Principles of toxicology

Indri Garnasih
from:
Chapter 2: David L. Eaton and Curtis D. Klaassen

in Cassaret & Doul’s
TOXICOLOGY
The Basic Science of Poisons
Curtis D. Klaassen
International Edition

INTRODUCTION TO TOXICOLOGY
 Different Area of Toxicology

 Spectrum of Toxic Dose

Different Area of Toxicologist  Activities of toxicologists:  Mechanistic  Descriptive  Regulatory .

biochemical and molecular mechanisms by which chemical exert toxic effects on living organisms  also useful in the design and production of safer alternative chemicals and in rational therapy for chemical poisoning and treatment of disease .Mechanistic toxicologists  Is concerned with identifying and understanding the cellular.

fish and balance to the ecosystem . provide information for safety evaluation and regulatory requirements • Toxicity tests in experimental animals are designed to yield information that can be used to evaluate risks posed to human and environmental = drugs and food additives • In the chemical industry.Descriptive toxicologist • is concerned directly with toxicity testing. not only potential to human. but potential to birds.

rodenticide. safe drinking water. on the basis of data provided by descriptive and mechanistic toxicologists  Example:  FDA (Food and Drug Administration) : allowing drugs. and food additives to be sold in the market  Environmental Protection Agency: for regulating most other chemicals: insecticide. cosmetics. etc .Regulatory Toxicologists  Has the responsibility for deciding.

) causing death in 50% of exposed animals . seriously injuring function or producing death  Among chemicals there is a wide spectrum of doses needed to produce deletirious effects. serious injury or death  LD50 is the dosage (mg/kg b.w.Spectrum of Toxic Dose  Poison as any agent capable of producing a deletirious response in a biological system.

w.001 0.2 0.000 4.000 1.5 0.10 0.500 900 150 5 2 1 0. 10.00001 .Approximate Acute LD50 of Some Representative Chemical Agents Agent Ethyl alcohol Sodium chloride Ferrous sulfate Morphine sulphate Phenobarbital sodium Picrotoxin Strychnine sulfate Nicotine d – Tubocurarine Hemicholinium-3 Tetrodotoxin Dioxin (TCDD) Botulinum toxin LD50 mg/kg b.

liver injury  Toxin: generally refers to toxic substances that are produced by biological systems such as plants. mutation. fungi or bacteria  Toxicant: used in speaking of toxic substances that are produced by or are a by product of anthropogenic (humanade activities) . kidney. hematopoietic system  Use: pesticide. depending on the interest and needs of the classifier  Example:  toxic agents are discussed in terms of their target organs: liver.CLASSIFICATION OF TOXIC AGENTS  Toxic agents are classified in a variety of ways. food additive  Source: animal and plant toxins  Effects: cancer. animals. solvent.

CHARACTERISTIC OF EXPOSURE  Route and Site of Exposure:  the route of administration can influence of toxicity of agents  Major route of exposure:  Ingestion: GI tract/ oral  Inhalation: lungs  Skin : dermal. percutaneous  Bloodstream: intravenous . topical.

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Ingestion Inhalation Intavenous Intraperitoneal Subcutaneous Intramuscular Lung Gastrointestinal Tract Dermal Portal blood Liver Extracellular fluid Bile Organs Kidney Feces Blood and Lymph Lung Bladder Alveoli Urine Expired air Secretory structures Soft tissues Secretion Bones Fat .

 Duration and Frequency of Exposure:  The exposure of experimental animals to chemical into four categories:  Acute : 24 h  Repeated exposure: Subacute: 1 month/ less than  Subchronic: 1 – 3 months  Chronic : more than 3 months  .

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INTERACTION OF CHEMICALS  The effects of two chemicals given simultaneously produce a response that may simply be additive of their individual or may greater or less than that expected by addition of their individual response:  Additive: 2 + 3 = 5. ex: organo phospate insecticide  Synergistic: 2 + 2 = 20. the hepatotoxicity of carbon tetra chloride is much greater  Antagonism = 2 + 4 = 3 or 4 + 0 = 1     Functional Chemical Dispositional Receptor . ex: carbon tetrachloride and ethanol (both hepatotoxic)  Potentiation: 0 + 2 = 10. isopropanol (nonhepatotoxic) and carbon tetrachloride (hepatotoxic).

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 mechanism are responsible for tolerance:  Is due to a decreased amount of toxicant reaching the site where the toxic effect is produced  Is due to a reduced responsiveness of a tissue to the chemical .

DOSE RESPONSE .

an individual in the population is classified as either a “responder” or a “nonresponder” .DOSE RESPONSE  Dose response relationship  The individual dose response relationship:  Response of an individual organism to varying doses of a chemical  A quantal dose response relationship  Distribution of response to different doses in a population of individual organism  all or none: at any given dose.

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 Susceptibility to chemicals among individuals = biological variation  Left: hypersusceptibility  Right: resistant Plot the top two panels .

ex: for anesthesia  Toxic dose: ex: effect such as liver injury  Lethal dose  TI (therapeutic index): ratio of the dose required to produce a toxic effect and the dose needed to elicit the desired therapeutic response  Ratio of doses of two different materials to produce an identical response  Ratio of doses of the same material necessary to yield different toxic effects .Evaluating the Dose Response  Effective dose.

VARIATION IN TOXIC RESPONSE  Selectivity Toxicity: That e chemical produces injury to one kind of living matter without harming another form of life even though the two may exist in intimate contact .

are applicable to human” it is important to recognize that both quantitative and qualitative differences in response to toxic substances may occur among different species ex: LD50 for highly toxic dioxin differs by more than 1000 fold between guinea pigs and hamster . when properly qualified. Species Differences basic tenet of toxicology: “experimental results in animals.

large interindividual differences in response to a chemical can occur because of subtle genetic differences . Individual Differences in Response even within a species.