CLINICAL TOXICOLOGY

MARY JHO-ANNE T. CORPUZ, RPh., PhD.

UST-Faculty of Pharmacy
INTRODUCTION TO TOXICOLOGY

 science of poisons, their adverse effects, and the

treatment of the disorders that they produce
INTRODUCTION TO TOXICOLOGY

 science of poisons, their adverse effects, and the

treatment of the disorders that they produce

 study of adverse or unwanted effects of any agent on a

biological system
INTRODUCTION TO TOXICOLOGY

 science of poisons, their adverse effects, and the

treatment of the disorders that they produce

 study of adverse or unwanted effects of any agent on a

biological system

 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
I. HISTORY and TERMINOLOGIES

1. Smith Papyrus
- 1600 BC; it cites the use of “charms against snake
poisons”

2. Mithridates IV, King of Pontus

- credited to be the first to have developed
Antidotes
- took mixture of 36 ingredients as protection
against assasination
- survived each and every poisoning attempt
3. Hippocrates – introduced clinical toxicology principles
by describing elemental concepts of bioavailability and
overdose.

4. Dioscorides – Greek pharmacist who made the first

attempt to classify poisons (plants, animals and
minerals). De Materia Medica (5-volume) systemic
description of approx 600 diff plants and 1000 different
medications. First systemic pharmacopoeia.
5. Socrates
- poison victim: executed by poison
hemlock
(active principle: coniine)

6. Philippus Aureolus Bombastus

Theophrastus von Hohenheim Paracelsus

“All substances known to man are poisons,

there is none which is not a poison and only
the dose determines the effect”
7. Mathieu Joseph Bonaventure Orfila - Father of Modern
Toxicology
-used autopsy material and chemical analysis as
proof of poisoning
POISON  aka “corpus delecti” or “body of evidence”
 any substance which can cause injury, disease and
death, when applied, introduced into, or developed
within the body

POISONING  clinical toxicity secondary to accidental exposure

TOXIN  a poison produced by natural sources (ex. snake
venom)
XENOBIOTIC  any foreign substance (not normally found in the
body)
INTOXICATION  the toxicity associated with any chemical substance

OVERDOSE  an intentional exposure with the intent of causing

self-injury or death
RISK  frequency of occurrence of adverse reactions
upon exposure to the poison
HAZARD  the likelihood that injury will occur in a given
situation or setting
TOXICITY  ability of a substance to cause biological
change, leading to adverse effects
SAFETY  the probability that harm will not occur under
specified conditions
TOXIDROME  a collection of signs and symptoms which
characterizes a specific toxicant
II. AREAS OF TOXICOLOGY

1. EXPERIMENTAL TOXICOLOGY
- deals with investigation of the toxic effect of the
substance on the biological system
- use of a living organism (animal models – mice, rat,
rabbit)
LD50  smallest dose that kills 50% of the population
(Median lethal dose)  poisons administered at any route except
inhalation

LC50  smallest concentration that kills 50% of the

(Median lethal population
concentration)  poisons administered through inhalation,
aquatic exposure

TLV  maximum amount of drug considered safe

(Threshold limit value)  the lower the TLV, the more dangerous the
substance

ED50 (Median effective  dose which produces the desired effect in 50% of
dose) subjects

Therapeutic index  measure of safety

 ratio of LD50 to ED50
2. CLINICAL / MEDICAL TOXICOLOGY

 involves the diagnosis and treatment (antidote) of

poisoning cases
 with emphasis on medical sciences, including signs and
symptoms (toxidromes)
CLASS OF DRUG TOXIDROME EXAMPLE
ANTICHOLINERGICS  Dry as a bone (dry mucosa)  Atropine
 Hot as a hare (hyperthermia)
 Blind as a bat (mydriasis)
 Mad as a hatter (delirium)
 Red as a beet (flushed skin  due to
vasodilation to eliminate body heat)

CHOLINERGICS  DUMBBELSS / SLUDGE

 Diarrhea, Urination, Micturition Organophosphate
 Bradycardia, Bronchoconstriction, Carbamates
Emesis
 Lacrimation, Salivation, Sweating
CLASS OF DRUG TOXIDROME EXAMPLE
SYMPATHOMIMETICS  Mydriasis,  Amphetamine
Tachycardia  Cocaine

 Hypertension,
Hyperthermia,
Seizures
OPIATES  Triad: Miosis  Morphine, Heroin
(pinpoint),
Hypotension, Coma
 Hyerventilation,
Bradycardia
3. ENVIRONMENTAL TOXICOLOGY
 deals with deleterious effects and impact of
chemicals (usually from air, soil, water),
present as pollutants of the environment, to
the living organism
3. ENVIRONMENTAL TOXICOLOGY
 deals with deleterious effects and impact of
chemicals (usually from air, soil, water),
present as pollutants of the environment, to
the living organism

4. REGULATORY TOXICOLOGY
 concerned with sampling and toxicity
testingwhich provide information for safety
evaluation and regulatory requirements
3. ENVIRONMENTAL TOXICOLOGY
 deals with deleterious effects and impact of
chemicals (usually from air, soil, water), present
as pollutants of the environment, to the living
organism

4. REGULATORY TOXICOLOGY
 concerned with sampling and toxicity testing which
provide information for safety evaluation and
regulatory requirements
5. FORENSIC TOXICOLOGY
 deals with the medical and legal aspects of
poisoning
6. MECHANISTIC TOXICOLOGY
 deals with the mechanisms by which chemicals
exert their toxic effects on organisms
7. OCCUPATIONAL TOXICOLOGY
- deals with the chemicals found in the workplace
- industrial and agricultural workers (Ex. Handles
pesticides) usually affected

Industrial setting: Major route of poisoning →

through Inhalation
POISONING EFFECTS
1. Local Effects
the impression made by the poison is to the body part it made
contact with
effect is confined to the area of administration

Ex.
Corrosives (acids): H2SO4 on cornea → coagulative
(solidification) necrosis

Caustics (alkalis): NaOH on cornea →

liquefactive (perforation) necrosis
2. Remote Effects
 the effect is produced in an area other than the
site of application
Ex. Atropine: taken PO → blurred vision
3. Combined
the poison possesses both local and remote
effects

Ex. Phosphorus: Local: cutaneous burns

Systemic: hepatic and renal failure
Cantharidin: Local: vesicant (blistering)
Systemic: aphrodisiac (irritant to the
genitourinary system)
SPECIFIC EFFECTS
POISON TYPE EFFECT EXAMPLES
Cause tissue Acids and alkalis
Irritants necrosis on contact;
caustic effect
IV. SPECIFIC EFFECTS
POISON TYPE EFFECT EXAMPLES
Cause tissue Acids and alkalis
Irritants necrosis on contact;
caustic effect
Neurotics Affect CNS Hallucinogens
IV. SPECIFIC EFFECTS
POISON TYPE EFFECT EXAMPLES
Cause tissue Acids and alkalis
Irritants necrosis on contact;
caustic effect
Neurotics Affect CNS Hallucinogens
Carcinogenic Stimulate Nitrosamines,
proliferation of aflatoxins
cancer cells
IV. SPECIFIC EFFECTS
POISON TYPE EFFECT EXAMPLES
Cause tissue Acids and alkalis
Irritants necrosis on contact;
caustic effect
Neurotics Affect CNS Hallucinogens
Carcinogenic Stimulate Nitrosamines,
proliferation of aflatoxins
cancer cells
Asphyxiants Cause dyspnea; CO, methane gas
Cause complete
suspension of
respiration
POISON TYPE EFFECT EXAMPLES
Lacrimators Stimulate flow of Cholinergics,
tears from lacrimal Carbamates,
glands Organophosphates
POISON TYPE EFFECT EXAMPLES
Lacrimators Stimulate flow of Cholinergics,
tears from lacrimal Carbamates,
glands Organophosphates
Sternutators Stimulate excessive Strychnine, Veratrine
sneezing
POISON TYPE EFFECT EXAMPLES
Lacrimators Stimulate flow of Cholinergics,
tears from lacrimal Carbamates,
glands Organophosphates
Sternutators Stimulate excessive Strychnine, Veratrine
sneezing
Asthenics Produce muscular Tubocurarine, NM
weakness; blockers
“Exhaustives”
POISON TYPE EFFECT EXAMPLES
Lacrimators Stimulate flow of Cholinergics,
tears from lacrimal Carbamates,
glands Organophosphates
Sternutators Stimulate excessive Strychnine, Veratrine
sneezing
Asthenics Produce muscular Tubocurarine, NM
weakness; blockers
“Exhaustives”
Narcotics Produce mental Opioids
weakness and
depression, stupor,
coma, respiratory
depression
Classification of Toxic Agents
1. Use (pesticide, solvent, food additive, etc.)
2. Source (animal and plant toxins)
3. Target organ (liver, kidney, hematopoietic system, etc.)
4. Effects(cancer, mutation, liver injury, etc.)
5. Physical state (gas, dust, liquid)
6. Chemical stability (explosive, flammable, oxidizer)
7. General chemical structure (aromatic amine, halogenated
hydrocarbon, etc.)
8. Poisoning potential (extremely toxic, very toxic, slightly toxic,
etc.).
9. Label requirements
10. Biochemical mechanism of action (e.g., alkylating agent,
sulfhydryl inhibitor, methemoglobin producer)
Characteristics of Exposure
1. Type of effect
2. Dose
Routes and Sites of Exposure
Major Routes
1. GIT
2. Lungs
3. Skin
4. Parenteral
Routes and Sites of Exposure
Major Routes
1. GIT
2. Lungs
3. Skin
4. Parenteral
Routes and Sites of Exposure
Major Routes
1. GIT
2. Lungs
3. Skin
4. Parenteral
Routes and Sites of Exposure
Major Routes
1. GIT
2. Lungs
3. Skin
4. Parenteral
• An approximate descending order of effectiveness for the
other routes:
• inhalation
• Intraperitoneal
• subcutaneous
• intramuscular
• Intradermal
• oral
• dermal
Duration and Frequency of Exposure
4 Categories:
1. Acute
2. Sub-acute
3. Sub-chronic
4. Chronic
Duration and Frequency of Exposure
4 Categories:
1. Acute
2. Sub-acute
3. Sub-chronic
4. Chronic
Duration and Frequency of Exposure
4 Categories:
1. Acute
2. Sub-acute
3. Sub-chronic
4. Chronic
Duration and Frequency of Exposure
4 Categories:
1. Acute
2. Sub-acute
3. Sub-chronic
4. Chronic
• Acute exposure - is defined as exposure to a chemical for
less than 24 h
• examples of exposure routes are intraperitoneal, intravenous, and
subcutaneous injection; oral intubation; and dermal application.

While acute exposure usually refers to a single administration,

repeated exposures may be given within a 24-h period for some
slightly toxic or practically non-toxic chemicals.

Acute exposure by inhalation refers to continuous exposure for less

than 24 h, most frequently for 4 h. Repeated exposure is divided
subacute, subchronic, and chronic.
1. Subacute exposure refers to repeated exposure to a
chemical for 1 month or less

2. Subchronic for 1 to 3 months

3. Chronic for more than 3 months.

These three categories of repeated exposure can be by

any route, but most often they occur by the oral route, with
the chemical added directly to the diet.
Evidences of Poisoning
1. Circumstantial
- evidence from various events, but are not very reliable
Evidences of Poisoning
1. Circumstantial
- evidence from various events, but are not very
reliable
2. Post-mortem
- after an autopsy is performed; after death → use of
tissue, organs, or body fluids
Evidences of Poisoning
1. Circumstantial
- evidence from various events, but are not very
reliable
2. Post-mortem
- after an autopsy is performed; after death → use of
tissue, organs, or body fluids
3. Experimental
- administering suspected substance to living
animal, and noting the effect or symptoms
Evidences of Poisoning
1. Circumstantial
- evidence from various events, but are not very
reliable
2. Post-mortem
- after an autopsy is performed; after death → use of
tissue, organs, or body fluids
3. Experimental
- administering suspected substance to living
animal, and noting the effect or symptoms
4. Chemical
- detection of suspected substance via analysis of
sample of body fluids collected
Evidences of Poisoning
1. Circumstantial
- evidence from various events, but are not very reliable
2. Post-mortem
- after an autopsy is performed; after death → use of
tissue, organs, or body fluids
3. Experimental
- administering suspected substance to living animal, and
noting the effect or symptoms
4. Chemical
- detection of suspected substance via analysis of
sample of body fluids collected
5. Symptomatic
- poisoning signs and symptoms are observed
Spectrum of Undesirable Effects
1. Allergic Reactions
2. Idiosyncratic Reactions
3. Immediate vs. Delayed Toxicity
4. Reversible vs. Irreversible Toxic Effects
1. Allergic Reactions
• Chemical Allergy
1. Allergic Reactions
• Chemical Allergy
• Immunologically mediated adverse reaction to a chemical
1. Allergic Reactions
• Chemical Allergy
• Immunologically mediated adverse reaction to a chemical
• Resulting from previous sensitization to a chemical (or
stucturally similar one)
1. Allergic Reactions
• Chemical Allergy
• Immunologically mediated adverse reaction to a chemical
• Resulting from previous sensitization to a chemical (or stucturally
similar one)
• Hypersensitivity – allergic state
1. Allergic Reactions
• Chemical Allergy
• Immunologically mediated adverse reaction to a chemical
• Resulting from previous sensitization to a chemical (or stucturally
similar one)
• Hypersensitivity – allergic state
Situation when pre-exposure of chemical is required to produce
toxic effect:
• Allergic reaction
• Sensitization reaction
2. Idiosyncratic Reactions
Chemical idiosyncrasy
• refers to a genetically determined abnormal reactivity to a
chemical.
• oversensitivity to the smallest dose or no effect even at
high doses
2. Idiosyncratic Reactions
Chemical idiosyncrasy
• refers to a genetically determined abnormal reactivity to a
chemical.
• oversensitivity to the smallest dose or no effect even at
high doses

Example:
• Succinylcholine - skeletal muscle relaxation
IR: Prolonged muscle relaxation
. G6PD deficient – C/I to sulfa drugs, antimalarial (develop hemolytic
anemia)
 3. Immediate vs. Delayed Toxicity
Immediate: toxicity within 24 hours
Ex. Anaphylactic shock - worst form of allergy
-  BP due to vasodilatation; with bronchoconstriction
ex. Corrosive H2SO4
 3. Immediate vs. Delayed Toxicity
Immediate: toxicity within 24 hours
Ex. Anaphylactic shock - worst form of allergy
-  BP due to vasodilatation; with bronchoconstriction
ex. Corrosive H2SO4

Delayed: effect after a long period of time

Ex. Carcinogens, teratogens, mutagens
Smokers → tar in cigarette smoke → component
benzopyrene (carcinogenic)
4. Reversible vs. Irreversible Toxic Effects
• Reversible - affected organ undergoes repair
Ex. Paracetamol affects the liver (organ has ↑
regeneration ability)
4. Reversible vs. Irreversible Toxic Effects
• Reversible - affected organ undergoes repair
Ex. Paracetamol affects the liver (organ has ↑
regeneration ability)

• Irreversible - affected organ does not undergo repair

Ex. Ethanol affects the brain cells (highly
differentiated cells)
5. Local or systemic
• Local
• occurs at the site of first contact
Ex. Acids - coagulative necrosis, Bases - liquefactive necrosis
Gases (Chlorine gas) – lung tissue
5. Local or systemic
• Local
• occurs at the site of first contact
Ex. Acids - coagulative necrosis, Bases - liquefactive necrosis
Gases (Chlorine gas) – lung tissue

• Systemic
• fatal since the poison is absorbed and distributed in the body
• Requires absorption and distribution of a toxicant to entry point
• Ex. Tetraethyl lead – from skin to CNS and other organs
Target Organ
• Often not the site of the highest concentration of the
chemical

• Order of frequency of involvement in systemic toxicity:

1. CNS
2. Circulatory system
3. Blood and hematopoietic system
4. Visceral organs (liver, kidney, lungs and skin)

*Muscle and bones – seldom target tissue for systemic

effects.
FACTORS AFFECTING THE EFFECT OF POISONS:

1. Poison-related

a. Route of Administration
 Principle: injected poison (IV) is more toxic than orally
administered poison (PO)
 IV: absorbed completely (100%), PO: 1st pass effect
Ex. Saponins: Administered PO → used as tonics
Administered IV → toxic hemolytic agents
V.FACTORS AFFECTING THE EFFECT OF POISONS:

b. Concentration
 Principle: as dose or concentration is increased,
toxicity is also increased

c. Solubility
 Principle: the higher the lipid solubility, the higher
the toxicity
Ex. Nerve gases (absorbed; via skin and inhalation
FACTORS AFFECTING THE EFFECT OF POISONS:
2. Patient-related
a. Age of patient
 Pediatric: liver (and other organ systems)
not fully developed, so, toxicity is
increased
 Geriatric: ↓ metabolizing rates; renal
function compromised compared to aged
20-40
b. Habit
 Smokers and chronic Alcoholics: Enzyme
induction, so, decreased effect of drug
 FACTORS AFFECTING THE EFFECT OF POISONS:
c. Tolerance
• Apparent state of decreased responsiveness to a
pharmacologically active agent resulting from repeated
exposure to the agent
• Must increase the dose to have the same effect
Ex. Nitrates: “Monday disease”
Nicotine: a true poison, but due to constant exposure, the
human body has well-tolerated the poison, increasing their
threshold levels
FACTORS AFFECTING THE EFFECT OF POISONS:

d. Idiosyncrasy / Unknown cause

• Genetic defects may lead to toxicity

Ex. G6PD deficient: develop hemolytic anemia with

sulfonamides, quinine, etc.
Assignment:
1. Enumerate the different mechanism of chemical
interaction, explain briefly

2. Give the 2 types of Dose-Response relationship and

explain briefly