Toxicology- Scope and Principles

SCOPE &
PRINCIPLES OF
TOXICOLOGY

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All substances are poisons; there is none that is not a
poison. The right dose differentiates a poison from a
remedy
Paracelsus

TOXICOLOGY
 Greek word- Toxicon = poison & Logos= to study
 Science of poisons
 Study of poisons that include their physical & chemical properties,
detection & identification, biological effects, treatment &
prevention of disease conditions produced by them
Study of the adverse effects of xenobiotics on living systems
 Assimilates knowledge & techniques from biochemistry, biology,
chemistry, genetics, mathematics, medicine, pharmacology,
physiology & physics
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POISON
Any substance which when taken inwardly or applied in any kind of
manner to body, depresses the health or entirely destroys life
TOXICANT
Synonym of poison
TOXIN
Poisons produced by living organisms in quantities- phytotoxins, mycotoxins,
zootoxins, bacteriotoxins,
VENOM
A toxicant synthesised in specialised gland & ejected by process of biting &
stinging
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XENOBIOTICS
 Greek Xeno= Alien or Strange
 Substances which are foreign to body & are biologically active
 Cannot be broken down to generate energy or be assimilated in a
biosynthetic pathway
 Natural & man made chemicals
Drugs, industrial chemicals, pesticides, alkaloids, secondary plant
metabolites, toxins of plants, molds & animals, environmental pollutants
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HISTORY
 Ebers Papyrus (1500 bc)- hemlock, aconite, opium, metals such as lead, copper
& antimony
 The Book of Job (1400 bc)- poison arrows
 Hippocrates (400 bc) -poisons and clinical toxicology- bioavailability in
therapy & overdosage
 Theophrastus (370–286 bc)- poisonous plants in De Historia Plantarum
 Dioscorides- classified poison as plant, animal, mineral De Materia Medica
 Mithridatic- antidote or protective mixture
 Sulla issued Lex Cornelia- first law against poisoning- regulatory statute
directed at careless dispensing of drugs
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Contd…..
 Arsenic containing poisons- Aqua toffana (Toffana)
 Socrates executed with the extract of hemlock
 Catherine de Medici- La Voisine- tested toxic concoctions, rapidity of the toxic
response (onset of action), the effectiveness of the compound (potency), the
degree of response of the parts of the body (specificity and site of action), & the
complaints of the victim (Clinical signs and symptoms)
 Writings of Maimonides- treatise on the treatment of poisonings from insects,
snakes, & mad dogs (Treatise on Poisons and Their Antidotes, 1198)
 Described bioavailability- milk, butter & cream delay intestinal absorption
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Contd…..
 Dosis facit venenum (dose that makes a poison)- Paracelsus
 Focused on the primary toxic agent as chemical entity
 Experimentation is essential in the examination of responses to chemicals
 One should make distinction between therapeutic and toxic properties of chemicals
 These properties are sometimes but not always indistinguishable except by dose
 One can ascertain degree of specificity of chemicals, their therapeutic or toxic effects
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Contd…..
 Occupational Toxicology- Miners’ Sickness and Other Diseases of Miners
(Paracelsus,1567) & Discourse on the Diseases of Workers (Bernardino
Ramazzini, 1770)
 Percival Pott’s (1775) - role of soot in scrotal cancer among chimney sweeps
first report of poly aromatic hydrocarbon carcinogenicity
 Modern Era
 Magendie, Orfila & Bernard ladi the ground work for pharmacology,
experimental therapeutics & occupational toxicology
 Friedrich Serturner- isolated specific narcotic substance from Opium & called it
as Morphine
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Contd…..
 M.J.B. Orfila- Father of Toxicology- Study of poisons
 Used autopsy material & chemical analysis systematically as legal
proof for poisoning
 Magendie studied the mechanism of action of emetine & strychnine
– Father of Experimental Pharmacology
 Louis Lewin- Classified drugs & plants according to their
psychological effects
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AREAS OF TOXICOLOGY
MECHANISTIC TOXICOLOGY
DESCRIPTIVE TOXICOLOGY
REGULATORY TOXICOLOGY
FORENSIC TOXICOLOGY
REPRODUCTIVE TOXICOLOGY
CLINICAL TOXICOLOGY
ENVIRONMENTAL TOXICOLOGY
DEVELOPMENTAL TOXICOLOGY
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MECHANISTIC TOXICOLOGY
Identifies the cellular,
biochemical, and molecular
mechanisms by which chemicals
exert toxic effects on living
organisms
DESCRIPTIVE TOXICOLOGY
Concerned directly with
toxicity
testing, which provides
information or safety
evaluation and regulatory
requirements
REGULATORY TOXICOLOGY
Decides whether a drug or
chemical poses a low risk to be
marketed for a stated purpose
based on the data provided by
descriptive and mechanistic
toxicology
FORENSIC TOXICOLOGY
Hybrid of analytic chemistry and
fundamental toxicologic principles
that focuses primarily on the
medicolegal aspects of the harmful
effects of chemicals on
humans and animals
CLINICAL TOXICOLOGY
Concerned with disease caused by
or uniquely associated with toxic
substances
ENVIRONMENTAL TOXICOLOGY
Focuses on the impacts of
chemical
pollutants in the environment on
biological organisms specifically
studying the impacts of chemicals
on nonhuman organisms such as
fish, birds, terrestrial animals &
plants
DEVELOPMENTAL
TOXICOLOGY
Study of adverse effects on
the developing organism that
may result from exposure to
chemical or physical agents
before conception (either
parent), during prenatal
development or postnatally
until the time of puberty
REPRODUCTIVE
TOXICOLOGY
Study of the occurrence of
adverse effects on the male or
female reproductive system
that
may result from exposure to
chemical or physical agents
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DOSE VS EXPOSURE
Amount of chemical an
organism is exposed to per
unit body weight (mg/Kg B.
W.) Concentration of chemical
in either air or water through
exposure occurs
ppt (g/L),ppm (mg/L,
μg/mL), ppb (μg/L,
ng/L)
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EXPOSURE
 Toxic effects in a biological system are not produced by a chemical
agent unless that agent or its metabolic breakdown products reach
appropriate sites in the body at a concentration and or a length of
time sufficient to produce a toxic manifestation
 Whether a toxic response occurs is dependent on the chemical and
physical properties of the agent, the exposure situation, how the
agent is metabolized by the system, and the overall susceptibility of
the biological system or subject
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ROUTE & SITE OF EXPOSURE
Intravenous (blood stream)
Inhalation (lungs)
Intraperitoneal
Subcutaneous
Intramuscular
Intradermal
Oral (ingestion)
Dermal
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ABSORPTION
Process of movement of
unchanged compound from its
site of administration or
exposure to blood stream
Rate & Extent
Duration & Intensity

DURATION & FREQUENCY OF
EXPOSURE
ACUTE Exposure less than 24 h
SUB-ACUTE Repeated exposure for 1 month or less
SUB-
CHRONIC
Repeated exposure for 1 month – 3 months
CHRONIC Repeated exposure for more than 3 months
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Factors Affecting Xenobiotic Distribution
Physico chemical properties of toxicant
Binding to tissue & plasma proteins
Blood flow & organ size
Specialised compartments & barriers
Availability of specialised transport system
Disease status
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DISTRIBUTION
Process by which
xenobiotics leave blood
stream & enter
extravascular fluid &
tissues

CHARACTERISTICS OF TOXIC
RESPONSE
 Every known chemical has the potential to produce injury or death if it is
present in a sufficient amount
 Chemicals producing death in microgram doses are often considered extremely
poisonous
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BIOTRANSFORMATION
 Chemical transformation of xenobiotics in body/living organism
 Inactivation/detoxification
DDT DDE & DDA
 Bioactivation/toxication
Malathion Malaoxon
 Activation
Thoicyanates Cyanide
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Active compound to equally active compound
Digitoxin Digoxin
Active compound to active metabolite with different
pharmacological action
Aflatoxin B1 Aflatoxin M1

EXCRETION
Process by which toxicants are irreversibly transferred from
body to external environment
Renal excretion
Extra renal excretion
 Faecal excretion
 Pulmonary excretion
 Mammary excretion
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DOSE- RESPONSE RELATIONSHIP
 Characteristics of exposure and the spectrum of effects come
together in a correlative relationship
Individual dose–response relationship- Describes the
response of an individual organism to varying doses of a chemical
 “Graded” response - Measured effect is continuous over a range of
doses (continual change in effect with changing doses)
Quantal dose–response relationship- Characterizes the
distribution of responses to different doses in a population of
individual organisms
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INDIVIDUAL/GRADED DOSE-RESPONSE
RELATIONSHIP
 Characterized by dose related increase in the severity of response
 Measured in a single biologic unit (a cell, a tissue or organ, or an entire
organism)
 Measured on a continuous scale and the intensity of effect is proportional to
the dose
 Most of the drugs fall in this category – contraction of SI produced by
carbachol, inhibition of ChE by OP insecticides
 Dose response curve - parabola with its origin at zero on both axes
 Response versus log dose curve- sigmoid (s-shaped) instead of hyperbolic
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Ceiling dose

QUANTAL DOSE RESPONSE
RELATIONSHIP
 Quantal or “all or none” in nature
 At any given dose, an individual in the population is classified as either a “responder” or a
“nonresponder
 It is always seen in a population because the assumption is made that individuals responds to
maximal possible or not at all
 Log dose response- sigmoid
 Normal or gaussian distribution
 Quantal response is more used in toxicology to determine LD50 and ED50
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 Animals responding at high frequency at the left end of the curve-
Hypersuceptible and those at right end- Resistant
 Flat dose response curve - large change in dose required to produce
significant change in response
 Steep response curve - small change in dosage cause large change
in response
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SHAPE OF DOSE- RESPONSE
CURVE
Essential nutrients
 Shape of the “graded” dose–response relationship is actually U-
shaped
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Hormesis
 Nonnutritional toxic substances may impart beneficial or stimulatory effects at
low doses but, at higher doses, produce adverse effects
 U-shaped dose–response curve
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Nonmonotonic Dose Response Curves
 Some chemicals, the endocrine disruptors, exert effects at low doses that are not
evident at high doses
 Produce nonmonotonic doseresponse curves
 Curves may result from upregulation of some receptors at low doses with
downregulation of those receptors at higher doses
 E.g. Bisphenol A
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VARIATION IN TOXIC RESPONSES
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SELECTIVE TOXICITY
Chemical produces injury to
one kind of living matter
without harming another form
of life even though the two
may exist in intimate contact
SPECIES DIFFERENCES
Both quantitative & qualitative
differences in response to
toxic substances may occur
among different species
INDIVIDUAL
DIFFERENCES IN
RESPONSE

SPECTRUM OF UNDESIRED
EFFECTS
 Pharmacological, pathological and genotoxic
 Depending upon the concentration of chemical, toxic effects are usually
reversible
 Pharmacological effects discontinue due to biotransformation, while
pathological and genotoxic effects are usually reversible
 Allergic reactions
 An adverse reaction that result from previous exposure to a particular chemical
or to one that is structurally similar
 Hapten + Endogenous protein antigen antibody complex subsequent
exposure allergy
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 Idiosyncratic reactions
 Genetically determined abnormal reactivity to a test
 This response could be in the form of extreme sensitivity to low
doses or increased insensitivity to high doses of a chemical
 These genetic polymorphism can be due to interindividual
differences in drug pharmacokinetics or pharmacodynamics
 This knowledge is used to individualize dosages in a science
known as pharmacogenomics
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 Local Vs Systemic toxicity
Local toxicity occurs at the site of first contact between the toxicant
and the biological system
Systemic toxicity requires absorption and distribution of the
toxicant
A toxicant may produce both effects
Severity of local toxicity depends on the portal of entry
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 Reversible Vs irreversible toxic effects
 Depends on the tissue capacity to regenerate at molecular, cellular
and tissue levels
 Immediate Vs Delayed toxicity
• Immediate toxicity-Develops rapidly after a single administration
• Delayed toxicity- occur after a lapse of some time
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XENOBIOTIC INTERACTIONS
 Additive
When the combined effect of two chemicals is equal to the sum of the effects of each agent given
alone
 Synergism
When the combined effects of two chemicals are much greater than the sum of the effects of each
agent given alone
 Potentiation
When one 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 (Isopropanol & CCl₄)
 Antagonism
When two chemicals administered together interfere with each others actions or one interferes with
the action of the other
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Functional antagonism
Occurs when two chemicals counterbalance each other by
producing opposite effects on the same physiologic function
• Eg- marked fall in BP during severe barbiturate intoxication can be effectively
antagonized by the intravenous administration of a vasopressor agent such as
norepinephrine or metaraminol
Chemical antagonism or inactivation
Simply a chemical reaction between two compounds that
produces a less toxic product
• Eg- chelators of metal ions decrease metal toxicity, antitoxins antagonize the action of
various animal toxins
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Receptor antagonism
 Occurs when two chemicals that bind to the same receptor produce less of
an effect when given together than the addition of their separate effects or
when one chemical antagonizes the effect of the second (often termed
blockers)
Dispositional antagonism
 Occurs when the absorption, biotransformation, distribution, or excretion of
a chemical is altered so that the concentration and/or duration of the
chemical at the target organ are diminished
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DECSCRIPTIVE ANIMAL TOXICITY
TESTS
 Effects produced by a compound in
lab animals, when properly
qualified, are applicable to humans
 Exposure of experimental animals to
toxic agents in high doses is a
necessary and valid method of
discovering possible hazards in
humans
 Toxicity tests are not designed to
demonstrate that a chemical is safe
but to characterize the toxic effects a
chemical can produce
ACUTE
SUB ACUTE
SUB CHRONIC
CHRONIC
SKIN & EYE IRRITATION
SENSITISATION
OTHER TESTS
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SCOPE
 Mixture of science, art & creative thinking
• Science: The observational and data gathering phase
• Art: Utilization of the data to predict outcomes in humans based
on in vitro and in vivo studies
• Creative Thinking: Determining the next hypothesis and how to
design experiments to actually answer the questions posed
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 Public Health:
• Recognition and identification of hazards
• Occupational exposure
• Development and use of pesticides
 Regulatory:
• Development of exposure standards
• Detection methods
 Environmental:
• Chemical effects on plants, animals & ecosystems
 Clinical:
• Development of antidotes & treatments
• Recognition of exposure
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Toxicology- Scope and Principles

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