Transcript WHAT CAN BE LEARNED FROM A DOSE

GENERAL PRINCIPLES OF
TOXICOLOGY
Laboratory of toxicology
Department of Pharmacology and Toxicology
College of Pharmacy, University of Baghdad
2015
TOXICOLOGY - PRACTICAL SYLLABUS
2015
 General Principles of Toxicology
 Determination of LD50
 Nicotine poisoning
 Guidelines for Seminar Presentations
 Seminar
 CCl4
 Ethanol and methanol
 Cyanide and carbon monoxide
 Organophosphorus and Organochlorine
SCIENCE OF TOXICOLOGY
 Toxicology is the study of the adverse effects of
chemicals on living organisms
 A toxicologist is trained to examine the nature of
those effects (including their cellular, biochemical, and
molecular mechanisms of action) and assess the
probability of their occurrence
 Toxicology testing (safety testing, toxicity testing)
 Conducted to determine the degree to which a substance
can damage a living or non-living organisms
 Routinely performed by pharmaceutical manufacturers in
the investigation of a new drug
 It is often conducted by researchers to comply with
governing regulations
TOXICOLOGY TESTING
Acute toxicity tests
in which a single dose is used in each
animal on one occasion only for the
determination of gross behavior and
LD50 or median lethal dose
Chronic tests
In which two species, one rodent
and one non rodent are dosed
daily for six months
Sub acute tests
In which animals (usually rats) are dosed
daily, starting at around expected
therapeutic level and increasing stepwise
every two to three days until toxic signs
are observed
TOXICOLOGY
DIFFERENT AREAS OF TOXICOLOGY
• Mechanistic toxicology
•Identifies the cellular, biochemical, and molecular mechanisms by
which chemicals exert toxic effects on living organisms
•Organophosphate pesticides inhibit AChE
• Descriptive toxicology
•Concerned directly with toxicity testing, which provides
information for safety evaluation and regulatory requirements
•Acute oral toxicity test, LD50 levels
• Regulatory toxicology
•Has the responsibility for deciding, on the basis of data provided
by descriptive and mechanistic toxicologists, whether a drug or
another chemical poses a sufficiently low risk to be marketed for a
stated purpose
•Warnings, cautions,…etc
ROUTE AND SITE OF EXPOSURE
 The major routes (pathways) by which toxic agents
gain access to the body are:
 Gastrointestinal tract (ingestion)
 Lungs (inhalation)
 Skin (topical, percutaneous, or dermal)
 Other parenteral (other than intestinal canal) routes
 Toxic agents generally produce the greatest effect
and the most rapid response when they are
introduced directly into the bloodstream (the
intravenous route)
ROUTE OF ADMINISTRATION
DURATION AND FREQUENCY OF
EXPOSURE
 Toxicologists usually divide the exposure of
experimental animals to chemicals into four categories:
 Acute exposure is defined as exposure to a chemical for
less than 24 h
 Subacute exposure refers to repeated exposure to a
chemical for 1 month or less
 Subchronic for 1 to 3 months
 Chronic for more than 3 months
SPECTRUM OF UNDESIRED EFFECTS
 Allergic Reactions
 Chemical allergy is an immunologically mediated adverse
reaction to a chemical resulting from previous sensitization to
that chemical or to a structurally similar ones
 Most chemicals and their metabolic products are not
sufficiently large to be recognized by the immune system as
foreign substances and thus must first combine with an
endogenous protein to form an antigen (or immunogen). This
kind of molecule is called a hapten. The hapten-protein complex
(antigen) is then capable of eliciting the formation of antibodies
 Chemical idiosyncrasy
 Genetically determined abnormal reactivity to a chemical
 The response observed is usually qualitatively similar to that
observed in all individuals but may take the form of extreme
sensitivity to low doses or extreme insensitivity to high doses of
the chemical
IMMEDIATE VERSUS DELAYED TOXICITY
 Immediate toxic effects occur or develop rapidly
after a single administration of a substance, whereas
delayed toxic effects occur after the lapse of some
period of time
 Carcinogenic effects of chemicals usually have long latency
periods, often 20 to 30 years after the initial exposure,
before tumors are observed in humans
REVERSIBLE VERSUS IRREVERSIBLE TOXIC EFFECTS
 If a chemical produces pathological injury to a tissue,
the ability of that tissue to regenerate largely
determines whether the effect is reversible or
irreversible
 Irreversible: cancer, necrosis
 Reversible: Neostigmine reversible inhibitor of cholinesterase
LOCAL VERSUS SYSTEMIC TOXICITY
 Local effects
 Occur at the site of first contact between the biological
system and the toxicant
 Target organs: hepatotoxicity
 Systemic effects
 Require absorption and distribution of a toxicant from its
entry point to a distant site at which deleterious effects
are produced
 CNS depression; multiple organic toxicities
INTERACTION OF CHEMICALS
 Additive effect
 When the combined effect of two chemicals is equal to the sum of
the effects of each agent given alone (example: 2 + 3 = 5)
 Synergistic effect
 When the combined effects of two chemicals are much greater
than the sum of the effects of each agent given alone (example:
2 + 2 = 20).
 Both carbon tetrachloride and ethanol are hepatotoxics, but
together they produce much more liver injury than the
mathematical sum of their individual effects at a given dose
 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 (example: 0 + 2 = 10)
 Isopropanol is not hepatotoxic, but when it is administered with
carbon tetrachloride, the hepatotoxicity of carbon tetrachloride is
much greater than is the case when it is given alone
ANTAGONISM
 Functional antagonism
 When two chemicals counterbalance each other by producing opposite
effects on the same physiologic function
 Severe barbiturate intoxication Vs norepinephrine
 Chemical antagonism or inactivation
 Chemical reaction between two compounds that produces a less toxic
product
 Chelators of metal ions decrease metal toxicity
 Dispositional antagonism
 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 altered
 The prevention of absorption of a toxicant by ipecac or charcoal, increased
activity of metabolizing enzymes with enzyme inducers, and the increased
excretion of a chemical caused by diuretics
 Receptor antagonism
 When two chemicals that bind to the same receptor produce less effect
when given together than the addition of their separate effects (example: 4
+ 6 = 8) or when one chemical antagonizes the effect of the second chemical
(example: 0 + 4 = 1)
 Often are termed blockers, beta blockers
TOLERANCE
 Tolerance is a state of decreased responsiveness to a
toxic effect of a chemical resulting from prior
exposure to that chemical or to a structurally related
chemical
 Two major mechanisms are responsible for tolerance:
 One is due to a decreased amount of toxicant
reaching the site where the toxic effect is produced
(dispositional tolerance)
 The other is due to reduced responsiveness of a tissue
to the chemical
DOSE RESPONSE
 The characteristics of exposure and the spectrum of
effects come together in a correlative relationship
customarily referred to as the dose -response
relationship
 Two types
 Individual to varying doses of a chemical, Response of an
individual organism to varying doses of a chemical (e.g.
enzyme activity, blood pressure)
 Population of individuals
DOSE-RESPONSE RELATIONSHIP
DOSE-RESPONSE RELATIONSHIP
WHAT CAN BE LEARNED FROM A DOSERESPONSE CURVE?
 LD50 – Median Lethal
Dose, quantity of the
chemical that is estimated
to be fatal to 50% of the
organisms
 LD50 values are the standard
for comparison of acute
toxicity between chemical
compounds and between
species
 TD50 – Median Toxic Dose
 ED50 – Median Effective
Dose
 LC50 – Median Lethal
Concentration
WHAT CAN BE LEARNED FROM A DOSERESPONSE CURVE?
 NOAEL Value – No Observed Adverse Effect Level, The
highest dose of a chemical that, in a given toxicity test,
causes no observable effect in test animals
 The NOAEL for the most sensitive test species and the most
sensitive indicator of toxicity is usually employed for regulatory
purposes
 LOAEL Value – Lowest Observed Adverse Effect Level, The
lowest dose of a chemical that, in a given toxicity test,
does cause an observable effect in test animals
WHAT CAN BE LEARNED FROM A DOSERESPONSE CURVE?
 Therapeutic Index = LD50 / ED50
 Margin of Safety = LD1 / ED99
WHAT CAN BE LEARNED FROM A DOSERESPONSE CURVE?
TOXICITY RATING FOR HUMANS (70 KG BODY
WEIGHT)
Rating/Class
Practically nontoxic
Slightly toxic
Moderately toxic
Very toxic
Extremely toxic
Super toxic
Dose
>15 g/kg
5 –15 g/kg
0.5 –5 g/kg
50 –500 mg/kg
5–50 mg/kg
<5 mg/kg
VARIATION IN TOXIC RESPONSES
 Selectively toxicity
 A chemical produces injury to one kind of living without
harming another of life
 Pesticides for agriculture are less toxic to the plant but
harmful to fungi
 Species differences toxicity and Individual difference
in response