thing on the slide [STILL FROM THE MISSING SLIDE]: 11 of 10,000 emergency room patients were found to have unexpectedly high CO levels in a recent study. There’s a lot more people exposed to it. People don’t even know it, and they’re suffering mild symptoms of CO poisoning. It is something that needs to be further addressed. This finding implies 11,000 cases per year undetected.
[NOW SLIDE 10]
Now the mechanism of action of carbon monoxide—it’s rather simple. It binds to the heme of hemoglobin. Heme contains iron. Heme has a very high affinity for carbon monoxide. How high? 220 times higher than the affinity of hemoglobin for oxygen. That’s what this proportionality constant (Pco) is. It says that carbon monoxide has about 200 times higher affinity for hemoglobin than oxygen. So that’s why it’s so toxic.
You can figure out in this diagram in your leisure, I don’t want to belabor the point, but what this shows is there is tissue P02 (partial pressure of oxygen). And it has to drop all the way down to red arrow [about 10 mm mercury of partial pressure of oxygen in the tissue] before the blood will deliver 5 mL of oxygen to the tissue. That’s far more severe than the usual case. Here’s 40. At 40, when oxygen reaches 40 mm mercury, then you get 5 mL of oxygen from hemoglobin.
If you have 50% anemia, that’s the dashed curve, it only has to drop to about 25. But with 50% carbon monoxide saturation of hemoglobin, it has to go all the way down to about 10 mL. That says that the severity of carbon monoxide poisoning when you have 50% carbon monoxide hemoglobin is far worse than even 50% anemia.
CO poisoning [S11]
I’ve mentioned most of this.
The blood is a cherry red color, the skin is very pink, but yet the person is starving of oxygen, because the hemoglobin is occupied by carbon monoxide.
The tissues are starving of oxygen, but the blood is pink, and the reason for that is that the carbon monoxide bound hemoglobin has a cherry-red color.
You can read this if you are interested. I’ve covered the main point, which is fainting occurs well before any difficulty breathing. The importance of terminating the exposure, I’ve already mentioned. It’s sufficient just to get person out of environment where CO is present and let them breathe air, and they’ll recover.
Use hyperbaric chamber if individual is unconscious. The person is exposed to 100% oxygen under a couple atmospheres of pressure to very rapidly replace the CO on the hemoglobin with O2. Has to be done quickly or the person will die.
Hyperbaric [S12]
That’s an example of a hyperbaric chamber in Bham.
The use of such a hyperbaric chamber is sometimes used for carbon monoxide poisoning.
Cyanide [S13]
Cyanide poisoning– Produced in fires when certain house materials are burned (like plastics or agents used in construction of furniture, etc.).
Cyanide is also a product of this drug called sodium nitroprusside. Sodium nitroprusside is used for treating angina. If sodium nitroprusside tablets are outdated, they are likely contaminated with cyanide.
Amygdalin is an organic cyanide containing compound present in high amounts in pits of fruits (apricots, peaches), so if someone decides they are going to go on a diet of peach pits, they can be poisoned by cyanide.
Organic cyanide compounds are broken down in stomach by bacteria to reduce the cyanide, which causes the poisoning.
Amygdalin was sold in Mexico as an anti-cancer agent, so people were exposed to it there too, but it’s not actually effective as an anti-cancer agent. So many people were misled and it had to be investigated.
Symptoms are bright red venous blood. In this case, the blood is hypersaturated with oxygen. The reason for that is because the tissues do not use oxygen, so even the venous blood is bright red in the case of someone poisoned by cyanide.
I smelled cyanide once when doing an experiment, and it scared the hell out of me.