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Principles of Toxicology
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PRINCIPLES OF
TOXICOLOGY
PRINCIPLES of TOXICOLOGY 1
OBJECTIVES:
To explain the general nature of toxic
action of substances
To describe the nature of toxic action and
the effects brought about by chemicals
To explain the potential stages in the
development of toxicity
PRINCIPLES of TOXICOLOGY 2
Introduction to Toxicology
Toxicology is the study of the adverse
effects of chemicals on living organisms.
Toxicologist- one who is trained to
examine the nature of those effects
( cellular, biochemical, and molecular
mechanisms of action) and assess the
probability of their occurrence
PRINCIPLES of TOXICOLOGY 3
BRANCHES OF TOXICOLOGY
PRINCIPLES of TOXICOLOGY 4
Clinical toxicology
Effects of substances to patients
PRINCIPLES of TOXICOLOGY 5
Experimental
Effects of chemicals in the biological
system
Measures laboratory parameters
PRINCIPLES of TOXICOLOGY 6
Descriptive toxicology
Toxicity testing
Provide information for safety evaluation
and regulatory requirements
SET LIMITS
PRINCIPLES of TOXICOLOGY 7
Mechanistic toxicology
Mechanism of action or MOA of
poisons
Data may be useful in the design and
production of safer chemicals and in
rational therapy for chemical poisoning
and treatment of disease
Data is useful in demonstrating that an
adverse outcome observed in laboratory
animals is directly relevant to humans
PRINCIPLES of TOXICOLOGY 8
Regulatory toxicology
Involved in the establishment of standards
for the amount of chemicals permitted in
foods, drugs, air, industrial atmosphere and
drinking water
PRINCIPLES of TOXICOLOGY 9
Environmental toxicology
Studying the impacts of chemicals on non
human organisms such as fish, birds,
terrestrial animals and plants
PRINCIPLES of TOXICOLOGY 10
Forensic toxicology
Medico-legal cases of poisoning and
intoxication
PRINCIPLES of TOXICOLOGY 11
All substances are poisons; there is none which is not a
poison.
The right dose differentiates
a poison from a remedy.
Paracelsus (1493-1541)
Paracelsus
PRINCIPLES of TOXICOLOGY 12
The sensitivity of the individual differentiates a
poison from a remedy. The fundamental
principle of toxicology is the individuals
response to a dose.
S. G. Gilbert (1997)
An Individual View
PRINCIPLES of TOXICOLOGY 13
Poison
Any agent that may cause harm or serious
injury
PRINCIPLES of TOXICOLOGY 14
every known chemical has the potential
to produce injury or death if it is present in
a sufficient amount
PRINCIPLES of TOXICOLOGY 15
Dose
The amount of chemical entering the body
This is usually given as
mg of chemical/kg of body weight = mg/kg
The dose is dependent upon
* The environmental concentration
* The properties of the toxicant
* The frequency of exposure
* The length of exposure
* The exposure pathway
PRINCIPLES of TOXICOLOGY 16
Dose-Response Relationship:
As the dose of a toxicant increases, so does the response.
2
3
4
0 1 DOSE
RESPONSE
0-1 NOAEL
2-3 Linear Range
4 Maximum Response
DOSE DETERMINES THE BIOLOGICAL RESPONSE PRINCIPLES of TOXICOLOGY 17
Dose response assumptions
response is due to chemical administered
the response is related to the dose
there is a receptor site with which the
chemical interacts
the degree of response is related to the
concentration at the site
the concentration at the site is related
to the dose administered
has a quantifiable method of measuring and a
precise means of expressing the toxicity
PRINCIPLES of TOXICOLOGY 18
Exposure: Pathways
Routes and Sites of Exposure
Ingestion (Gastrointestinal Tract)
Inhalation (Lungs)
Dermal/Topical (Skin)
Injection
intravenous, intramuscular, intraperitoneal
PRINCIPLES of TOXICOLOGY 19
Rapidity of response with respect to route
of exposure
Intravenous
Inhalation
Intraperitoneal
Subcutaneous
Intramuscular
Intradermal
Topical
PRINCIPLES of TOXICOLOGY 20
Exposure: Duration
Acute < 24hr usually 1 exposure
Subacute 1 month repeated doses
Subchronic 1-3mo repeated doses
Chronic > 3mo repeated doses
Over time, the amount of chemical in the
body can build up, it can redistribute, or it
can overwhelm repair and removal
mechanisms PRINCIPLES of TOXICOLOGY 21
Toxins = toxic substances
produced naturally
PRINCIPLES of TOXICOLOGY 22
Toxicants = toxic substances that are
produced or a by-product of
human activities
PRINCIPLES of TOXICOLOGY 23
Adverse effects
any change from an organisms normal state
dependent upon the concentration of active compound at the target site for a sufficient
time.
PRINCIPLES of TOXICOLOGY 24
Tolerance
state of decreased responsiveness to a
toxic effect of a chemical, resulting from
previous exposure
dispositional tolerance; a decreased amount of drug reaching the site
cellular; reduced responsiveness of a tissue
PRINCIPLES of TOXICOLOGY 25
Toxicity
describes the degree to which a
substance is poisonous or can cause
injury.
PRINCIPLES of TOXICOLOGY 26
Major factors that influence
toxicity
route of administration
duration and frequency of exposure
dose or concentration
shape and structure of the chemical itself,
and individual human factors.
PRINCIPLES of TOXICOLOGY 27
PRINCIPLES of TOXICOLOGY 28
What is toxicodynamics ?
It examines the mechanism by which toxicants
produce unique cellular effects within the
organism
Mechanism of toxic action
The alteration to the cells plasma membrane,
organelles, nucleus, cytoplasm, enzyme
systems, biosynthetic pathways, development
or reproduction
PRINCIPLES of TOXICOLOGY 29
1. Toxic action of a drug is not necessarily
an exaggeration of its therapeutic action.
2. One toxicant may exert several mechanisms
of toxic action.
3. The toxic action may be brought about by the
parent compound and/or its metabolites.
4. The mechanisms of toxic action in acute
exposure may differ from those in chronic
exposure.
5. Intensity of a toxic effect depends primarily on
the concentration and persistence of the ultimate
toxicant at its site of action.
PRINCIPLES of TOXICOLOGY 30
1. Allergic Reactions
Chemical allergy : immunologically
mediated adverse reaction to a
chemical or to structurally
similar one
PRINCIPLES of TOXICOLOGY 31
2. Idiosyncratic Reactions:
Chemical idiosyncrasy : refers to a
genetically determined abnormal
reactivity to a chemical; the
response observed may take the
form of extreme sensitivity to low
doses or extreme insensitivity to
high doses of a chemical
E.g. Nitrites :
deficiency in NADH-methemoglobin reductase
PRINCIPLES of TOXICOLOGY 32
3. Immediate vs. Delayed Toxicity:
Immediate : occurs or develops
rapidly after a single administration
of a substance
Delayed: occurs after a lapse of some
Time (months or years)
PRINCIPLES of TOXICOLOGY 33
4. Reversible vs. Irreversible Toxic Effects:
E.g.
Reversible: injury to the liver by
paracetamol
Irreversible: injury to the CNS by
ethanol
PRINCIPLES of TOXICOLOGY 34
5. Local vs. Systemic Toxicity:
Local : site of first contact between
biological system and toxicant
E.g. Caustics skin, gastrointestinal mucosa Chlorine gas lung tissue
Systemic: absorption and distribution of
toxicant from its entry point to a distant
site at which deleterious effects are
produced
E.g. Caustics (phenol) kidney damage
PRINCIPLES of TOXICOLOGY 35
Casarett & Doulls, 7th edition PRINCIPLES of TOXICOLOGY 36
TOXICATION Biotransformation to
harmful products
E.g. Ethylene glycol converted to
oxalic acid which produces
acidosis and hypercalcemia
PRINCIPLES of TOXICOLOGY 37
Non-covalent binding
Covalent binding
Electron transfer
Enzymatic reaction
PRINCIPLES of TOXICOLOGY 38
Third step: Alteration of regulatory
or maintenance function of the cell
PRINCIPLES of TOXICOLOGY 39
CELLULAR REGULATION
1. Dysregulation of gene expression
Dysregulation of transcription PRINCIPLES of TOXICOLOGY 40
2. Dysregulation of on-going cellular activity
Alteration in neurotransmitter levels
Methamphetamine/amphetamine increases release and inhibit reuptake of norepinephrine, dopamine
and serotonin
Organophosphates decrease hydrolysis of acetylcholine
PRINCIPLES of TOXICOLOGY 41
2. Dysregulation of on-going cellular activity
Toxicant-neurotransmitter receptor interaction
INHIBITION
Atropine & atropine-like drugs produce inhibitory
effect on the muscarinic receptors (M2 and M3)
Increased heart rate
Decreased bowel sounds
Decreased salivation
Decreased perspiration
STIMULATION
Benzodiazepine stimulating GABA A receptor
Sedation PRINCIPLES of TOXICOLOGY 42
2. Dysregulation of on-going cellular activity
Toxicant-signal transducer interactions
DDT, pyrethroids act on
Voltage-gated Na+ channels
Neuronal activation
Overexcitation
Convulsion
PRINCIPLES of TOXICOLOGY 43
2. Dysregulation of
on-going cellular activity Enzyme reactions
Enzyme Inhibition Pyridoxine kinase Glutamic acid decarboxylase Monoamine oxidase Nicotinamide adenine dinucleotide (NAD) (co-enzyme)
EFFECTS:
Seizure Acidosis Increased sympathetic activity
PRINCIPLES of TOXICOLOGY 44
1. Impaired Internal Maintenance
CELLULAR MAINTENANCE
Inhibition of hydrogen delivery to ETC (1)
(fluoroacetate inhibits
aconitase enzyme)
IMPAIRED ATP SYNTHESIS
Inhibition of electron transport complexes (2)
(Cyanide, CO inhibits
cytochrome oxidase)
Inhibition of oxygen delivery to electron
transport chain (3)
(CO, hydrogen sulfide,
nitrites)
Inibition of ADP phosporylation (4)
(DDT & chlordecone
inhibit ATP synthase )
PRINCIPLES of TOXICOLOGY 45
CELLULAR MAINTENANCE
1. Impaired Internal Maintenance
Impaired membrane function
Ethanol and organic solvents increase membrane fluidity Lipid solvents destroy plasma membrane Hydrocarbons destroy lysosomal membranes
2. Impaired External Maintenance
Toxicities interfering with cells specialized to provide support to other cells, tissues or whole organism
Inhibition of hepatic synthesis of coagulation factors by coumarin
PRINCIPLES of TOXICOLOGY 46
REPAIR
Molecular Cellular Tissue
Protein
Lipid
DNA Proliferation Apoptosis
Cells ECM
Repair Mechanisms PRINCIPLES of TOXICOLOGY 47
Tissue necrosis
Fibrosis
Cancer
PRINCIPLES of TOXICOLOGY 48
DYSREPAIR
Failure of DNA repair Failure of apoptosis Failure to terminate cell proliferation
PRINCIPLES of TOXICOLOGY 49
SIGNIFICANCE OF TOXICODYNAMICS:
Choice of antidotal therapy
Determine magnitude and extent of toxicity
More effective and adequate treatment plan
PRINCIPLES of TOXICOLOGY 50
PRINCIPLES of TOXICOLOGY 51
Study of how a substance gets into the body and what happens to it in the body
Modeling and mathematical description of the time course of disposition of
toxicants in the whole organism
PRINCIPLES of TOXICOLOGY 52
Toxicokinetics Only the absorbed dose that makes it to the target organ is capable
of producing an effect
Xenobiotic
Excretion
The effect which a chemical produces is not only dependent on the dose administered but more on
the concentration of the chemical in the target
organ.
The concentration in turn depends on the disposition of the chemical.
The kinetics of a chemical/drug may differ from therapeutic dose to its toxic dose.
The study of toxicokinetics is important in predicting plasma concentration of a chemical.
PRINCIPLES of TOXICOLOGY 54
A result of a number of opposing
actions
Some promotes delivery of the
Toxicant towards the target
Others promote toxicant delivery
Away from the target
The net effect determines how
much of the toxicant
makes it to its site of action
PRINCIPLES of TOXICOLOGY 55
Concentration at site of action
Duration of the Ultimate Toxicant
At Its Site of Action
Intensity of toxic action
The Ultimate Toxicant is the species that interacts with the target or critically modifies the biological microenvironment
PRINCIPLES of TOXICOLOGY 56
The ultimate toxicant can be:
The parent compound
A metabolite of the parent
A reactive Oxygen or Nitrogen species
An endogenous compound
PRINCIPLES of TOXICOLOGY 57
FOUR PROCESSES IN TOXICOKINETICS
ABSORPTION is the process by which a chemical enters the body
DISTRIBUTION is the stage when a substance moves from the site of entry to other organs/areas of the body
METABOLISM is when the body transforms the chemical into metabolites
EXCRETION is the process wherein the parent chemical and its metabolites leave the body
PRINCIPLES of TOXICOLOGY 58
Absorption, Distribution,
Metabolism, and Excretion
Once a living organism has been exposed
to a toxicant, the compound must get into
the body and to its target site in an active
form in order to cause an adverse effect.
The body has defenses:
Membrane barriers
passive and facilitated diffusion, active transport
Biotransformation enzymes, antioxidants
Elimination mechanisms
FACTORS AFFECTING KINETIC PROCESSES
Duration and concentration at the portal of entry
the higher the concentration, the greater will the damage be
Rate and amount of chemical absorbed rate of absorption is slow and the amount absorbed is small,
the toxicity will be low
Distribution of the toxicant within the body most of the toxicants are distributed in highly perfused organs which have vital functions such as the brain
and the kidneys.
the organ in which a chemical is most highly concentrated is not necessarily the organ where most tissue
damage occurs.
PRINCIPLES of TOXICOLOGY 60
FACTORS AFFECTING KINETIC PROCESSES
Efficiency of biotransformation and nature of metabolites
a chemical maybe converted to a toxic metabolite which is
more toxic than the parent compound
Ability of the chemical or its metabolites to pass through cell membranes and come into contact with specific cell
components
a chemical can pass through the placenta or the blood brain
barrier
Amount and duration of storage of the chemical or its metabolites in body tissues
some chemicals are stored in body tissues for a long period
of time and would produce its effect long after the
initial exposure
PRINCIPLES of TOXICOLOGY 61
PRESYSTEMIC ELIMINATION First pass effect
DISTRIBUTION AWAY FROM THE TARGET SITE Binding to plasma proteins because protein-bound chemicals do not exert toxic action
Specialized barriers such as blood-brain barrier which prevent entry of hydrophilic chemicals into the brain
Storage sites which are not target sites of chemicals and where the chemicals are highly concentrated
Association with intracellular binding proteins which are non-target intracellular sites
Export from cells wherein chemicals are transported back into the extracellular space
PRINCIPLES of TOXICOLOGY 62
DETOXIFICATION
Biotransformation of chemical prevents its formation I
nto ultimate toxic metabolites and enhances
its elimination
EXCRETION The liver and the kidneys can remove efficiently highly
hydrophilic, usually ionized chemicals such as weak
acids and bases. Other processes include the bile,
gastrointestinal tract and the breastmilk.
PRINCIPLES of TOXICOLOGY 63
Involves the movement of chemcials
across cell membranes
Phospholipid bilayer
PRINCIPLES of TOXICOLOGY 64
Factors affecting gastrointestinal absorption of drugs/
chemicals in their toxic states
Type of cells at the specific site Contact time pH of the stomach and small intestine Concentration of the drug/chemical at absorption site
Presence of food or binding substances Rate of gastric emptying Gastrointestinal motility Large absorbing surface of the small intestines
Blood flow to the site Intestinal microflora and GI enzymes General condition of the patient Product formulation
PRINCIPLES of TOXICOLOGY 65
Solubility of the chemical in
the blood
(blood/gas coefficient)
If low, rate of transfer from alveoli to blood is dependent on perfusion
If high, rate of transfer from alveoli to
blood is dependent on ventilation
Particle size
Water solubility
PRINCIPLES of TOXICOLOGY 66
Condition of the skin
Body region
Lipid solubility
PRINCIPLES of TOXICOLOGY 67
Movement of chemicals throughout the body within the bloodstream
PRINCIPLES of TOXICOLOGY 68
Blood flow/perfusion limitation Permeability limitation Capillary membrane passage
Cell membrane passage
Apparent volume of distribution Protein binding Effect of pH Age Tissue reservoir/depots Plasma proteins
Liver and kidneys
Fat
Bone
PRINCIPLES of TOXICOLOGY 69
Process by which the body alters chemicals, typically for energy
production
Biotransformation process by which both endogenous, and exogenous substances that enter
the body are changed from hydrophobic to
hydrophilic molecules to facilitate elimination.
PRINCIPLES of TOXICOLOGY 70
The highest capacity
for biotransformation
is the liver.
PRINCIPLES of TOXICOLOGY 71
Metabolism =
Toxification /Detoxification
Toxication = increase in toxicity
Detoxification = decrease in toxicity
PRINCIPLES of TOXICOLOGY 72
Toxication
Change in Structure increases
interaction with target molecule
Changes in general reactivity lead to the formation of
electrophiles
free radicals
nucleophiles
PRINCIPLES of TOXICOLOGY 73
Detoxication
To be eliminated from the body more
efficiently must be hydrophilic and
ionized
Compounds with no functional groups
Phase I - oxidation via CYP450
Phase II - addition of endogenous acid (conjugation)
Product: hydrophilic organic acids
Electrophiles conjugation with
glutathione a thiol nucleophile
PRINCIPLES of TOXICOLOGY 74
Phase I reactions Oxidation, reduction,
hydrolysis, hydration
Phase II reactions Glucuronidation,
sulfation
TOXICANT PHASE I
PRIMARY PRODUCT
PHASE II
SECONDARY
PRODUCT
ELIMINATION FROM BODY
PRINCIPLES of TOXICOLOGY 75
When does detoxication fail?
Toxicants overwhelm the detoxication processes
Reactive toxicants deactivate a detoxicating enzyme
Conjugation reactions are reversed
Reactive degradation products are formed by detoxicating enzymes
PRINCIPLES of TOXICOLOGY 76
Age Sex Pharmacogenetic factors Pregnancy Nutritional status/ body size and weight
Disease states Bioactivation Enzyme induction/inhibition Changes in kinetic mechanisms
PRINCIPLES of TOXICOLOGY 77
Process by which the body
separates and discharges wastes
or toxic substances from the
body
PRINCIPLES of TOXICOLOGY 78
Most important organ for excretion is the kidney.
Other routes:
Fecal
Respiratory
Cerebrospinal fluid
Milk
Sweat
Saliva
PRINCIPLES of TOXICOLOGY 79
Age
Disease states Rate of excretion Enterohepatic recirculation Ion trapping
PRINCIPLES of TOXICOLOGY 80
Phenomenon by which drugs emptied
through the bile into the small intestine can
be reabsorbed from the intestinal lumen into
systemic circulation. When reaching the
distal ileum, bacterial flora convert the
parent drug and its active metabolites back
into lipophilic states
PRINCIPLES of TOXICOLOGY 81
Removal of Chemicals from the
body
Primary Structures:
Kidney
Glomerular filtration
Tubular excretion
Liver
Usually water soluble and ionic, weak acids and bases
No effective removal of lipophilic, persistent molecules
Some volatiles and non-reactives may leave via the lung
PRINCIPLES of TOXICOLOGY 82
Retention of Chemicals in the Body
In the renal tubule, toxicants can be
reabsorbed prior to excretion:
PRINCIPLES of TOXICOLOGY 83
In the GI tract, compounds secreted
as ionics can be modified by gut
bacteria then reabsorbed
Enterohepatic Recirculation
Aspirin
Carbamazepine Dapsone Digoxin Methamphetamine Paracetamol Phencyclidine Phenothiazine Phenobarbital Phenytoin Quinine
Rifampicin Salicylates Theophylline Anticoagulants Naphthalene Organochlorine
pesticides
PRINCIPLES of TOXICOLOGY 84
Winston Churchill
PRINCIPLES of TOXICOLOGY 85