Upload
others
View
2
Download
2
Embed Size (px)
Citation preview
Laboratory of toxicology
Department of Pharmacology and Toxicology
College of Pharmacy, University of Baghdad
2015
GENERAL PRINCIPLES OF TOXICOLOGY
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
TOXICOLOGY - PRACTICAL SYLLABUS 2015
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
SCIENCE OF TOXICOLOGY
Chronic tests In which two species, one rodent
and one non rodent are dosed daily for six months
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
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
• 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
DIFFERENT AREAS OF TOXICOLOGY
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 AND SITE OF EXPOSURE
ROUTE OF ADMINISTRATION
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
DURATION AND FREQUENCY OF EXPOSURE
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
SPECTRUM OF UNDESIRED EFFECTS
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
IMMEDIATE VERSUS DELAYED TOXICITY
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
REVERSIBLE VERSUS IRREVERSIBLE TOXIC EFFECTS
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
LOCAL VERSUS SYSTEMIC TOXICITY
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
INTERACTION OF CHEMICALS
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
ANTAGONISM
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
TOLERANCE
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
DOSE-RESPONSE RELATIONSHIP
DOSE-RESPONSE RELATIONSHIP
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 DOSE-RESPONSE 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 DOSE-RESPONSE CURVE?
Therapeutic Index = LD50 / ED50
Margin of Safety = LD1 / ED99
WHAT CAN BE LEARNED FROM A DOSE-RESPONSE CURVE?
WHAT CAN BE LEARNED FROM A DOSE-RESPONSE CURVE?
Rating/Class Dose
Practically nontoxic >15 g/kg Slightly toxic 5–15 g/kg
Moderately toxic 0.5–5 g/kg
Very toxic 50–500 mg/kg
Extremely toxic 5–50 mg/kg Super toxic <5 mg/kg
TOXICITY RATING FOR HUMANS (70 KG BODY WEIGHT)
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
VARIATION IN TOXIC RESPONSES