INTRODUCTION TO TOXICOLOGY

TOXICOLOGY - poison, adverse effect, treatment of

disorder that they produce
- adverse effect or unwanted effect of any agent
on a biological system
TOXICOLOGIST - trained to examine the nature of those
effects and ssess the probability of the occurrence
I. HISTORY

Smith Papyrus
- 1600BC; use of charms against snake poison
- Ebers Papyrus - oldest writing to known
poison (hemlock, aconite, opium, etc)
- Book of Jobs - poison arrows

Mithridates IV, King of Pontus

- 1st developed an antidote
- took 36 ingredients as protection against
assassination
- survived every poisoning attempt

Hippocrates - describe elemental concepts of

bioavailability and overdose

Dioscorides - greek pharmacist

- first attempt to classify poisons
- De Materia Medica - 5 volumes, 600 plants,
1000 medications; first systemic pharmacopeia

Sulla - issued Lex Cornelia (law against poison)

Socrates - poison victim; executed by hemlock

- coniine (active principle)

Maimonides - treat posion from snake, insects,

dogs; bioav of milk, butter (delay absorp)
- Treatise on Poisons & Their antidotes

Catherine de Medici - tested toxic concoction,

onset, potency, specifiity

Philippus Aureolous Bombastus Theophrastus von

Hohenheim Paracelsus
- De Historia Planatarum - poisonus plants
- All substances know to man are poison
there is none which is not a poison and only the
dose determines its effect

Paracelsus - revolutionary views on toxicology

- On Miners Sickness

Mathieu Joseph Bonaventure Orfila

- Father of modern toxicology
- autopsy material and chemical analysis as
proof of poisoning (Forensic toxicology)

Magendie - MOA of emetine and strychnine

Claude Bernard - Experimental medicine

Oswald Schmiedeberg - trained 120 students

Ellenbog - toxicity of Hg and Pb

Bernardino Ramazzini - occupational toxicology

(Doscourse on disease..)
II. PRINCIPLES

Poison - Corpus delecti or body of evidence

- cause injury, disease, death

Poisoning - accidental exposure

Toxin - produced by natural substance

Xenobiotics - foreign substance not found in the

body

Intoxication - toxicity associated with chemical

substance

Overdosage - intentional exposure with intent of

causing self injury

Risk - frequency of occurrence of adverse effect

upon exposure
Hazard - injury with occur in a given situation
Toxicity - cause biological change, leading to
adverse effect
Safety - harm will not occur
Toxidrome - collection of signs ans symptoms
which characterizes a specific toxicants

III. AREAS OF TOXICOLOGY

1. Experimental Toxicology
- investigation of toxic effect of substance on
biological system
- use of living organism (mice, rat, rabbit)
LD50 - smallest dose that kills 50% of the
population, any route except inhalation
LC50 - smallest concentration that kills 50% of
the population
- administered through inhalation, aquatic
exposure
TLV - Threshold Limit Value
- maximum amount of drug considered safe
- low TLV = more dangerous
ED50 - dose which produces the desired effect
in 50% of subject; Median effective dose
Therapeutic Index - measure safety; ratio of
LD50 to ED50
2. Clinical/ Medical Toxicology
- diagnosis and treatment of poisoning cases
- with emphasis on medical scinces, including
signs and symptoms (toxidrome)
CLASS
Antichloinergic
Cholinergics

Sympathomime
tics
Opiates

3.

4.

TOXIDROME
Dry, hyperthermia,
mydriasis delirium,
flushed skin
DUMBBELSS/SLUDGE
- Diarrhea, urination
micturition
bradycardia
bronchoconstriction
emesis
mydriasis tachycardia
hypertension
hyperthermia seizure
Triad: miosis
(pinpoint)
hypotension coma
hyperventilation
bradycardia

EXAMPLE
Atropine
Organophosphat
es, carbamates

Amphetamine
cocaine
Morphine Heroin

Environmental Toxicology - deleterious effect and

impact of chemicals (air,soil,water) present as
pollutants of environment to bring organism
- Exotoxicology - impact of toxic in ecosystem
Developmental toxicology - adverse effct due to
exposure to chemicals substance (prenatal)
- Teratology - study of defects conception to

birth
5. Regulatory toxicology - establishment of
standards for chemicals
6. Descriptive toxicology - concerned with sampling
and toxicity testing which provide information for
safety evaluation and regulatory requirements
7. Forensic Toxicology - medical and legal aspects
or poisoning or harful effects of chemicals to
human
8. Mechansticl toxicology - mechanism by which
chemicals exert their toxic effect on organism

- Toxicogenomics - application of genomic,

trascriptomic,
9. Occupational Toxicology - deals with chemical
found in workplace
- industrial andagricultural workers usually
affected
- industrial setting: major route of poisoning
(inhalation)
IV. POISONING EFFECT
1. Local Effect - the impression made by the poison
to the body part it made contact
- effect is continued to the area of
administration
Example:
Corrosive (Acids) - H2SO4 on cornea
Coagulative (Solidification
Necrosis
Caustic (Alkali) - H2SO4 on cornea
Liquefactive (Perforation)
Necrosis

2.

Remote effects - the effect is produced in an area

other than the site of application

3.

Combine - the poison posses both local and

remote effects

Example: Atropine PO

Blurred vision

Example: Phosphorous: Local (Cutaneous burns)

Systemic(Hepatic&Renal failure)
Cantharidine: Local (Vesicant - blistering)
Systemic (Aphrodisiac - irritant
to
genitourinary system)

4.

Specific effect

POISON
TYPE
Irritants
Neurotic
Carcinogenic
Asphyxiants
Lacrimators

Sternutators
Asthenics
Narcotics

EFFECT
Cause tissue necrosis
on contact: caustic
effect
Affect CNS
Stimulate proliferation
of cancer cells
Cause dyspnea; cause
complete suspension of
respiration
Stimulate the flow of
tears from the lacrimal
glands
Stimulate excessive
sneezing
Produce musculat
weakness Exhaustive
Produce mental
weakness & depression,
stupor, coma,
respiratory depression

EXAMPLE
Acid & alkali
Hallucinogens
Nitorsamines
Aflatoxin
CO, Methane
Cholinergic,
Carbamates,
Organophospahte
s
Strychnine,
Veratrine
Tubocurarine, NM
blockers
Opiods

Topical, percutaneous, dermal - skin

Parenteral
3. Duration of exposure

Acute - <24hrs, <4 (Inhalation)

Subacute - 1 month or less

Subchronic - 1 to 3 months

Chronic - more than 3 months

4. Frequency of Exposure (Workplace)

Acute - single episode/ incident

Subchronic - repeatedly over weeks or

months

Chronic - months or years

VI. EVIDENCES OF POISONING
1. Circumstantial - evidence from various events
but not very reliable
2. Post-mortem - after an autopsy is performed;
after death - use of tissue organs or body fluid
3. Experimental - administering suspected
substance to living animal and noting the effect
or symptoms
4. Chemical - detection of suspected substance
via analysis of sample body fluid collected
5. Symptomatic - poisoning signs and symptoms
observed
VII. SPECTRUM OF UNDESIRABLE EFFECTS
1. Allergic reaction - chemical allergy

immunologically medicated adverse

reaction to a chemical

resulting from previous sensitization to a

chemical (or structurally similar one)

Hypersensitivity - allergic state

Situation when pre-exposure of chemical is

required to produce toxic effect:
Allergic reaction
Sensitization reaction
2. Idiosyncratic reaction - chemical idiosyncrasy

refers to genetically determined abnormal

reactivity to chemical

oversensitivity to smallest dose or no effect

even at high doses

3.

Example:
Succinylcholine - skeletal muscle relaxation (ester short acting)
- IR: Prolonged muscle relaxation (long
acting)
G6DP deficient - C/I to sulfa drugs (Sulfonamides),
antimalarial
drugs (developed
hemolytic anemia)

Example: Anaphylactic Shock - worst form of

allergy
- lower BP vasodilation,
bronchoconstrict
Corrosive H2SO4

V. CLASSIFICATION OF TOXIC AGENTS

VI. CHARACTERISTICS OF EXPOSURE
1. Concentration - High Conc = High Toxicity

Single dose - more toxic

Multiple dose - less toxic

2. Route & Site of Exposure - descending order of
effectiveness ( inhalation, intraperitoneal, SQ,
IM, ID, oral, dermal)

Ingestion - GIT

Inhalation - lungs

Immediate vs Delayed Response

Immediate - toxicity with n 24 hours

Delayed - effect after a long period of time

(10-30yrs)
Example: Carcinogens, Teratogens, Mutagens
Smokers - tar in cigarette (smoke),
components of
benzopyrene
(carcinogenic)

4.

Reversible vs Irreversible Toxic effects

Reversible - affected organ undergoes
repair
Example: Paracetamol affects liver (regenerating
ability)

Irreversible - affected organ does not

undergo repair
Example: Ethanol affects brain cells
(differentiated cells)

5.

Local vs Systemic
Local - occurs at the site of first contact
Ex: Acids - coagulative necrosis
Base - liquefactive necrosis
Gases (Chlorine gas) - lung tissue

Systemic - fatal since the poison is absorbed

and distributed in the body
-Requires absorption and distribution of
toxicant to entry point
Ex: Tetraethyl Lead - from skin to CNS and other
organs

Target organ - often not the site of highest

concentration of chemical

Order of frequency of involvement in

systemic toxicity

CNS

Circulatory system

Blood & hematopoietic system

Visceral Organs (Liver, kidney, lungs,

skin)

Muscle & Bone - seldom target tissue

for systemic effect

VIII. FACTORS AFFECTING THE EFFECT OF POISON

1. Poison-related
a. Route of administration
- Principle: Injected poison (IV-absorbed
completely) is more toxic than orally
administered poison (PO-1st pass effect)

- Ex: Saponins b.

PO (used as tonics)
IV ( toxic, hemolytic agents)

Concentration
- Principle: High dose/ conc = high toxicity
c. Solubility - vehicle
- Principle: High lipid solubility = high
toxicity
- Ex: Nerve gases (Absorbed via skin & inhalation)
2. Patient-related
a. Age of patient
- Pediatric: liver (other organ system) are
not fully developed = high toxicity
- Geriatric: decrease metabolizing rates;
renal function compromised compare to
aged 20-40
b. Habit
- Smokers & Chronic alcoholics - enzyme
induction, so, decrease effect of drug
c. Tolerances - apparent state of decreased
responsiveness to a pharmacologically
active agent from repeated exposure to the
agents.
- must increase the dose to have the same
effect
- Ex: Nitrates: Monday disease

d.

Nicotine: a true poison, but due to constant

exposure, the human body has welltolerated the poison, increasing their
threshold levels

Idiosyncrasy/ Unknown cause

- genetic defects may lead to toxicity
- Ex: G6DP deficient: develop hemolytic anemia
with sulfonamides, quinine, etc.