PHAR 303 Lecture Notes - Lecture 5: Phthalate, Xenobiotic, Chemical Warfare
11 May 2018
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Lecture 1 Pharmacology 303: Principles of Toxicology
Toxicology
• The study of the adverse effects of xenobiotics on biological and ecological systems.
• The key word in the definition is the word “adverse”, as opposed to desired.
• Pharmacology is the desired effect
• Our concern is how a substance or condition adversely affects a system
Xenobiotic
• Any substance that is foreign to a biological system.
• In fact, toxicology is even broader than this, because if you take a substance that is
endogenous to a biological system like salt, if you give an excess of salt or water, you
can kill somebody.
Toxic substances can be classified according to why the chemicals exist:
• Drugs
o High doses of any drug will give a toxic response.
o The specificity of a drug is inversely related to the number of papers published
on it. The more we know about the chemical, the more it has wider effects.
o The higher the dose of anything, you can kill anything.
• Food additives
o Meant to be regulated and safe but not all food additives are.
• Pesticides
o Chemicals that have increased the productivity and agriculture in remarkable
ways, but they do that by killing bugs.
o Most of them work by acting on the nervous system, usually blocking
cholinergic transmission.
o We have cholinergic transmission as well, so most pesticides, at high enough
doses will affect humans.
o They meant to be selective and specific for the bugs that are for differents
crops.
• Industrial chemicals
o The least regulated chemicals
o Drugs and pesticides are very tightly regulated, but not industrial chemicals.
o Many of them will go into the environment, so the line between industrial
chemicals and environmental pollutants is very small.
• Environmental pollutants
• Cosmetics
o People dont consider cosmetics as drugs
o The skin is wonderful for absorbing chemicals
o Gloss comes from phthalates.
o Phthalates are lipopholic and will get absorb in the body
o When you smell a new car, you inhale large doses of phthalates
• “Natural” toxins in the environment
• Household poisons
o “things under the sink”, cleaning solutions
o Most of the household poisons come from plants
• Chemical warfare agents
Natural substances: Poisonous Plants
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• The fact that it is a natural product does not mean it is safe.
• Nature has wonderful poisons. Many could kill you.
• Belladonna “beautiful lady, beautiful eyes”
• Plants have been used to extract chemicals that can be used as drugs.
• Some of them are very helpful and some of them are not.
Toxicology vs Pharmacology
• Undesired vs. desired effects of therapeutic agents
o Every time you give a drug as a pharmacologist, your intent is the desired
effect
o A toxicant would be an undesired effect. In can be a therapeutic agents or
another environmental or workplace exposure
• Actions of poisons / toxins that would not be used as therapeutic agents
o That would not be used in a therapeutic context
o If you have studied snake venom as toxicant or spider venom, you wouldnt use
most of those in a therapeutic context. You study chemicals that some of them
are drugs but not the ones that you would use for therapy.
• Effects of chemicals in/on the environment - indirect effects on human health
o You directly expose people to drug in pharmacology. You know what you are
giving (dose, reason why given).
o In toxicology, you don’t know what you are being exposed to, you don’t know
what it does and you have no way of knowing whether you should or should
not be taking some of the things you are exposed to.
o Much more challenging field, than pharmacology, because you cannot do
control studies in humans.
Historical Perspective
Chinese : Emperor Shen Nung – father of Chinese medicine
• →rote Pen Ts’ao – the Great Herbal or Chinese Materia Medica 2735 BCE , which
includes all pharmacology. There was a whole section on poisons, but they weren’t
treated as poisons.
Ebers papyrus (Egypt, ~1500 BCE)
• Recognizes many poisons such as hemlock
• Aconite (helmet flower), Chinese arrow poison, opium
• Heavy metals (lead, copper and antimony) were the biggest concerns, even though
some other chemicals were used.
• Cleopatra testing poisons on criminals would see what would happen at them.
Greece : Hippocrates (400 BCE)
• Hippocrates came up with the idea of bioavailability
• Exposure is very important, but if you are exposed to something that doesn’t get into
you, then it doesn’t matter.
• Limited things for toxicology that can get into you.
• The bioavailability can be altered by different behaviors. If someone is exposed to a
toxin, you have them throw up ( don’t do that anymore, but there are different ways).
• Identifies several additional poisons
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• First to articulate principles of clinical toxicology relating to bioavailability in therapy
and overdosage.
Rome : King Mithridates VI (132-63 BCE)
• Was terrified of being poisoned. He would test the mixtures on some of his people. He
would give them a poison, then an antidote and see if the antidote was preventing
them from dying from the chemical he was giving to them.
• Did acute toxicity experiments on accused criminals
• Claimed to have discovered mixture of antidotes against all poisons
• Treated himself with a mixture of 36 such chemicals
• Mithridatic mixtures is a combination of chemicals that act as an antidote
o antidotal or protective mixture
• He ended up dying of poisoning
Medieval Spain: Maimonides
• The first big name in the history was Maimonides.
• Poisons and Their Antidotes (1198) : the first book entirely dedicated to poisons and
had to prevent poisons killing the person.
• First volume to systematically describe treatments for poisoning from insects, snakes
and mad dogs
• Noted that milk, butter and cream could delay intestinal absorption, I.e.,
bioavailability
o He pushed the concept to give milk or butter to decrease the absorption
o It was Hippocrates idea of decreasing bioavailability, but he did it in a very
practical way, saying how you are going to decrease the bioavailability.
o The idea Is that that heavy fat will absorb the poison in the GI tract and prevent
it from going in the body. The body will get rid of it through the GI tract.
Catherine de Medici (Italy/France 1519-1589)
• She took Cleopatra’s approach to an extreme. She wanted to see how people were
dying when exposed to different chemicals.
• She kept records and her books are still available.
• Obtained direct evidence to identify most effective poisons and carefully noted:
• Rapidity of response - onset of action
• Effectiveness of compound - potency
• Degree of response of body parts - specificity
• Complaints of victim - clinical signs and symptoms
• She was a very good clinical toxicologist, observing, record the action of poisons. She
didn’t try to help anybody, she just tried to see how it happened.
Paracelsus (1493-1541)
• Father of “Modern” Toxicology
• “All substances are poisons; there is none which is not a poison; the right dose
differentiates a poison from a remedy”.
• The idea that the extreme end of a dose response curve is the toxicological end has
been the dogma from the time he said it which what about hundreds years ago up to
about 15-20 years ago.
• It is still not the case today because there are many chemicals that have effects at low
doses that are different from effects at high doses. They have funny shaped curves.
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Document Summary
Xenobiotic: any substance that is foreign to a biological system. In fact, toxicology is even broader than this, because if you take a substance that is endogenous to a biological system like salt, if you give an excess of salt or water, you can kill somebody. Toxic substances can be classified according to why the chemicals exist: drugs, high doses of any drug will give a toxic response, the specificity of a drug is inversely related to the number of papers published on it. Natural substances: poisonous plants: the fact that it is a natural product does not mean it is safe, nature has wonderful poisons. Many could kill you: belladonna beautiful lady, beautiful eyes , plants have been used to extract chemicals that can be used as drugs, some of them are very helpful and some of them are not.
