Toxicology

• Toxicology


  The study of the adverse effects of chemical or physical agents on living organisms
• Areas toxicology is concerned with

  • Mechanisms of action and exposure to chemicals as a cause of acute and chronic illness
  • Identification and quantification of hazards resulting from occupational exposure to chemicals and the public health aspects of chemicals in air, water, other parts of the environment, food, and drugs
  • Development of standards and regulations to protect human health and the environment from the adverse effects of chemicals
• Risk assessment

  The quantitative estimate of the potential effects on human health and environmental significance of various types of chemical exposures
• Risk assessment examples


  • Pesticide residues on food
  • Contaminants in drinking water
• Mechanistic toxicology


  Concerned with identifying and understanding the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms
• Toxic potential of


  • Organophosphate insecticides (Mechanism: inhibition of acetylcholinesterase)
  • Cause muscle weakness, fatigue, muscle cramps, paralysis
• Mechanistic studies have demonstrated that bladder cancer is induced only when saccharin is at such a high concentration in the urine that it forms a crystalline precipitate
• Descriptive toxicology

  Concerned directly with toxicity testing, which provides information for safety evaluation and regulatory requirements
• Regulatory toxicology

  A regulatory toxicologist is responsible for deciding, on the basis of data provided by descriptive and mechanistic toxicologists, whether a drug or other chemical poses a sufficiently low risk for human or environmental exposure
• There is a wide spectrum of doses among chemicals that is needed to produce deleterious effects, serious injury, or death
• LD50

  The dosage of chemicals needed to produce death in 50% of treated animals
• Measures of acute lethality such as LD50 may not accurately reflect the full spectrum of toxicity, or hazard, associated with exposure to a chemical
• Some chemicals with low acute toxicity may have carcinogenic, teratogenic, or neurobehavioral effects at doses that produce no evidence of acute toxicity
• Paracelsus: '"All substances are poisons; there is none which is not a poison. The right dose differentiates poison from a remedy"'
• Ways toxic agents are classified

  • Target organs (liver, kidney, blood, etc.)
  • Use (pesticide, solvent, food additive, etc.)
  • Source (animal, plant toxins)
  • Effects (cancer, mutation, liver injury, etc.)
  • Physical state (gas, dust, liquid)
  • Chemical stability or reactivity (explosive, flammable, oxidizer)
  • Poisoning potential (extremely toxic, very toxic, slightly toxic, etc.)
  • General chemical structure (Polycyclic Aromatic Hydrocarbons)
  • Biochemical mechanisms of action (e.g. cholinesterase inhibitor, methemoglobin producer)
  • General classification (irritants and corrosives)
• No single classification is applicable to the entire spectrum of toxic agents
• Combinations of classification systems provide the best rating system for a special purpose
• Immediate toxic effects

  Occur or develop rapidly after a single administration of a substance
• Delayed toxic effects

  Occur after the lapse of some time
• Most substances produce immediate toxic effects but do not produce delayed effects
• Carcinogenic effects of chemicals usually have a long latency period; often 20 to 30 years after the initial exposure before tumors are observed in humans
• Reversible toxic effects

  Some toxic effects of chemicals are reversible
• Irreversible toxic effects

  Some toxic effects of chemicals are irreversible
• If a chemical produces pathological injury to a tissue, the ability of that tissue to regenerate determines whether the effect is reversible or irreversible
• Injury to the CNS is largely irreversible because differentiated cells of the CNS cannot divide and be replaced
• Carcinogenic and teratogenic effects of chemicals, once they occur, are usually considered irreversible toxic effects
• Most frequent target organs of systemic toxicity

  • CNS
  • Circulatory system
  • Visceral organs such as the liver, kidney, and lung
  • Skin
  • Muscle
  • Bone
• Hormesis

  The effects of hormesis results in a "U-shaped" dose–response curve, when plotting dose versus response over a wide range of doses
• NOEL


  No observable adverse effect level
• Threshold

  A dose below which no response occurs
• LOAEL

  Lowest observed adverse effect level
• Physiologic functions that can indicate toxicity when deviated from the norm

  • Heart rate
  • Blood pressure
  • Electrical activity of heart muscle, nerve, and brain
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to detect liver damage
• Studies on lethality as an end point are not enough to establish toxicity studies
• Selective toxicity

  Occurs because the toxic substance is accumulated mainly by certain cells or the substance reacts fairly specifically with a certain target
• Selective toxicity in


  • Agriculture (pesticides)
  • Pharmacology (Antibiotics)
• Reproductive toxicology


  The study of the occurrence of adverse effects on the male or female reproductive system that may result from exposure to chemical or physical agents
• Teratology


  The study of defects induced during development between conception and birth
• Teratogens are most effective when administered during the first trimester, the period of organogenesis
• Mechanisms of Toxicity


  • Delivery from the site of exposure to the target
  • Reaction of the ultimate toxicant with the target molecule
  • Cellular dysfunction and resultant toxicities
  • Inappropriate repair and adaptation
• Tetrodotoxin (Puffer fish poison)


  1. After ingestion, this poison reaches the voltage-gated Na+ channels of motor neurons (Step 1)

  2. Interaction with the channel (Step 2a) results in blockade of Na+ channels, inhibition of the activity of motor neurons (Step 3) and ultimately skeletal muscle paralysis