Good morning everyone
Welcome to
the Basic and Clinical Pharmacology
In this class I am going to talk about
the introduction to toxicology
and occupational
and environmental toxicants
First of all let me give you one example
So let us look at these two pictures
This is taken from the same person
within five months
Do you know who he is
He is Viktor Yushchenko
the third president of Ukraine
from 2005 to 2010
So how can we image the person
has been changed so much
within five months
Actually the first photo
was taken on July 3 2004
In September 2004
he was poisoned by one of
the most potent chemical dioxin
And then five months later
he was becoming the picture
taken at the right side
So from his case we can see
the toxic compound can have
severe effects on human
and also on animals
Sometimes it can cause death of people
The first question we may ask about is
what the toxicology studies
Toxicology is the study of poisons
or the adverse effects of chemical
and physical agents on living organisms
basically on human or animals
So the main topic here is
chemical and physical agents
We need to study the poisonous
or the adverse effects and other effects
for these agents
Actually toxicology has been developed
for a long time and has more than
five thousand years¡¯ histories
For example on about 2700 BC (before Christ)
Chinese journals have already recorded
plant and fish poisons to people
Between 1900 and 1200 BC
Egyptian documents have instructions
for collection preparation
and administration of more than
800 medical and poisonous recipes
In about 800 BC
Hindu medicines have included notes on
poisons and antidotes which can be used
to eliminate or reduce the effects of poisons
For 50-100 AD
the Greek physicians have classified
over 600 plants animals and mineral poisons
So between 50-400 AD
Romans have already used poisons
for killing people for execution for prisoners
or assassination for political opponents
One of the examples we can see
at that time is for a great thinker Socrates
So he is a great thinker in Greek
He taught radical ideas to the youth
and he was against the government
Eventually the government
used a compound from a plant
shown in the right side of this image hemlock
and killed him
In about 1200 AD
Spanish scholars wrote first-aid books
for poisonings poisons and their antidotes
So in about 1500s
A Swiss physician called Paracelsus
He defined the toxicology for the first time
and defined how the difference
between the therapeutic effect of a drug
and the toxic effect of the substance
What he said is
¡°All the substances are poisons:
there is none which is not a poison
The right dose differentiates
a poison from a remedy¡±
Actually for a drug at very low dose
it can have benefit effect
and can help us to fight disease
However when we increase the amount of dose
then this compound the drug
will be a toxic compound
and will have a severe adverse effect
to human body
So when toxicology become scientific discipline
it has happened in 1815
until a Spanish physician Orfila
established toxicology
as a distinct scientific discipline
In the 20th Century
there are many developments in toxicology
However I will only briefly
talk about one issue here
Here I want to mention about Paul Ehrlich
He developed a staining procedure
to observe cells and tissues
And then pioneered the understanding
how toxicants can influence living organisms
Because of his scientific achievement
he received the Nobel Prize
in Physiology or Medicine in 1908
These images showed
he was working in his office
and also doing experiment in his lab
As well as a result
he observed from the microscope
how the toxicants can affect the living cells
So in the 1950s the poisons led to
the public awareness
about the environmental issues
At that time a writer called Rachel Carson
She wrote a book called Silent Spring
In this book she documented many pesticides
and herbicides which have deleterious effects
on the living animals
Then this book made publics aware
about the potent effects
used in agriculture and in industry
After that the public know about
the deleterious effects of the toxicants
and then led to the creation of the US
Environmental and Protection Agency
In the next few minutes I am going to talk about
the basic concepts in Toxicology
The first of two concepts I am going to talk about
is the Dose Makes the Poisonous
For example if we have apparent
nontoxic material or chemicals at low dose
it is completely nontoxic
and at high dose it will become toxic
For example we use table salt
in food ingredient every day
However when the salt concentration
reaches much high level
for example if we take 4 g/kg of body weight
then the salt becomes lethal
It means too much of a good thing
can be bad things
The second concept is highly toxic chemicals
can be life saving compound
when we give it in appropriate dose
It means the poisons are not harmful
at a sufficiently low dose
One of the examples I would like to talk about
is arsenic trioxide
This is we know a toxic compound
Think about history there
is a French leader called Napoleon
Some people suspected
he was killed by arsenic trioxide
However nowadays in about 50 years ago
some people found that
we can use Arsenic trioxide to cure some cancers
such as acute promyelocytic leukemia
Here I would like to briefly discuss
the dose of the chemicals and the response
of the human body to adverse effect
This curve showed the agent A
has the adverse effect when the dose increased
with a linear relationship
So here we can see agent A
does not have a safe dose
So the question we want to ask is
Is there such a thing as a ¡®safe¡¯ dose?
The second example is the curve is for agent B
At very low dose before this point
we can see even we increase
the concentration of the compound B
then there is no observe adverse effect at all
It means below that curve
the chemical compound is safe for people
When the concentration increases again
then the deleterious effect
will be increased significantly
For most drugs we will have
this type of effect on human or animals
This slide defined three parameters
showing in the right image
The first concept is the EDf
It is called the effective dose
for the f% of population
It is a desired reversible response
This is why we can use this compound
to treat disease
This is showing in the left curve of the image
The second parameter is called TDf
It is Toxic dose for the f% of population
It is an undesirable irreversible response
This is what we do not need
The response of the drug
is showing in the middle curve in the image
The third concept is the LDf
is called the lethal dose
for the f% of the population
This means the dose of a chemical
which produces death in the f% of a population
of the tested animals regardless
how this compound is administered to the body
The response curve is showed
in the right side of the image LD
Once we have these three parameters
we can defined other terms
used to define the safety of the drugs
They are the Therapeutic Margin in short TM
equals to LD50% - ED50%
then the Therapeutic Index TI = LD50%/ED50%
the third one is Margin Of Safety
in short MOS = LD5% - ED95%
the last one is Safety Index
in short SI = LD5%/ED95%
This slide showed the LD50s of some compounds
In the top of the list we can see alcohol and salt
The LD50s for these two compounds
are very high normally they are nontoxic at all
But remember if you like drink you can drink
but you should not drink too much
If it reaches a certain amount
it will become lethal for human
For some chemicals or drugs
such as Aspirin and DDT have LD50s 250 mg/kg
There are moderate toxic
For other chemicals such as the compound
mentioned on the first slide Dioxin
This compound is very toxic
the LD50 is only 1 ?g/kg
Other compounds such as the bee venom
the LD50 is too low to detect
This slide showed the classification
of general toxic compounds
based on the dosage of LD50
we can classify them to the following categories
Such as Practically nontoxic compounds
which have LD50 larger than 15g/kg
Slightly Toxic compounds
and Moderately Toxic compounds
and Very Toxic compounds
which have LD50 between 50 to 500 mg/kg
Some of them are defined
as Extremely Toxic and the last is Supertoxic
these compounds have LD50 below 5 mg/kg
The last five compounds listed in the previous slides
belongs to the last category they are very toxic
So what is the effect of the toxic compounds
different toxic compounds have different effects
on human and animals
For example arsenic or cyanide can cause death
Ozone or lead can cause organ damage
and UV light can cause mutagenesis
We can look at the image the skin of the person
has been significantly changed
after strong and long time UV treatment
Other chemicals such as Benzene
and asbestos are carcinogenesis
Thalidomide can cause teratogenesis effect
In the next few minutes I am going to talk about
the molecular mechanisms of the toxicants
There are six categories of mechanisms
for toxicology
So the first one is the Adverse Drugs Reactions
is called ADRs
ADRs are notorious unintended responses
occurring at therapeutic doses
and account for about 5%
of all acute hospital admissions
There are two categories here
One is Type A is called augmented ADRs
and the other is Type B bizarre ADRs
The type A has following effects
The effect is related to
the known pharmacology but undesirable
It is very common it is also related to
the dose given to the patients
and it can be predicted
However bizarre ADRs have the following effects
These effects are unrelated to
known pharmacology
These effects are very rare
and can not be predicted
they are often idiosyncratic
That is why sometimes the bizarre ADRs
are more dangerous than the type A ADRs
Some examples for Type A and Type B ADRs
are showing at the right side of this table
So the second mechanism
is linked to receptors ion channels and enzyme
they can mediate the toxicity
of the chemical compounds
There are four major families for receptors
The first one is Ligand
can be gate ion channels ionotropioc receptors
and voltage gated ion channels
The second group is G-protein coupled receptors
The third one is enzyme-linked receptors
regulating tyrosine kinase activities
The forth one is nuclear receptors
which can regulate gene expression
The enzymes also catalyze the metabolic
and catabolic pathways
If they are affected
then the metabolism system of the human body
will be significantly changed
Other proteins including carrier proteins
which can uptake or transport proteins
in or out of cells
Some other proteins
such as involved in vesicle release
can also belong to this category
This table showed some toxins
from plants and bacteria
There are many many names showing here
Basically most of them block the RNA polymerase
inhibit the potassium calcium channels etc
This slide showed several compounds
from the animal venoms and toxin environments
For example we can see the dendrotoxins
can block the potassium channels
and agatoxin can block the calcium channels
This slide showed the mechanism of
?-bungarotoxin which is from the banded krait
How can it affect the ion channel process
So this compound actually
can block the acetylcholine receptor (AChR)
and then it can inhibit the ion channel flow
shown in the right side of this image
And eventually leads to paralysis
and death of animals or humans
The third mechanism of the toxicology
is the alteration of biological pathways
For example cyanide
can inhibit mitochondrial cytochrome c oxidase
to prevent cellular respiration
Carbon monoxide displaces oxygen
from haemoglobin causing hypoxia
Under normal condition
when we have oxygen supplies haemoglobin
can be gradually saturated
However in the presence of carbon monoxide
then haemoglobin can be quickly occupied
by carbon monoxide
It can not carry oxygens
That is why even with 0.01% of carbon monoxide
in atmosphere it will cause headache
When the concentration is higher than 0.2%
it can cause potential death for people
The fourth mechanism for toxicology
is linked to the organ-directed toxicity
For example lead compound can cause defects
on the central nervous system
which will have severe effects on children
Isocyanates can cause immune system problems
ethanol and acetaminophen
can cause liver damages
and tobacco smoke asbestos
and ozone can cause respiratory tract problems
UV lights as I mentioned can cause skin
and eye problems
metals can cause kidney dysfunctions
And other compounds
such as dibromochloropropane
can cause problems in reproductive systems
The fifth mechanism is linked to
mutagenesis and carcinogenesis
Mutagens are compounds which
can cause DNA mutation
This mutation can cause disease
If this process can make neoplastic cells
the agent is termed a carcinogen
There are two major classes of genes
which are involved in carcinogenesis
The first type is proto-oncogenes
which can promote cell cycle progression
For example the constitutive active growth factor
tyrosine-kinase receptors
can cause neoplastic transformation
The second type here
is the tumor-suppressor genes
If these genes have mutation
then it can inhibit cell cycle progression
For example the mutations
in tumor suppression genes
can produce p53 mutations
and cause many many cancers in human body
The last one I would like to mention
is teratogenicity
Actually those are compounds
which can cause birth defects
during the development
One of the cases I would like to mention to you
is the thalidomide story
As we know thalidomide
was used as a sedative in 1960s
However later on
it is found that this compound can cause defect
showing in the right side of this slide
for example birth defects on the feet legs
and also on hands
Actually later on people found
that this compound has two different enantiomers
and these two enantiomers
have different functions
Here is a little bit history about thalidomide
This compound was synthesized in 1950s
When it was tested in all the animals at that time
there was non-toxic effect
Then this drug was introduced in 1956
as sedative to reduce nausea
and vomiting during pregnancy
In 1961 thalidomide became
the best-selling sleeping pill
in West Germany and the United Kingdom
However when it was taken
by the pregnant women
then thalidomide produced teratogenic effects
in 100% of foetuses exposed
between 3-6 weeks of gestation
There is an estimated about 8 000-12 000 infants
born with birth defects caused by thalidomide
However only about 5 000 of them
survived beyond childhood
After this disaster
the United States and European countries
implemented drug testing new rules
Although this drug is toxic for people today
this drug is still useful for some of the disease
For example it can be used to treat leprosy
and multiple myeloma
This table showed us the effect of toxic drugs
on the fetal development
The first stage is the blastocyte formation
It is within 16 days of the gestation
Some cytotoxic drugs such as alcohol
can affect the cell division at this stage
The second stage is the organogenesis
It is between 17-60 days
Some of the teratogens
such as thalidomide retinoids and warfarin
can affect cell division migration differentiation
and even cause death
The third stage is the maturation stage
In that stage alcohol nicotine and steroids
can affect cell division migration differentiation
and even cause death
In the next few minutes I will briefly mention
the occupational and environmental toxicology
The goals for the occupational toxicology
are to deal with the chemicals found
in the workplace
to identify chemicals and agents
in that environment
to identify the acute and chronic diseases
that they can cause
And to define the conditions under which
they may be used safely
Also it studies to prevent the absorption
of harmful amounts of these chemicals
Sometimes the environmental toxicology
also defines and carries out programs
for the surveillance of exposed workers
and the environment in which they work
The goals for the environmental toxicology
are to deal with the potentially deleterious impact
of chemicals in the environment
on living organisms
And to study the toxic chemicals
in air soil and water pollution
To identify chemicals
used in the agricultural environment
as pesticides or in food processing
that may persist as residues or ingredients
in food product
Here I would like to briefly mention hazard and risk
Hazard is the ability of a chemical agent
to cause injury in a giving situation or setting
the conditions of use
and its exposure are primary considerations
It includes the inherent toxicity
and the amount of chemicals
absorbed to the body
Risk here is defined as the expected frequency
of the occurrence of an undesirable effect
arising from exposure to a chemical or physical agent
There are mainly three routes
for exposure of toxicants
They are inhalation skin contact and oral ingestion
Here are some of the properties
we can estimate the potential hazard of a compound
The first one is the degradability
If a compound is poorly degradable
then it may exist in human bodies for a long time
For examples such compounds
are organic pollutants polychlorinated biphenyls
which are highly hazard
The second property is the mobility
If a chemical is highly mobile
through the air water and soil
then it will have more adverse effect
It will affect more people
The third property is bioaccumulation
For examples some of the compounds
such as lipophilic substances such as DDT
It can accumulate in the body fat showing
in the upper part of this image
When an animal grows from childhood to the adult
then this kind of chemicals
will accumulate in their body
The fourth one is biomagnification
This is a process that a chemical can be transported
from different animals to other animals
That is why if a compound
has biomagnifications properties
then it will accumulate in large animals
and even in human
There are five major pollutants
They are air pollutants solvents pesticides herbicides
and environmental pollutants
I will briefly introduce them in the next few slides
The first one is air pollutants
Carbon monoxide accounts for ~52%
of the air pollutants
It can bind to the oxygen binding sites
of hemoglobin to form carboxyhemoglobin
Brain and heart are the most affected organs
The second one is sulfur oxide
It accounts for about 14% of the air pollutants
It can form sulfurous acid with moisture
and can cause irritant to eyes respiratory tract
and also affect skins
The third one is nitrogen oxides
It accounts for about 14% of air pollutions
It can damage type I and II alveolar cells
cause pulmonary edema or death
The next one is ozone
The chemical formula is O3
It occurs in earth atmosphere
around high-voltage electrical device
or ozone producing devices
This is an irritant of mucous membranes
can irritate upper respiratory tract
cause deep lung irritation pulmonary edema
and so on
The last category is hydrocarbons
It accounts for about 14%
and the particulate matter
it is called PM
It accounts for ~4%
For solvent pollutants there
are mainly two categories
One is halogenated aliphatic hydrocarbons
includes carbon tetrachloride chloroform etc
These kinds of compounds
can cause central nervous system depression
cause liver and kidney injury cardiotoxicity etc
The second group is aromatic hydrocarbons
such as benzene toluene xylene
These compounds
can cause many deleterious effects
mostly can cause cancer such as blood cancer
cause defects in central neural systems
For pesticides there are mainly four categories
One is organochlorine pesticides
such as DDT and its analogs benzene hexachlorides
and so on
These kinds of compounds
can interfere with inactivation
of the sodium channel in excitable membrane
and can cause rapid repetitive firing
in most neurons
can inhibit calcium ion transport
they are slowly degraded
and have bioaccumulation effect
The second group is organophosphorus pesticides
such as trichlorfon diazinon etc
They can inhibit acetylcholinesterase
The last two groups are carbamate pesticides
and botanical pesticides
Some of the examples
are aldicarb aminocarb nicotine rotenone
and pyrethrum
This slide showed some of the herbicides
The first one is chlorophenoxy herbicides
Two of the examples are shown
on the top of this slide
2,4-D, 2,4,5-T
There are multiple chlorine atoms
in these compounds
The next one is glyphosate
This is nonselective herbicide
can cause eye and skin irritant
and may cause death
The structure is shown in the middle of this slide
So the third group is bipyridyl herbicides
One of the examples is shown
at the bottom of this image
This kind of herbicide can accumulate in lung
and cause lung edema
Here are some of the environmental pollutants
The first group actually also contains
lots of chlorine atoms such
as polychlorinated biphenyls
Some of the examples are shown in this slide
such as TCDD and PCDD
They can cause dermatologic problems
and elevate plasma triglycerides
Another group is endocrine disruptors
They have estrogen-like
or anti-androgenic properties
have adverse effect on reproductive cancers
The third one is asbestos
It can cause progressive lung disease
In this class I have briefly
talked about the following things
We need to know how toxicology is developed
We need to know the brief history of the toxicology
and what are the effective dose toxic dose
and lethal dose for a compound what are
the therapeutic margin therapeutic index margin
of safety and safety index
what are the types of toxic effects
what are the molecular mechanisms of toxicology
what are the properties
for estimating potential hazards
what are the major air pollutants
major toxic solvents pesticides herbicides
and environmental pollutants
Thank you very much
I would like to see you next class
Bye-bye