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1. BASIC PRINCIPLES OF
TOXICOLOGY
P. E. Owusu Agyei

2. Objectives
• Definitions
• Toxicological studies
• Discuss the factors that affect and/or modify
the actions of poisons (Dose-response
correlations)
• Understand the toxicokinetics and
toxicodynamics of toxicants.

3. Introduction
• Toxicology is the science of the adverse
effects of chemicals, including drugs, on living
organisms.
• descriptive toxicology
• mechanistic toxicology
• regulatory toxicology

4. • Adverse effects
Undesired deleterious or harmful effect in the
organism caused by a medication or an
intervention.
• Toxicant (Poison)
– any agent capable of producing a deleterious
response in a biological system

5. So Toxicology is the study of how
toxicants:
• enter the organism
• Influence the organism
• are eliminated from (leave) the organism
All substances are toxic if taken in the wrong
quantities

6. Physiological/ pharmacological
classification of poisons
– Corrosive:
– strong mineral/organic acids;
– strong alkalis
– Irritant:
– metallic e.g. mercury
– vegetable e.g. castor oil
– gas e.g. ammonia
– Hypnotic/narcotic: e.g. barbiturate, morphine
– Deliriant/convulsant e.g. cocaine, strychnine
– Paralytic/anti-cholinesterase e.g. nicotine
– Abortifacient e.g. ergot, quinine
– Poisonous gases e.g. carbon monoxide, prussic acid
• Miscellaneous e.g. botulinum

7. Types of toxic reactions
• Pharmacological, Pathological, or Genotoxic
• Local versus Systemic Toxicity
• Reversible and Irreversible Toxic Effects
• Delayed Toxicity
• Idiosyncratic Reactions
• Interactions between chemicals

8. Types of toxic reactions
(by Toxidroms)
• Sympathomimetics: upregulate sympathetic NS
• Anticholinergic
• Cholinergic
• Sedative/hypnotic
• opioid

9. Toxicokinetics & Toxicodynamics
• Toxicokinetics (Determines the no. of molecules
that can reach the receptors)
• Uptake
• Transport
• Metabolism & transformation
• Sequestration
• Excretion
• Toxicodynamics (Determines the no. of receptors
that can interact with toxicants)
• Binding
• Interaction
• Induction of toxic effects

10. Toxicodynamics
• Relationship between dose and intended
pharmacological response and /or resultant
toxicological response.
• Eg. Acetaminophen and ethanol

11. Target Sites:
Mechanisms of Action
• Adverse effects can occur at the level of the
molecule, cell, organ, or organism
• Molecularly, chemical can interact with
Proteins Lipids DNA
• Cellularly, chemicals can
– interfere with receptor-ligand binding
– interfere with membrane function
– interfere with cellular energy production
– bind to biomolecules
– perturb homeostasis (Ca+)

12. Dose
• The amount of chemical entering the body
mg/kg and/reaching the site of action.
 The environmental concentration
 The properties of the toxicant
 The frequency of exposure
 The length of exposure
 The exposure pathway

13. What is a Response?
• Change from normal state
– could be on the molecular, cellular, organ, or
organism level--the symptoms
• Local vs. Systemic
• Reversible vs. Irreversible
• Immediate vs. Delayed
• Graded vs. Quantal
– degrees of the same damage vs. all or none

14. 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

15. LD50
• Quantal responses can be treated as
gradient when data from a population is
used.
• If Mortality is the response, the dose that is
lethal to 50% of the population LD50 can be
generated from the curve

16. LD50 Comparison
Chemical LD50 (mg/kg)
Ethyl Alcohol 10,000
Sodium Chloride 4,000
Ferrous Sulfate 1,500
Morphine Sulfate 900
Strychnine Sulfate 150
Nicotine 1
Black Widow 0.55
Curare 0.50
Rattle Snake venom 0.24
Dioxin 0.001
Botulinum toxin 0.0001

17. Toxicokinetics
• Time course of blood and tissue concentration
profile.
• Toxicokinetics and factors affecting/modifying
action of poisons include:
– Dose/concentration
– age
– route of absorption/administration
– rate of administration
– state of poison
– health
– tolerance
– idiosyncrasy etc.

18. Exposure: Pathways
• Routes and Sites of Exposure
– Ingestion (Gastrointestinal Tract)
– Inhalation (Lungs)
– Dermal/Topical (Skin)
– Injection
• intravenous, intramuscular, intraperitoneal
• Typical Effectiveness by Route of Exposure
iv > inhale > ip > im > ingest > topical

19. 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

20. 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

21. Absorption:
• Inhalation--readily absorb gases into the blood
stream via the alveoli. (Large alveolar surface,
high blood flow, and proximity of blood to
alveolar air)
• Ingestion--absorption through GI tract stomach
(acids), small intestine (long contact time, large
surface area--villi; bases and transporters for
others)
– 1st Pass Effect (liver can modify)
• Dermal--absorption through epidermis (stratum
corneum), then dermis; site and condition of skin

22. Uptake of Toxicants
1. Passive diffusion
2. Facilitated transport: Calmodulin for
facilitated transport of Ca
3. Active transport: P-glycoprotein pump
for xenobiotics
– Ca-pump (Ca2+ -ATPase)
4. Pinocytosis: Airborne toxicants across
alveoli cells
– Carrageenan across intestine

23. Uptake by Passive diffusion
• Uncharged molecules may diffuse along conc.
gradient until equilibrium is reached
• Not substrate specific
• Small molecules of < 0.4 nm (e.g. CO, N20) can
move through cell pores
• Lipophilic chemicals may diffuse through the
lipid bilayer

24. Distribution:
• Blood carries the agent to and from its site
of action, storage depots, organs of
transformation, and organs of elimination
• Rate of distribution (rapid) dependent upon
– blood flow
– characteristics of toxicant (affinity for the
tissue, and the partition coefficient)
• Distribution may change over time

25. Distribution:
Storage and Binding
• Storage in Adipose tissue -Very lipophylic
compounds (DDT) will store in fat.
• Storage in Bone -Chemicals analogous to
Calcium: Fluoride, Lead, Strontium
• Binding to Plasma proteins - can displace
endogenous compounds.

26. Target Organs:
• Not all organs are affected equally
– greater susceptibility of the target organ
– higher concentration of active compound
• Liver: high blood flow, oxidative reactions
• Kidney: high blood flow, concentrates chemicals
• Lung: high blood flow, site of exposure

27. • Neurons: oxygen dependent, irreversible
damage
• Myocardium: oxygen dependent
• Bone marrow, intestinal mucosa -rapid divide

28. Deposition
Toxicant Target organs
Pb Bone, teeth, brain
Cd Kidney, bone, gonad
OC, PCB Adipose tissue, milk
OP Nervous tissue
Aflatoxin Liver

29. Metabolism & Transformation
• Principle of detoxification:
1. Convert toxicants into more water soluble
form (more polar & hydrophilic)
2. Dissolve in aqueous/gas phases and
eliminate by excretion (urine/sweat) or
exhalation
3. Sequestrate in inactive tissues (e.g bone, fat)

30. Metabolism:
• The process by which the administered chemical
(parent compounds) are modified by the
organism by enzymatic reactions.
• 1o objective--make chemical agents more water
soluble and easier to excrete
– decrease lipid solubility →
decrease amount at target site
– increase ionization → increase excretion rate
→ decrease toxicity

31. Biotransformation (Metabolism)
• Can drastically
affect the rate of
clearance of
compounds
• Can occur at any
point during the
compound’s
journey from
absorption to
excretion
Compound Without
Metabolism
With
Metabolism
Ethanol 4 weeks 10mL/hr
Phenobarbital 5 months 8hrs
DDT infinity Days to weeks

32. Biotransformation
• Key organs in biotransformation
– LIVER (high)
– Lung, Kidney, Intestine (medium)
– Others (low)
• Biotransformation Pathways
* Phase I--make the toxicant more water soluble
* Phase II--Links with a soluble endogenous agent
(conjugation)

33. Excretion:
• Urinary excretion
– water soluble products are filtered out of the
blood by the kidney and excreted into the
urine
• Exhalation
– Gas (e.g. ammonia) and Volatile compounds
are exhaled by breathing

34. Excretion
• Biliary Excretion via Fecal Excretion
– Compounds can be extracted by the liver and
excreted into the bile. The bile drains into the
small intestine and is eliminated in the feces.
• Milk; Sweat; Saliva
• Lipid soluble and non-ionised toxicants may be
reabsorbed (systemic toxicity)

35. Sequestration
• Animals may store toxicants in inert
tissues (e.g. bone, fat, hair, nail) to reduce
toxicity
• Lipophilic toxicants (e.g. DDT) may be
stored in milk at high concentration and
passed to the young

36. Individual Susceptibility
• Genetics: species, strain variation,
interindividual variations (still can extrapolate
between mammals - similar biological
mechanisms)
• Gender (gasoline nephrotoxic in male mice only)
• Age -young (old too)
– underdeveloped excretory mechanisms
– underdeveloped biotransformation enzymes
– underdeveloped blood-brain barrier

37. Individual Susceptibility
• Age -old
• Nutritional status
• Health conditions
• Previous or Concurrent Exposures
– additive --antagonistic
– synergistic

38. Adverse drug reactions
• Dose-related (Augmented)
• Non-dose-related (Bizarre),
• Dose-related and time-related (Chronic),
• Time-related (Delayed),
• Withdrawal (End of use),
• **Failure of therapy (Failure).

39. Adverse drug reactions -
Presentation
• Type I: anaphylaxis
– Penicillins
– Cephalosporins
– Sulphonamides
• Type II: Cytotoxic
Haemolytic anaemia
- sulphonamides,
penicillin, quinidine,
methyldopa
Agranulocytosis
- carbimazole,
clozapine
Thrombocytopenia
- quinidine, heparin

40. • Type III: Immune
complex mediated
– Penicillins
– Sulphonamides
– thiazides
• Type IV: T-cell mediated
– Penicillins
– Cepholosporins
– Local anaesthetics
– phenytoin

41. Toxicant specificity/generalization
Mercury readily
covalent bond
with sulfur
Chelation with dimercaprol and penicillamine
Along fluid and electrolyte ballancew
Aspirin: acid-base
disturbances
requires urinary alkalinization, or haemodialysis
botulinum toxin:
neurotoxin
ASAP with antibiotics