Introduction to Toxicology

4th
Year Clinical Pharmacology
Toxicology
Department of Pharmacy
School of Health Sciences
UNZA
1st Lecture
Andrew M Bambala
[email protected]

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General Outline

 Introduction and Principles of Toxicology

 Mechanisms of Toxicity

 Specific Toxic agents (Gases, Pesticides and heavy metals)

Drug overdose (Aspirin, paracetamol, quinine, benzodiazepines,

herbal medicine toxicity)

 Drug abuse, drug dependence and its management

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Lecture Outline

 History of Toxicology
 Toxicology and its areas of application
 Key Terminologies
 Classification of Toxic agents
 Factors influencing Toxicity
 Duration and Frequency of Exposure
 Toxicokinetic and Toxicodynamic
 Dose- Response relationships
 Model for Studying Toxicity
 Principles of Poison management

Andrew Bambala- 8th July, 2020. 3

Toxipedia.org
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Dose (1538)

Paracelsus (1493-1541)

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Toxicology ?
?????

• study of the adverse effects of chemical, physical, or biological

agents on living organisms and the ecosystem, including the
prevention and amelioration of such adverse effects

• Study of interaction between chemicals or physical agents and

living organisms resulting in unwanted/(toxic) effects

• Provides protection to humans, animals and environment from

toxic effects of harmful chemicals

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 Interconnections between different areas

identifying and
understanding the cellular,
biochemical, and
molecular mechanisms
Deciding on the basis of data
provided by descriptive and
mechanistic toxicologists

concerned directly with

toxicity testing, which
provides information
for safety evaluation
and regulatory
The process of analyzing
requirements
information to determine
if a potential toxic agent
(hazard ) can elicit a toxic/ Casarett andDoull’s

adverse
Kristian effect
Dreij - 3 September 2018 when 7
Different areas of Toxicology

Toxicological research
 Mechanisms of action, methods for testing
Clinical toxicology
 Diagnosis and treatment of poisoning in humans
Forensic toxicology
 Medicolegal aspects of the harmful effects of chemicals on humans and animals.

Epidemiology in toxicology
 Relationship between disease and chemicals

Risk assessment / Safety assessment

 Scientific assessment based on data on toxicity andexposure

Regulation and risk management

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Key Terminologies

• Poisons- A chemical or physical substance that can produce an

adverse response (toxic) in biological organism.

• Toxic Effect (Adverse)– undesirable harmful change in

biological system following exposure to a poison/ Toxic
substance

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 Toxicology
Biologic system
Chemical compound
• Cells,
• All elements,
• Cell components,
• chemical substances,
• organs or complete
• endogenous compounds
organisms (animals,
and other natural
humans)
compounds

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Classification of Toxic agents

• Toxicant- produced or by-product of anthropogenic (human-

made) activities e.g. Pharmaceuticals

• Toxins - produced by biological systems (Naturally) such as

plants, animals, fungi, or bacteria e.g. poisonous
mushrooms/flowers

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Classification of Toxic agents
Classified depending on the interests and needs of the classifier.

Source; Plant-morphine, Animal-venoms, Mineral-copper,

Physical state; Liquid- Sulphuric acid. Solid- atropine.

Physical characteristics; Explosive / Non-explosive

Physical effects; Irritant / Non-Irritant Corrosive / Non-corrosive

Target organ/system; action on the primary target site

Hepatotoxins, Neurotoxins.

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Classification of Toxic agents

Chemical nature: Inorganic and. Organic - Oxides of carbon,

Toxic effects; Carcinogens - Vinyl chloride, Mutagens UV rays

Principal uses: Insecticides, e.g. organophosphorus

Mechanism of action; Anticholinesterase agents/cholinesteras

Environmental and human health consideration; Air pollutants,

water pollutants, radiation hazards, occupational hazards

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Spectrum of Undesirable Effects

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Spectrum of Undesirable Effects

1. Allergic reactions - Mediated by immune system, resulting from

previous sensitization to a particular drug/ chemical or with a similar
structural.
Type I: Anaphylactic Reactions,

Type II: Cytolytic Reactions.

Type III: Arthus Reactions.
Type IV: Delayed Hypersensitivity Reactions.

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Spectrum of Undesirable/Toxic Effects

2. Idiosyncratic reactions- an abnormal reactivity to a chemical that

is peculiar to a given individual;
Sensitive to low doses or extreme insensitivity to high doses
of drugs e.g. Immunological reaction

3. Dose-dependent reactions
Pharmacological e.g. Barbiturates

Pathological e.g. Acetaminophen,

Genotoxic e.g. Ionizing Radiation

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Toxicity
Toxicity – The ability or degree of a substance to cause damage to a
living organism (toxic effect)
Local Toxicity (Non-specific)
 Effects at the contact place, e.g. irritation, corrosion, skin, eyes,
mucous membranes (respiratory tract, gastro-intestinal tract)
Systemic Toxicity (remote)
 Effect in target organ(s) after absorption, distribution, metabolism )

Carcinogenicity, Developmental Toxicity, Genetic Toxicity

Both local and Systemic e.g. Allergic reactions

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Toxicity

Other Classification

• General versus specific toxicity

• Reversible versus Irreversible effects

• Immediate versus Delayed toxicity

• Single-dose toxicity (Acute toxicity)

• Repeat-dose toxicity (sub acute, Sub chronic, Chronic toxicity)

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Interactions with Chemicals

• Decrease toxicity (antagonism) (eg,4 + (−4) = 0;

Negative interference -Functional, Chemical ,Dispositional and Receptor
antagonism

• Add to toxicity (2 + 3 = 5) (Additivity)

combined effect of 2 chemicals is equal to the sum of the effects of each
agent given alone.

• Increase toxicity (2 + 2 = 20) (Synergism)

combined effects of 2 chemicals are much greater than the sum of the
effects of each agent given alone

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Interactions with Chemicals

• Increase toxicity (0 + 2 = 10) (Potentiation)

occurs when 1 substance does not have a toxic effect on a certain organ
or system but when added to another chemical makes that chemical much
more toxic.

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Interactions with Chemicals

• Tolerance - Decreased in sensitivity or response of chemical

after exposure

• Resistance - Complete insensitivity towards a chemical after

exposure

• Interaction can occur at Absorption, Distribution (Protein

Binding), Metabolism and Receptor binding (Toxicokinetics and
Toxic dynamics

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Toxicokinetic and Toxicodynamic

Toxicokinetic , similar to
pharmacokinetics , study of the
absorption, distribution, metabolism,
and excretion (ADME) of a xenobiotic
(Drug) under circumstances that
produce toxicity

Toxicodynamic describes the mechanism or mode of action of toxic

agents at particular concentrations/dose and time.

Dose- Toxicity relationships (Dose-Response relationships)

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Factors Influencing Toxicity (Organism)

Kinetics (ADME)

 Absorption, Distribution, Biotransformation/Metabolism,

Elimination

Individual sensitivity

 Genetics

 Risk groups ; age, gender, nutritional status, Health status

Species

 Rats vs Human e.g Thalidomide

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Factors influencing Toxicity (Substance)

Physical-chemical properties Characteristics of exposure

• Source form, e.g. Hg+ vs • Dose

Methyl-Hg, • Concentration
• Contaminants, vehicle • Time (duration)
• Lipid Solubility • Frequency
• Chemical Composition – • Route of
Mixed Chemicals exposure/administration
• Molecular Size

• Physical form; Gases, Liquid

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Routes and Sites of Exposure

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Routes and Sites of Exposure

Important determinant of the ultimate DOSE

different routes may result in different rates of absorption.

Dermal (skin)

Inhalation (lung)

Oral (GI)

 Parental

The ROUTE of exposure may be important if there are tissue-specific

toxic responses. Toxic effects may be local (in a specific tissue) or
systemic (throughout the organism)

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Duration and Frequency of Exposure

• Acute Toxicity
 A single dose or a series of doses received within a 24-hour
period. Death can be a major concern in cases of acute
exposures.

• Sub acute Toxicity

 Repeated exposure to a chemical for 1 month in dose range
finding studies in animals

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Duration and Frequency of Exposure

• Sub chronic toxicity

 Results from repeated exposure for several weeks to months
(3 months-12 month e.g. warfarin

• Chronic toxicity
 Represents cumulative damage to specific organ systems and
takes many months or years to become a recognizable clinical
disease

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Toxicity

• Both mechanisms and target organ can differ for acute and
chronic toxicity.

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Dose–Response relationship

Correlative relationship between characteristics of exposure (dose) and the

spectrum of toxic effect

Correlates exposures with changes in body functions or health

Based on observed data from experimental animal, human clinical,

or cell studies.

establishes:

Causality — that the chemical has induced the observed effects.

Threshold effect — the lowest dose where an induced effect occurs.

The slope for the dose response — the rate at which injury builds up.

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Dose–Response relationship

• NOAEL (No Observed Adverse Effects Level)— Highest dose at

which there was not an observed toxic or adverse effect

• LOAEL (Lowest Observed Adverse Effect Level)— Lowest dose at

which there was an observed toxic or adverse effect

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Dose-Response Relationships

• Median Effective Dose (ED 50) the dose at which 50% of

individuals exhibit the specified quantal (present or absent)
effect

• Median Toxic dose (TD 50) is the dose required to produce a

defined toxic effect in 50% of subjects

• Median Lethal dose (LD 50) is the dose required to kill 50% of
subjects

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Dose-Response

ED50, LD50: 23 mg/kg

Evaluation of the DR curve is used for determining therapeutic

indexes (TI) and margins of safety and exposure (MOS)

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 Margin of Safety
• Margin of Safety (MOS) is the ratio of the toxic dose to 1% of the
population (TD1) to the dose that is 99% effective to the population
(ED99) MOS=TD1/ED99 .

• Ratio of NOAEL obtained from animal toxicology studies to the estimated

human exposure level or dose

• Equivalent to MOE. It is often used to assess the safety of cosmetic

ingredients. MOS = NOAEL/Estimated Exposure Dose

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Determining the Safety of a Drug

• Therapeutic index (TI) is the ratio of the TD50 to ED50 ,

• A parameter which reflects the selectivity of a drug to elicit a

desired effect rather than toxicity (TI = LD50/ED50)

• e.g. A higher value on the Therapeutic Index indicates a more

favorable safety profile 3 vs 10 (Which one is safer) ?

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Determining the Safety of a Drug

 Therapeutic window/margin/range is the range between the

minimum toxic dose and the minimum therapeutic dose,
 The range of doses over which the drug is effective for most
of the population and the toxicity is acceptable.
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Potency vs. Efficacy

• Potency is the concentration (EC50) or dose (ED50) of a drug

required to produce 50% of that drug's maximal effect.
• Amount of a given drug/chemical required to produce a given effect

• Efficacy (Emax) is the maximum effect which can be expected

from this drug (i.e. when this magnitude of effect is reached,
increasing the dose will not produce a greater magnitude of
effect).
• The maximum effect the drug will produce in regardless of the dose

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Potency vs. Efficacy

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RISK ASSESSMENT

Risk = Toxicity × Exposure

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RISK ASSESSMENT

Hazard is the potential for the toxicity to be realized in a specific

setting or situation

Risk is the probability of a specific adverse effect to occur.

It is often expressed as the percentage of cases in a given
population and during a specific time period.

Human health risk assessment is the process of analyzing

information to determine whether an hazard/Exposure might
cause harm to exposed persons (EPA 2004)

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Basis for health risk assessment
Standard tests according to guidelines, ensure quality and reliability

 Chemical characterization (purity, mixture etc.)

 Kinetics
 Acute toxicity (single dose)
 Local toxicity
 Sensitization, immunotoxicity
 Repeated-dose toxicity
 Genotoxicity
 Carcinogenicity
 Reproductive toxicity
 Mechanism of action

 Human studies (epidemiology)

 Exposure
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Toxicity and Risk
 What effects?
Critical effect?
Mechanism of action?
 At low doses?
 Thresholds
 Humans?
 Sensitive individuals/groups?
Age, genetics, sex, nutrition, illness, drugs

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Toxicity and Risk

 The most important effect in the low-dose area

 Often the most sensitive among adverse effects
 Critical study identified to select starting point

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 Critical effects
Target organ toxicity
 Nervous system (CNS) Characteristics of target
 Liver organs:
 Kidney
 High blood flow
 Lung
 High metabolic capacity
 Blood
 Directly exposed
 Immune system
 Specific sensitivity
 Cardiovascular system
 Reproductive system
 Skin
 Eye

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Mechanism of action

 Is it known?  Dose-response relationship

 Parent compound or  Biomarkers
metabolite?
 CYP, P-450 super family
Ligand
 Species specific
metabolism AhR
XAP2

 Species specific effects? p23

Hsp90 Arnt

 Not relevant for humans e.g. CYP1A1

NMO1
XRE

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 Models to study toxicity

In vitro
Animals (In vivo) Humans
In silico
- Molecular models - Toxicology - Clinical trials
- Cell/Tissue culture - Toxicokinetics - Epidemiology
- Isolated organs - Case reports
- QSAR - Adverse Drug
Reactions (ADR)
• The models complement each other
• Have qualities by their own
• Do not function optimal without each other
• In animals all relations/interactions may be studied
Provides an overall knowledge

Kristian Dreij - 3 September 2018 47

The Three Rs ( Alternative Testing )

The current practice for toxicity testing emphasizes on Three

(3Rs)
Principles for Humane and ethical reasons.
Replacing- animals in science by in vitro, in silico, and
other approaches.

Reducing -the number of animals used in the testing

experiments without losing the meaningful data.

Refining-care and procedures to minimize pain and

distress to animals.

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Principles of Treatment -Poisoning
1.Maintain-vital physiological functions through supportive care;
ventilation and blood pressure support

2. Reduce or prevent-absorption and enhance elimination to

minimize the tissue concentration of

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Principle of Treatment of Poisoning

3. Enhance Elimination

• by alkalinization /Acidification of urine for weak acids and

bases respectively,

• Hemodialysis and hemoperfusion increase the elimination of

specific agents from the blood.

4. Counteract
use of antidotes e.g. acetaminophen with N-acetylcysteine

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