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What is toxicology?
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).
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
Modern Toxicology
• Exogeneous agents
• Endogenous compounds
– Oxygen radical
– Reactive intermediates generated from
xenobiotics and endobiotics
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
History of Toxicology
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.“
Bernardino Ramazzini (1633-1714)
Bernardino Ramazzini (1633-1714):
Percival Pott (1715 – 1788)
correlation between the occupation of chimney
sweeps and scrotal cancer
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
Modern Toxicology
•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 Sinclair’s book The Jungle
describing the meat packing industry…all of
these things brought about the signing of
the Wiley Bill – first of many food/drug laws
19th Century: Industrial Revolution
Phosgene (COCl2) and mustard gas (bis[Bchloroethyl]sulfide) used in WW1.
By 1880 over 10,000 organic compounds had
been synthesized (chloroform, carbon
tetrachloride, many petroleum products)
Late 1800’s- early 1900’s
Development of early advances in analytic
methods
Early mechanistic studies
Introduction of new toxicants and antidotes
•After World War II
“You too can be a toxicologist in two easy
lessons, each of ten years” – Arnold Lehman
•1950s - U.S. FDA was strengthen under
Lehman’s 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 limits…20 to 100
ppm then, now ppt is common and ppq are
possible
•1960s…
–Thalidomide incident
–Rachel Carson’s 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’
Mechanistic Toxicology
• Identification and understanding
cellular, biochemical and molecular
basis by which chemicals exert toxic
effects.
– Saccharin and bladder cancer
– Thalidomide
– 6-mercaptopurine leukemia
Descriptive Toxicology:
• The science of toxicity testing to provide
information for safety evaluation and
regulatory requirements.
-Toxicity tests
Regulatory Toxicology
• Determination of risk based on
descriptive and mechanistic studies, and
developing safety regulations.
– FDA (FFDCA)
– EPA (TSCA, FIFRA)
– OSHA
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 毒藥物防治諮詢
http://www.pcc.vghtpe.gov.tw/index.asp
Occupational Toxicology: Combines occupational
medicine and occupational hygeine.
Environmental Toxicology: Integrates toxicology
with sub-disciplines such as ecology,
wildlife and aquatic biology, environmental
chemistry.
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 air
Other commonly used dose units for substances
in media are parts per million (ppm), parts per
billion (ppb) and parts per trillion (ppt).
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
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.
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)
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
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.
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.
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/insensitivity to the chemical.
• Succinylcholine and prolonged apnea
(butyrylcholinesterase)
•
Stevens-Johnson syndrome
carbamazepine, phenytoin, allopurinol
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)
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
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.
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.
(2+2=4)
 Synergistic: When the combined effect
of the two chemicals is far greater than
the sum of the effects of each agent
given alone (2+2=10)
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 (0+2=10).
 Antagonism: Occurs when two
chemicals administered together
interfere with each others action or one
interferes with the action of the other
(2+2=1; 4+0=2)
E. Interaction of Chemicals
 Antagonism (con’t)
 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.
E. Interaction of Chemicals
• Antagonism (con’t)
– 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
(2+2=2 or 2+0=0).
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
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
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 > inhale > ip > im > ingest > topical
Exposure: Duration
Acute
exposure
Subacute
Subchronic
Chronic
< 24hr
usually 1
1 month repeated doses
1-3mo
repeated doses
> 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
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.
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.
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
Normal equivalent deviations(NEDs)
NED for 50% response is 0
NED for 84.1% response is 1
Probit (probability unit)=NED+5
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.
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
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
Descriptive animal toxicity tests
Two main principle
1. 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.
Testing Scheme for toxicological
evaluation of New chemicals
• Fig.2-11
• Table 2.3
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 34 weeks
Subacute Multiple doses administered for up
to 14 days establish doses for subchronic
study
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
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.
CURRENT POLICIES
Food and Drug Administration:
•Does not require the use of the Classical
LD50 test.
•Accepts alternatives.
•Refers to the Limit test.
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.
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.
Toxicogenomics
•
•
•
•
Genomics
Transcriptomics
Proteomics
Metabonomics/metabolomics
small molecules in metabolic process
• Bioinformatics
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?
4. Some people are very sensitive to nitrite and
suffer from a serious lack of oxygen delivery to
tissue, explain the reason.