GENERAL PRINCIPLES OF
TOXICOLOGY
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Objectives
 To define toxicology
 To list the different branches of toxicology with their respective
responsibility
 To explain the scopes of toxicology
 To describe the core events in the history of toxicology
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Which chemicals do you consider to be toxic?
Which chemicals do you consider safe?
 Paracelsus (1493–1541):
“All substances are poisons; there is none
which is not a poison. The right dose
differentiates a poison and a remedy.”
 Emil Mrak:
“There are no harmless substances, only
harmless ways of using substances.”
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Definitions
Toxicology
 Derived from toxikón, an ancient Greek term for poisons into
which arrows were dipped
 The study of the adverse effects of chemical, physical or biological
agents on living organisms
 Investigates the nature, incidence, mechanism, and risk factors
for the development of adverse effects of toxic substances
 Includes the prevention & amelioration of such adverse effects
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Definitions
Toxicology
 Assimilates knowledge and techniques from biochemistry,
biology, chemistry, genetics, mathematics, medicine, pharmacology,
physiology, and physics.
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Definition of terms
Xenobiotics
 Chemicals that are foreign to the body (xenos-strange, bios-life)
Poisons = Toxicants
 Any substances that cause deleterious effects in a living organism
 Biologic origin, naturally occurring chemicals, synthetic
Toxicity
 Any adverse/deleterious effect within a living organism
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Definition of terms
Toxins
 Poisonous substances of biologic origin( such as a plant, animal
and micro-organism)
 Phytotoxins, zootoxins, bacteriotoxins and mycotoxins
 Strychinine,
Batrachotoxins,
Diamphotoxin
Strychnos toxifera
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Phyllobates terribilis
Diamphidia nigro-ornata
Definition of terms
Poisoning = Intoxication = Toxicosis
 The disease state which results from exposure to a poison
Exposure
 The actual contact of a poison with the biological organism
Hazard
 The intrinsic toxic properties of poisons
Risk
 The probability that an adverse effect will occur under specific
exposure conditions
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Definition of Terms
The Median Lethal Dosage (LD50)
 The dose (dosage) of a chemical substance that produces death in
50% of a population of test animals
 Normally expressed as milligrams of the chemical substance per
kilogram of animal body weight
 Chemicals with low LD50 are highly toxic/hazardous
 Chemicals producing death in microgram doses are often
considered extremely poisonous
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Approximate LD50 of some chemicals
Agent
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LD50, mg/kg
Ethanol
10, 000
Sodium chloride
4, 000
Ferrous sulfate
1,500
Morphine sulfate
900
Phenobarbital sodium
150
Picrotoxin
5
Strychnine sulfate
2
Nicotine
1
Tubocurarine
0.5
Tetrodotoxin
0.1
Dioxin (TCDD)
0.001
Botulinum toxin
0.00001
Routes of Exposure
 Ingestion
 Inhalation
 Dermal/Topical
 Injection (intravenous, intramuscular…)
 The risk for the occurrence of ADR via d/t routes of exposure:
 i.v. > inhalation> i.m. > ingestion > topical
 Toxic response depends on the chemical and physical properties
of the agent, the exposure situation, metabolism by the system,
and the overall susceptibility of the biological system or subject.
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Duration of exposure
Acute exposure
 A single/repeated exposure lasting less than 24 hours
Subacute exposure
 Repeated exposure for several days to 1 month
Subchronic exposure
 Repeated exposure lasting for1-3 months
Chronic exposure
 Repeated/continuous exposure lasting ≥ 3 months
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Toxicity
Acute Toxicity
 Toxicity that occurs following exposure to a single high dose
 Symptoms of poisoning develop within a relatively short time,
ranging from almost immediately to within several days
Chronic Toxicity
 Develops following repeated exposure to toxic substance in low
dose for a long period
 Symptoms appear after a long period (months or years)
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Toxicity
Local Toxicity
 Adverse effect that is manifested at the toxicant’s site of contact
 Sites: skin; eye, nose, mouth, throat or anywhere along the
respiratory or gastrointestinal system
Systemic Toxicity
 Requires absorption and distribution to a distant site
 Occurs throughout the organism or in an organ distant from the
point of entry of the toxicant
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Toxicity
Reversible/irreversible Toxicity
 Reversible toxicity—an adverse effect that can be reversed once
the exposure is stopped
 Reversibility depends on extent of exposure and the ability of the
affected tissue to repair or regenerate itself
 Liver has high regenerative ability (most are reversible)
 CNS has differentiated cells (largely irreversible)
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Toxicity
Immediate toxicity
 Develops rapidly after exposure to a substance
Delayed or latent toxicity
 Appear long after the initiation or cessation of exposure
 Secondary cancer many years after curing the primary cancer
by anticancer agents
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Toxicity
Hypersensitivity reaction

Immunologically mediated adverse reaction

Can be immediate or delayed
Idiosyncratic reaction

Genetically determined abnormal reaction to a chemical

Individuals who are extremely sensitive to low doses or
extremely insensitive to high doses
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Toxicity
Type I hypersensitivity reaction
 AKA immediate hypersensitivity rxn
 IgE-mediated, with symptoms usually occurring within minutes
following the patient’s reencounter with antigen
 Results from cross-linking of membrane-bound IgE on mast cells,
basophils, or eosinophils by antigen
 The cross-linking causes cells to degranulate and release
inflammatory mediators such as histamine, leukotrienes, and PGs
 Induce hay fever, urticaria (hives), asthma or anaphylaxis
 Penicillins could cause type I hypersensitivity rxn
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Toxicity
Type II hypersensitivity reaction
 Antibody mediated cytotoxic rxn
 Results from formation of antigen-antibody (IgM/IgG) complexes
 In Rh hemolytic disease of the newborn (erythroblastosis fetalis)
 Anti-Rh IgG antibodies produced by Rh-negative mother cross
the placenta, bind to RBC of an Rh-positive fetus
 Activate the complement cascade, generating a membrane
attack complex that lyses the fetal Rh-positive erythrocytes
 Penicillins bind on RBC/other cells…induce complement mediated
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red cell or other cell lysis
Toxicity
Type III hypersensitivity reaction
 Occurs due to the deposition of antigen-antibody complexes on
basement membranes in tissues and vessels
 Activates complement (C5a, C3a, C4a)

Increase vascular permeability and recruit neutrophils
(release lytic enzymes)
 Cause skin rashes, glomerulonephritis, and arthritis
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Toxicity
Type IV hypersensitivity reaction
 AKA delayed hypersensitivity reaction
 TH1 cells mediated reaction
 Responses occur 2–3 days after re-exposure to the sensitizing
antigen
 Induces a local inflammatory response that causes tissue damage
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Different branches of toxicology
Descriptive Toxicology
 Work focuses on the toxicity testing of chemicals
 Assumes that toxic effects produced by a chemical in laboratory
animals, when properly qualified, are applicable to humans
 Exposure of experimental animals to high doses of toxic agents is
necessary & valid method to discover possible hazards in humans
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Different branches of toxicology
Descriptive Toxicology
 Identify all possible acute and chronic toxicities, including the
teratogenic, genotoxic & carcinogenic potential of the test agent
 Characterize the dose response relationship
 Analyze the manner of chemical ADME
 Provides info. for safety evaluation and regulatory requirements
 Provide important clue to a chemical MOA
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Different branches of toxicology
Mechanistic Toxicology
 Concerned with understanding the cellular, biochemical & molecular
mechanism by which chemicals exert toxic effects on living organism
 Beneficial outcomes:
• Understanding Physiology, Pathology and Pharmacology
• Risk assessment & development of exposure guide line by regulatory
toxicologists
• Design and production of safer alternative chemicals
• Development of antidote of chemical poisoning/rational therapy
• Development of agents for treatment of disease
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Different branches of toxicology
Mechanistic Toxicology

Thalidomide was originally marketed in Europe & Australia as a
sedative agent


Phocomelia (shortening or absence of limbs)
Mechanistic studies have demonstrated that the phocomelia
effect is because of the inhibition of angiogenesis

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It has been “rediscovered” as a valuable therapeutic agent

Leprosy and multiple myloma
Different branches of toxicology
Regulatory Toxicology
 Decide whether a drug or other chemical poses sufficiently low
risk to be marketed for the stated purpose
 Based on of data provided by descriptive & mechanistic toxicologists
 Establish standards for the permitted level of chemicals in ambient
air, industrial atmospheres & drinking water…
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Different branches of toxicology
Forensic Toxicology
 A hybrid of analytical chemistry and toxicology
 Concerned with the medical and legal aspects of drugs and poisons
 Concerned
with determination of chemicals responsible in
exposure situations of abuse, overdose, poisoning, and death that
become of interest to the police and medical examiners
Clinical Toxicology
 Concerned with prevention, diagnosis & treatment of poisoned pts
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Different branches of toxicology
Environmental Toxicology
 Concerned with the adverse effects of chemicals in the env’t and
food chain to the biota
Occupational Toxicology
 Concerned with the adverse effects of substance exposure in the
workplace
 Works to prevent the impairment of the health of the workers
associated with the job
 Work to determine permissible exposure to potentially toxic
agents
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Scopes of toxicology
 Toxicology gather data/information via tests on experimental
animals and observation
 Toxicology utilize the data to
predict outcomes of exposure in
human and animal populations
 TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces
hepatocellular carcinoma in rats is a fact
 The conclusion that it will also do so in humans is extrapolation, a
prediction or a hypothesis
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Scope of toxicology
 Investigates the nature, incidence, mechanism, and risk factors for
the development of adverse effects of toxic substances
 Could help to understand physiology, pathology & pharmacology
 Discovery and development of new drugs and pesticides
 Participate in the development of standards and regulations
designed to protect human health and the environment from the
adverse effects of chemicals
 Develop antidotes & treatment regimes to ameliorate poisoning
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Brief history of toxicology- Antiquity
 History of toxicology ≈ history of the human race
 The early humans must have learnt to discriminate between
things that were good to eat and those that were not
 Through time human get knowledge on animal venoms and plant
extracts…start using for hunting, warfare, and assassination
(presumably predate recorded history)
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Brief history of toxicology- Antiquity
Ebers papyrus (circa 1500 B.C)
 The oldest well preserved medical document
 Contains 110 pages on which anatomy and physiology, toxicology,
spells, and treatment are recorded
 More than 800 medicinal and poisonous recipes
 Described many recognized poisons
 Hemlock, aconite, opium
 Lead, copper, antimony
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Brief history of toxicology - Antiquity
Socrates (470-399 B.C.)
 He was found guilty of corrupting the minds of the youth of
Athens and sentenced to death by drinking a mixture containing
hemlock
Theophrastus (370–286 b.c.)
 Included numerous poisonous plants in his De Historia Plantarum
Sulla (Roman general and director, 138-78 BC)
 Poisonings in politics became so extensive
 Issue the Lex Cornelia ( circa 82 BC), which appears to be the
first law against poisoning
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Brief history of toxicology-Antiquity
Cleopatra – Queen of Egypt (69-30 B.C.)
 Experimented with strychnine & other poisons on prisoners &
poor
 Committed suicide with Egyptian Asp
Dioscorides (40-90 A.D.)
 Made the first attempt to classify poisons on his book De Materia
Medica ( plant, animal and mineral)
 Wrote usefulness of emetics in poisoning management
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Brief history of toxicology -Antiquity
King Mithridates VI of Pontus
 Who was so fearful of poisons
 He regularly ingested a mixture of 36 ingredients as protection
against assassination
 On the occasion of his imminent capture by enemies, his attempt
to kill himself with poison was failed because of his successful
antidote concoction
 This tale leads to the use of mithridatic as an antidote or
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protective mixture
Brief history of toxicology- Middle ages
Maimonides (Moses Ben Maimon,1135-1204 A.D)
 Wrote poisoning and their antidotes
 Extensive work describing remedies for poisoning involving
insects ,snakes ,and mad dogs
 He describe the subject of bioavailability noting that milk,
butter, and cream could delay intestinal absorption
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Brief history of toxicology- Middle ages
Catherine de Medici (1519-1589)
 Under the guise of delivering provender to the sick and the
poor, she tested toxic concoctions, carefully noting
 The rapidity of the toxic response (onset of action)
 The effectiveness of the compound and the potency
 The degree of response of parts of the body
 Complaints of the victim (clinical symptoms)
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Brief history of toxicology- Renaissance
Paracelsus (1493-1541)
 Credited with being “the father of modern toxicology”
 All substances are poisons; there is none which is not a poison.
The right dose differentiates a poison from a remedy”
 Laid the groundwork for the develop’t of modern toxicology
 He also belief in the value of experimentation
 Investigated the dose- response relationship
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Brief history of toxicology- Renaissance
 Ellenbog ( cira 1480) warned on the toxicity of mercury and
lead from goldsmithing
 Agricol published a short treatise on mining diseases in 1556
 Paracelsus had also published a major work on Miners’ Diseases
in 1567 which addressed the etiology of miners’ disease along
with treatment and prevention strategies
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Brief history of toxicology- Renaissance
 Bernardino Ramazzini advanced occupational toxicology
further by his published discourse on the “Diseases of Workers”
in 1700, which discussed occupations including miners, midwives,
printers, weavers, and potters
 Percival Pott’s (1775) recognized the role of soot in scrotal
cancer among chimney sweeps
 Led to improved preventive medical practices
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Brief history of toxicology- Age of enlightenment
 Experimental toxicology developed rapidly during the 19th century
 Toxicology as it is currently understood began in the late 1850s
Orfila (1787-1853)
 A Spanish physician in the French court
 The 1st to use autopsy material and chemical analysis as systematic
legal proof of poisoning
 Father of forensic toxicology
 Wrote the 1st comprehensive toxicology text (1814)
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Brief history of toxicology- Age of enlightenment
 Magendie: studied the absorption & distribution & mechanism of
action of emetine and strychnine
 Oswald Schmiedeberg: trained approximately 120 students
who later populated
the most important laboratories of
pharmacology and toxicology throughout the world
 Louis Lewin: published the toxicity of
glycerol, acrolein, and chloroform
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narcotics, methanol,
Brief history of toxicology- 20th century
 The prevalent use of “patent” medicines led to several incidents
of poisonings….passage of the Wiley Bill in 1906, the first of
many U.S. pure food and drug laws
 As a response to acute kidney failure after taking sulfanilamide in
ethyleneglycol solutions…Copeland bill was passed in 1938
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Brief history of toxicology- 20th century
Chemical Warfare (1915)
 Chemicals had been developed to be used as weapons
 Agents such as Chlorine, Chloropicrin, Phosgene and Mustard gas
were all used in chemical warfare
Gerhard Schrader (1903-1990)
 Accidentally developed the toxic nerve agents Sarin,Tabun,
Soman, and Cyclosarin
 These highly toxic gases were utilized during World War II by the
Nazi's.
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Brief history of toxicology- 20th century
 The 1960s tragic thalidomide incident, in which several thousand
children were born with serious birth defects
 Initiate attempts to understand the effects of chemicals on
the embryo and fetus
 The publication of Rachel Carson’s Silent Spring (1962)
 Initiate attempts to understand the effects of chemicals on
the environment
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