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What is toxicology?

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What is toxicology? Modern Toxicology Exogeneous agents Endogenous compounds Oxygen radical Reactive intermediates generated from xenobiotics and endobiotics ... – PowerPoint PPT presentation

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Title: What is toxicology?


1

What is toxicology?
2
Definitions of Toxicology
  • The science that studies the poisonous, or toxic,
    properties of substances.
  • (NSC)
  • The study of chemical and physical agents that
    produce adverse responses in the biological
    systems with which they interact.
  • Williams and Burson
  • The study of the adverse effect of chemical
    agents on biological systems.
  • (Cassaret and Doull).

3
Definition of Toxicology
  • The study of the adverse effects of xenobiotics
    on living organisms
  • What is a xenobiotic?
  • Foreign compound
  • Chemicals that are not endogenous to the
    biological system
  • Chemicals that have little or no value in
    sustaining normal biochemistry/cell function

4
Modern Toxicology
  • Exogeneous agents
  • Endogenous compounds
  • Oxygen radical
  • Reactive intermediates generated from xenobiotics
    and endobiotics

5
Contributions of toxicologists
  • Mechanism of action
  • Exposure to chemicals as a cause of illness
  • Using toxic chemicals to understand physiological
    phenomena
  • Recognition, identification and quantification of
    hazards from occupational exposure and public
    health aspects of chemicals in the environment,
    food and drugs.
  • Involved in discovery and development of new
    drugs, food additives, and pesticides
  • Development of standards and regulations designed
    to protect human health and environment from the
    adverse effects of chemicals

6
History of Toxicology
7
The "father" of toxicology (1493-1541). He
determined that specific chemicals were actually
responsible for the toxicity of a plant or animal
poison. 
Paracelsus is often quoted for his statement 
"All substances are poisons there is none which
is not a poison.  The right dose differentiates a
poison and a remedy." "The dose makes the
poison.
8
Bernardino Ramazzini (1633-1714)
Bernardino Ramazzini (1633-1714)
9
Percival Pott (1715 1788) correlation between
the occupation of chimney sweeps and scrotal
cancer
10
  • Mathieu Orfila (1787-1853)
  • the father of modern toxicology
  • First to use autopsy material and chemical
    analysis to prove if someone was poisoned
    (forensic toxicology)
  • Wrote the first book on toxicology
  • ,A General System of Toxicology, in 1815

11
Modern Toxicology
12
  • During the last two or three decades, toxicology
    has entered a phase of rapid development and has
    changed from a science that was almost entirely
    descriptive, to one in which the mechanisms of
    action are widely studied
  • Much of this exponential growth can be attributed
    to the WWII era.
  • Greater use of industrial chemicals, organic
    compounds used as anesthetics, patent
    medicines, Upton Sinclairs book The Jungle
    describing the meat packing industryall of these
    things brought about the signing of the Wiley
    Bill first of many food/drug laws

13
19th Century Industrial Revolution Phosgene
(COCl2) and mustard gas (bisB-
chloroethylsulfide) used in WW1. By 1880 over
10,000 organic compounds had been synthesized
(chloroform, carbon tetrachloride, many petroleum
products) Late 1800s- early 1900s Development
of early advances in analytic methods Early
mechanistic studies Introduction of new toxicants
and antidotes
14
  • After World War II

15
  • You too can be a toxicologist in two easy
    lessons, each of ten years Arnold Lehman
  • 1950s - U.S. FDA was strengthen under Lehmans
    leadership
  • Formulized an experimental program for the
    appraisal of food, drug, and cosmetic safety
  • Delaney clause no carcinogens in the food
    supply
  • What constitutes a carcinogen?
  • One Hit model
  • Analytical detection limits20 to 100 ppm then,
    now ppt is common and ppq are possible

16
  • 1960s
  • Thalidomide incident
  • Rachel Carsons Silent Spring
  • 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or
    dioxin) contaminant in Agent Orange
  • 1970s
  • EPA, OSHA
  • Love Canal
  • Toxic Substances Control Act
  • Suferfund Bill
  • Recently, a new public concern environmental
    hormone or endocrine disruptor

17
Mechanistic Toxicology
  • Identification and understanding cellular,
    biochemical and molecular basis by which
    chemicals exert toxic effects.
  • Saccharin and bladder cancer
  • Thalidomide
  • 6-mercaptopurine leukemia

18
Descriptive Toxicology
  • The science of toxicity testing to provide
    information for safety evaluation and regulatory
    requirements.
  • -Toxicity tests

19
Regulatory Toxicology
  • Determination of risk based on descriptive and
    mechanistic studies, and developing safety
    regulations.
  • FDA (FFDCA)
  • EPA (TSCA, FIFRA)
  • OSHA

20
Forensic Toxicology the cause of death in a
postmortem investigation Clinical Toxicology
Diagnosis and treatment of poisoning evaluation
of methods of detection and intoxication,
mechanism of action in humans and animals ???????
http//www.pcc.vghtpe.gov.tw/index.asp Occupation
al Toxicology Combines occupational medicine and
occupational hygeine. Environmental Toxicology
Integrates toxicology with sub-disciplines such
as ecology, wildlife and aquatic biology,
environmental chemistry.
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Spectrum of toxic Dose A common dose measurement
is mg/kg body weight. The commonly used time
unit is one day and thus, the usual dosage unit
is mg/kg/day. Environmental exposure units are
expressed as the amount of a xenobiotic in a unit
of the media. mg/liter (mg/l) for liquids
mg/gram (mg/g) for solids mg/cubic meter
(mg/m3) for airOther commonly used dose units
for substances in media are parts per million
(ppm), parts per billion (ppb) and parts per
trillion (ppt).
23
The most important parameters for dosage are
the number of doses, frequency, and total time
period of the treatment.For example 650 mg
Tylenol as a single dose 500 mg Penicillin every
8 hours for 10 days 10 mg DDT per day for 90
days
24
Fractionating a total dose usually decreases the
probability that the total dose will cause
toxicity.  The reason for this is that the body
often can repair the effect of each subtoxic dose
if sufficient time passes before receiving the
next dose.  In such a case, the total dose,
harmful if received all at once, is non-toxic
when administered over a period of time.  For
example, 30 mg of strychnine swallowed at one
time could be fatal to an adult whereas 3 mg of
strychnine swallowed each day for ten days would
not be fatal.
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Classification of toxic agents
  • Many ways to classify a chemical
  • Target organ (liver, kidney)
  • Use (food additive, drug, pesticide)
  • Source (animal or plant)
  • Effects (carcinogen, mutagen)
  • Physical state (gas, liquid)
  • Chemistry (Amine, hydrocarbon)

27
  • Poisoning potential (extremely toxic, slight
    toxic, etc)
  • Biochemical mechanism of action (alkylating
    agent, AchE inhibitor)
  • "Toxin"refers to toxic substances that are
    produced by biological systems
  • "Toxicant"substance that is produced by
    anthropogenic origin

28
Spectrum of undesired effects Each drug produces
a number of effects, but only one is associated
with the primary objective of the therapy all
other effects are considered undesirable or side
effects. Side effects may be beneficial
(antihistamine) The effects that are always
undesirable are referred to as adverse,
deleterious or toxic effects of the drug.
29
1. Allergic Reactions
  • Chemical allergy is an immunologically mediated
    adverse reaction to a chemical
  • Results from previous sensitization to the
    chemical or to a structurally similar one.

30
2. Idiosyncratic Reactions
  • Genetically determined abnormal reactivity to a
    chemical. (polymorphisms)
  • The response observed is usually qualitatively
    similar to that observed in other individuals but
    may take the form of extreme sensitivity/insensiti
    vity to the chemical.
  • Succinylcholine and prolonged apnea
    (butyrylcholinesterase)
  • Stevens-Johnson syndrome
  • carbamazepine, phenytoin, allopurinol

31
3. Immediate versus delayed Toxicity
  • Immediate responses are those that occur rapidly
    after a single administration of a substance
  • Delayed toxic effects are those that occur after
    a lapse of some time.
  • Cancer is example of delayed (20-30 years)

32
4. Reversible versus Irreversible Toxic Effects
  • If a chemical produces pathological injury to a
    tissue the ability of that tissue to repair
    itself will determine whether the effect is
    reversible to irreversible.
  • Liver regenerates rapidly
  • CNS does not
  • Carcinogenic and teratogenic effects are
    generally irreversible

33
5. Local versus Systemic Toxicity
  • Local effects occur at the site of first contact
    between the biological system and the toxicant.
  • Systemic effects require absorption and
    distribution of a toxicant from its entry point
    to a distant site at which deleterious effects
    are produced.

34
Interaction of Chemicals
  • Additive When the combined effect of the two
    chemicals is equal to the sum of the effects of
    each agent given alone. (224)
  • Synergistic When the combined effect of the two
    chemicals is far greater than the sum of the
    effects of each agent given alone (2210)

35
E. Interaction of Chemicals
  • Potentiation Occurs when one substance has no
    toxic effect but when added to another chemical
    makes that one much more toxic (0210).
  • Antagonism Occurs when two chemicals
    administered together interfere with each others
    action or one interferes with the action of the
    other (221 402)

36
E. Interaction of Chemicals
  • Antagonism (cont)
  • Functional Occurs when two chemicals counter
    balance each other by producing opposite effects
    on the same physiological function
  • Chemical A chemical reaction between two
    chemicals that produces a less toxic product.

37
E. Interaction of Chemicals
  • Antagonism (cont)
  • Dispositional Occurs when the disposition is
    altered or the concentration or duration of
    action and the target site is diminished.
  • Receptor When two chemicals bind to the same
    receptor and produce less of an effect than the
    two when given separately (222 or 200).

38
Tolerance Tolerance is a state of decreased
responsiveness to a toxic effect of a chemical
resulting prior exposure to that chemical or to a
structurally related chemical. Dispositional
tolerance CCl4-decrease reactive metabolite
Cd-induction of metallothionein Reduced
responsiveness
39
Whether a toxic response occurs is dependent
on The chemical and physical property of the
agent The exposure situation How the agent is
metabolized by the system or subject
40
Exposure Pathways
  • Routes and Sites of Exposure
  • Ingestion (Gastrointestinal Tract)
  • Inhalation (Lungs)
  • Dermal/Topical (Skin)
  • Injection
  • intravenous, intramuscular, intraperitoneal
  • Typical Effectiveness of Route of Exposure
  • iv gt inhale gt ip gt im gt ingest gt topical

41
Exposure Duration
  • Acute lt 24hr usually 1 exposure
  • Subacute 1 month repeated doses
  • Subchronic 1-3mo repeated doses
  • Chronic gt 3mo repeated doses
  • Over time, the amount of chemical in the body can
    build up, it can redistribute, or it can
    overwhelm repair and removal mechanisms

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Dose Response The dose-response relationship is
a fundamental and essential concept in
toxicology.  It correlates exposures and the
spectrum of induced effects.  Generally, the
higher the dose, the more severe the response. 
The dose-response relationship is based on
observed data from experimental animal, human
clinical, or cell studies.
44
Knowledge of the dose-response relationship
establishes causality that the chemical has in
fact induced the observed effects establishes
the lowest dose where an induced effect occurs -
the threshold effect determines the rate at
which injury builds up - the slope for the dose
response.
45
Dose Response Individual, or graded,
dose-response relationship results from an
alteration of a specific biochemical
process Quantal dose-response relationship in a
population-all or none determination of the
LD50
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Normal equivalent deviations(NEDs) NED for 50
response is 0 NED for 84.1 response is 1 Probit
(probability unit)NED5
49
Classical LD50 The Classical LD50 test is used to
determine the lethal dose (LD50) of a substance
that will kill 50 of test animals. Typically,
this method can use 100 or more animals. The test
material is administered in increasing doses,
usually 5 or more, to groups of 10 male and 10
female animals. Mortalities are recorded within a
given period, and the LD50 is determined with the
aid of statistical calculations.
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Median lethal dose LD50 Therapeutic index
provides safety index expresses as ratio of
lethal or toxic dose to therapeutic dose TI
LD50/ED50 (larger ratio indicates greater margin
of safety) Margin of Safety TD1/ED99
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Variation in toxic responses
  • Selective toxicity
  • Biological diversity
  • -Uneconomic form vs. economic form
  • (parasite vs. host)
  • Difference in
  • -Accumulation, absorption, biotransformation, or
    excretion of the toxicant
  • -cytology,
  • -biochemistry
  • Species differences
  • -Lethal dose for TCDD in guinea pig and human
  • -Responses to carcinogens
  • Individual difference
  • Genetic polymorphism

57
  • Descriptive animal toxicity tests
  • Two main principle
  • The effects produced by a compound in laboratory
    animals, when properly qualified, are applicable
    to humans.
  • 2. The exposure of experimental animals to toxic
    agents in high dose is necessary and valid method
    of discovering possible hazards in human.

58
Testing Scheme for toxicological evaluation of
New chemicals
  • Fig.2-11
  • Table 2.3

59
Descriptive animal toxicity tests Acute Single
dose with effects occurring for a short period of
time (usually up to 96 hr) Inhalation-4h Acute
lethality LD50 (Median Lethal Concentration) Skin
eye irritation Sensitization Multiple
administrations over 3-4 weeks Subacute
Multiple doses administered for up to 14 days
establish doses for subchronic study
60
Subchronic Continuous dosing for up to 90
days NOAEL-no observed adverse effect
level Chronic Continuous dosing for up to 6
months to 2 years carcinogenic potential
Acute effects do not predict chronic effects
Doses causing chronic effects may not cause
acute or sub-acute effects Chronic effects of
a chemical exposure may manifest themselves as a
common disease and go unnoticed
61
2. Limit Test Acute toxicity test in which, if no
ill-effects occur at a pre-selected maximum dose,
no further testing at greater exposure levels is
required. Five to ten animals of each sex or 10
animals of the susceptible sex are administered a
dose specified by regulations. Toxic responses
occurring within a given period are recorded.
Based on the results, a regulatory action or
additional testing may be required.
62
  • CURRENT POLICIES
  • Food and Drug Administration
  • Does not require the use of the Classical LD50
    test.
  • Accepts alternatives.
  • Refers to the Limit test.

63
  • Organization for Economic Cooperation and
    Development
  • Discourages the use of Classical LD50 test.
  • Recommends the Limit test (2 g/kg dose).
  • When compound related mortality occurs in the
    limit test, then 5 animals per dose, at least 3
    dose levels are used to produce a range of toxic
    effects and mortality rates clinical
    observations and pathological investigations are
    conducted.
  • A fixed dose procedure, which uses morbidity
    instead of mortality as the end point, is also
    recommended.

64
  • British Toxicology Society
  • The LD50 should only be determined with any
    accuracy where scientifically and ethically
    justified. Such cases are relatively rare.
  • Examination of few animals in detail rather than
    many for statistical purposes.
  • Limit tests could be used, provided animals in
    distress are killed humanely, if this would not
    interfere with the objectives.
  • For classification of substances and
    preparations, a fixed-dose procedure targeted to
    acute signs could replace the current practice of
    LD50 determination.

65
Toxicogenomics
  • Genomics
  • Transcriptomics
  • Proteomics
  • Metabonomics/metabolomics
  • small molecules in metabolic process
  • Bioinformatics

66
Homework 1. Define the following term for
interaction of chemicals additive synergistic
potentiation chemical antagonism disposition
antagonism idiosyncratic reaction 2.Explain
the concept of hormesis. 3. What are the goals
of acute, subacute, subchronic, chronic toxicity
tests?
67
  • 4. Some people are very sensitive to nitrite and
    suffer from a serious lack of oxygen delivery to
    tissue, explain the reason.
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